c-peptide and Hypoglycemia

Although insulin is an essential medicine and a life-saving drug, it has also been incriminated in many poisoning deaths; accidental, suicidal and some with malicious intent. Overdosing with insulin precipitates a life-threatening state of hypoglycemia and if untreated leads to coma, irreversible brain damage and death. Normally, the pancreatic β-cells secrete equimolar amounts of insulin and C-peptide into the portal venous blood, although under physiological conditions the plasma concentration ratio (insulin/C-peptide) is less than unity, because insulin is more susceptible to hepatic first-pass metabolism. A high ratio of insulin/C-peptide in plasma from a poisoned patient is compelling evidence that pharmaceutical insulin was administered, which does not contain C-peptide. The analysis of insulin and C-peptide was traditionally done by immunoassay methods (RIA and/or ELISA), although high resolution LC-MS/MS is more suitable for forensic purposes and permits the identification of insulin analogues. Use of insulin as a murder weapon is exemplified by the case of Colin Norris, a male nurse found guilty of murdering four elderly patients and the attempted murder of a fifth by injecting them with insulin. However, the prosecution evidence against Norris was mainly circumstantial and hearsay. Toxicological evidence against Norris consisted of a high insulin/C-peptide concentration ratio in plasma from one of the victims. This analysis was done by an immunoassay method at a clinical laboratory and not a forensic laboratory. Analytical procedures, including chain-of-custody routines, are more stringent at forensic laboratories. Since his conviction, some of the medical evidence against Norris has been called into question, especially the prevalence of spontaneous attacks of hypoglycemia in elderly and frail patients with co-morbidities.

Topics: Aged; C-Peptide; Chromatography, Liquid; Homicide; Humans; Hypoglycemia; Insulin; Male; Tandem Mass Spectrometry

Bariatric surgery is the most effective treatment in individuals with obesity to achieve remission of type 2 diabetes. Post-bariatric surgery hypoglycaemia occurs frequently, and management remains suboptimal, because of a poor understanding of the underlying pathophysiology. The glucoregulatory hormone responses to nutrients in individuals with and without post-bariatric surgery hypoglycaemia have not been systematically examined.. The study protocol was prospectively registered with PROSPERO. PubMed, EMBASE, Web of Science and the Cochrane databases were searched for publications between January 1990 and November 2021 using MeSH terms related to post-bariatric surgery hypoglycaemia. Studies were included if they evaluated individuals with post-bariatric surgery hypoglycaemia and included measurements of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide and/or glucagon concentrations following an ingested nutrient load. Glycated haemoglobin (HbA. From 377 identified publications, 12 were included in the analysis. In all 12 studies, the type of bariatric surgery was Roux-en-Y gastric bypass (RYGB). Comparing individuals with and without post-bariatric surgery hypoglycaemia following an ingested nutrient load, the standardised mean difference in peak GLP-1 was 0.57 (95% CI, 0.32, 0.82), peak GIP 0.05 (-0.26, 0.36), peak insulin 0.84 (0.44, 1.23), peak C-peptide 0.69 (0.28, 1.1) and peak glucagon 0.05 (-0.26, 0.36). HbA. Following RYGB, postprandial peak plasma GLP-1, insulin and C-peptide concentrations are greater in individuals with post-bariatric surgery hypoglycaemia, while HbA

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin

A case of hypoglycemic coma caused by a giant borderline phyllodes tumor of the breast has been described. The patient, a 63-year-old woman, was admitted with recurrent unconsciousness. She had a giant breast tumor with decreased blood glucose, insulin, and C-peptide. The patient's hypoglycemia resolved rapidly after resection of the breast tumor. Pathological examination indicated a borderline phyllodes tumor of the breast, and immunohistochemistry suggested high expression of insulin-like growth factor-2 (IGF-2) in the tumor tissue. A literature review is also included to summarize the clinical characteristics of such patients and to serve as a unique resource for clinical diagnosis and treatment of similar cases.

Topics: Breast Neoplasms; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Middle Aged; Phyllodes Tumor

Diabetes mellitus as a chronic metabolic disease is threatening human health seriously. Although numerous clinical trials have been registered for the treatment of diabetes with stem cells, no articles have been published to summarize the efficacy and safety of mesenchymal stem cells (MSCs) in randomized controlled trials (RCTs).. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to provide a reliable numerical summary and the most comprehensive assessment of therapeutic efficacy and safety with MSCs in diabetes. PubMed, Web of Science, Ovid, the Cochrane Library and CNKI were searched. The retrieval time was from establishment of these databases to January 4, 2020. Seven RCTs were eligible for analysis, including 413 participants. Meta-analysis results showed that there were no significant differences in the reduction of fasting plasma glucose (FPG) compared to the baseline [mean difference (MD) = -1.05, 95% confidence interval (CI) (-2.26,0.16), P<0.01, I2 = 94%] and the control group [MD = -0.62, 95%CI (-1.46,0.23), P<0.01, I2 = 87%]. The MSCs treatment group showed a significant decrease in hemoglobin (Hb) A1c [random-effects, MD = -1.32, 95%CI (-2.06, -0.57), P<0.01, I2 = 90%] after treatment. Additionally, HbA1c reduced more significantly in MSC treatment group than in control group [random-effects, MD = -0.87, 95%CI (-1.53, -0.22), P<0.01, I2 = 82%] at the end of follow-up. However, as for fasting C-peptide levels, the estimated pooled MD showed that there was no significant increase [MD = -0.07, 95%CI (-0.30, 0.16), P<0.01, I2 = 94%] in MSCs treatment group compared with that in control group. Notably, there was no significant difference in the incidence of adverse events between MSCs treatment group and control group [relative risk (RR) = 0.98, 95%CI (0.72, 1.32), P = 0.02, I2 = 70%]. The most commonly observed adverse reaction in the MSC treatment group was hypoglycemia (29.95%).. This meta-analysis revealed MSCs therapy may be an effective and safe intervention in subjects with diabetes. However, due to the limited studies, a number of high-quality as well as large-scale RCTs should be performed to confirm these conclusions.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemia; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Randomized Controlled Trials as Topic; Treatment Outcome

Awareness about Insulin Autoimmune Hypoglycaemia (IAH) and its management remains limited.. We describe two cohorts: Cohort 1 (n = 7) included patients with IAH from a tertiary care centre in India and Cohort 2 (n = 294) included systematic review of published English literature from PubMed. They were compared with our insulinoma patients (n = 41).. Cohort 1 included seven female patients where two had drugs (carbimazole and thiocolchicoside) as triggering factors. Except for one patient requiring oral prednisolone, others had spontaneous remission. The unique features from our series are being first case series of IAH from India and reporting of second case of thiocolchicoside triggered IAH. Cohort 2 had 294 patients identified from 149 publications. Mean age was 54 ± 19 years. Thirty-five different triggers were identified from 160 cases. Antithyroid drugs were most common triggers in Japanese patients and most common HLA allele was DRB1*0406, while it was alpha-lipoic acid and HLA DRB1*0403 in non-Asians. Serum Insulin >100 µIU/mL and insulin to C-peptide molar ratio (ICMR) >0.25 had specificity of 100% and 97.5%, respectively, for IAH as compared to insulinoma. 56% patients had remission with complex carbohydrate diet and trigger removal while 43% required immunosuppressants. 70% achieved remission within 6 months.. Middle age remains most common age group. Sulfhydryl drugs are most common triggers. Serum Insulin >100 µIU/mL and ICMR > 0.25 in critical sample are good predictors for diagnosis of IAH, which needs to be confirmed by IAA. Conservative management with dietary modification and trigger removal usually suffices in majority. Rests need immunosuppressants.

Topics: C-Peptide; Cohort Studies; Female; Humans; Hypoglycemia; India; Infant, Newborn; Insulin; Middle Aged

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Autoantibodies; Autoimmune Diseases; C-Peptide; Dexamethasone; Diazoxide; Diet, Diabetic; Female; Glucose; Glucose Intolerance; Humans; Hyperinsulinism; Hypoglycemia; Immunosuppressive Agents; Insulin; Liver Neoplasms; Polyethylene Glycols; Proinsulin; Sigmoid Neoplasms

β-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplantation Association held a workshop to develop consensus for an International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplant Association Statement on the definition of function and failure of current and future forms of β-cell replacement therapy. There was consensus that β-cell replacement therapy could be considered as a treatment for β-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA1c) and the occurrence of severe hypoglycemia. Optimal β-cell graft function is defined by near-normal glycemic control (HbA1c ≤6.5% [48 mmol/mol]) without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Good β-cell graft function requires HbA1c less than 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production. Marginal β-cell graft function is defined by failure to achieve HbA1c less than 7.0% (53 mmol/mol), the occurrence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed β-cell graft is defined by the absence of any evidence for clinically significant C-peptide production. Optimal and good function are considered successful clinical outcomes.

Topics: Biomarkers; Blood Glucose; C-Peptide; Consensus; Diabetes Mellitus; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Risk Factors; Treatment Outcome

Insulinoma is an exceedingly uncommon pancreatic islet cell neuroendocrine tumor. Its estimated incidence is approximately four cases per million individuals per year.. We report the case of sporadic insulinoma in an exceptionally very young 10-year-old boy who presented with a 1-month history of episodic tremulousness, diaphoresis, increased hunger, confusion and fainting. Initial laboratory investigations showed low blood glucose (64 mg/dL) and high blood insulin (6 μU/mL) levels. Patient was admitted in view of frequent hypoglycemic symptoms and possible pancreatic insulinoma. A 48-hour mentored fasting test was done and ceased within 3 hours due to occurrence of hypoglycemic symptoms. During the episode, blood was drawn and results showed low blood glucose level and high insulin, pro-insulin and C-peptide levels. The hypoglycemic symptoms were relieved greatly by glucose administration and Whipple's triad for insulinoma was met. An abdominal contrast-enhanced computed tomography scan showed a 10 x 12 x 17 mm, small, well-demarcated, heterogeneously enhancing lesion within the body of pancreas without dilatation of pancreatic duct. No evidence of lymphadenopathy or distant metastasis was identified. Patient underwent enucleation of pancreatic tumor. Histopathological and immunohistochemical examination of the pancreatic mass confirmed neuroendocrine tumor (insulinoma). Patient had an uneventful recovery. A post-operative 6-month follow-up showed resolution of hypoglycemic symptoms, normalized blood glucose, insulin, pro-insulin and C-peptide levels, and no evidence of recurrence.. Although rare, sporadic insulinoma should be considered in the differential diagnosis of any young individual presenting with frequent hypoglycemic symptoms (neuroglycopenic and/or autonomic nervous system symptoms). Furthermore, a literature review on insulinoma is presented.

Topics: Blood Glucose; C-Peptide; Child; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Pancreatectomy; Pancreatic Neoplasms; Recurrence; Tomography, X-Ray Computed

The association of paraneoplastic hypoglycemia [Doege-Potter syndrome] and finger clubbing [Pierre-Marie-Bamberg syndrome] with pleural solitary fibrous tumour is rare. We present a previously unpublished but typical example of this rare occurrence together with a detailed updated literature review of previously published cases of pleural SFT discussing the histopathology of SFT; pathophysiology of the hypoglycemia and finger clubbing; treatment and outcome of pleural SFT. The patient, a 57-year-old African male was admitted at our hospital with recurrent episodes of hypoglycemia. He was found to have digital clubbing and decreased breath sounds in the right lower chest but no other significant clinical findings. His insulin level measured during an episode of hypoglycemia was undetectable. Chest radiograph and CT-scan revealed a lobulated mass in the right chest which was diagnosed to be SFT on histology. Surgical excision of the mass resulted in cure of the hypoglycemic episodes and rapid regression of the clubbing. Less than 65 cases of pleural SFT manifesting with hypoglycemia with or without finger-clubbing have been published in the English literature. The mean diameter of these tumours manifesting with hypoglycemia is 20 cm, 54% being benign while 42% were malignant. They predominantly present in the 6th-8th decade, average age of 64 years and a slight male preponderance at 58%. Complete surgical resection remains the most important predictor of clinical outcome in terms of recurrence and metastases, while providing instant cure for the hypoglycemia and rapid resolution of the finger clubbing.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Neoplasm Recurrence, Local; Osteoarthropathy, Secondary Hypertrophic; Paraneoplastic Syndromes; Solitary Fibrous Tumor, Pleural; Treatment Outcome

Murder by insulin-whether attempted, suspected or proven-is rare. Only 66 cases worldwide could be found for this review. A conviction was secured in 31 cases and additional weapon was employed in 11. Differentiation of attempted homicide from Munchausen syndrome by proxy in the young and from 'mercy killing' in the elderly was not attempted. Most perpetrators were close relatives and most victims were alive when discovered and responded to treatment. Hypoglycaemia is the first clue to homicidal insulin use in living subjects and requires the demonstration of a plasma insulin concentration of generally more than 1000 pmol/L and undetectable plasma C-peptide concentration to establish the diagnosis. Serum glucose measurements are valueless in victims found dead. The presence near the body of insulin vials, syringes or needles, loose talk by the suspected perpetrator or their ready access to insulin may be the only clue. The demonstration of insulin in tissue around an injection site by immunohistopathology or by measuring it in an extract clinches the diagnosis. Immunoassays suitable for clinical use to detect and measure insulin and C-peptide are subject to random errors and cannot be relied upon unless special precautions including separation by gel filtration or HPLC are undertaken prior to analysis. They do not detect or measure accurately a new generation of synthetic insulin analogues. Mass spectrometry will be required to do this and to validate clinical immunoassays, upon which convictions have always had to rely in the past.

Topics: C-Peptide; Chromatography, High Pressure Liquid; Euthanasia, Active; Female; Homicide; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoassay; Insulin; Male; Mass Spectrometry; Munchausen Syndrome by Proxy

Type 1 diabetes is a chronic disease characterized by progressive destruction of the pancreatic beta cells, what leads to insulin deficiency and hyperglycemia. However, a significant secretory function may persist for long periods in a few patients, what is clinically evident through the detection of serum C peptide. This phenomenon might reduce the risk of chronic complications, severe hypoglycemias and allow easier metabolic control. It is possible that these advantages are caused, at least partially, by C peptide itself, acting directly in its target tissues.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Glucose; C-Peptide; Child; Child, Preschool; Chronic Disease; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Young Adult

We will describe insulin and C-peptide levels observed in sulfonylurea-induced hypoglycemia and determine whether these levels differed if obtained before or after hypoglycemic therapy.. We performed a systematic review of the English literature to identify Medline articles containing "sets" (glucose <60 mg/dL with insulin and C-peptide levels). These "sets" were categorized as being obtained BEFORE, AFTER, or UNKNOWN with respect to hypoglycemic therapy.. 22 articles, 76 patients, and 97 "sets" were included. Mean glucose (mg/dL), insulin (muIU/mL), and C-peptide (ng/mL) for all "sets' were 28.6 (+/-12.6; 26.1 to 31.2), 54.4 (+/-126.3; 28.3 to 80.5), 7.2 (+/-6.2; 5.9 to 8.5). The BEFORE measures were 24.3 (+/-7.3; 18.7 to 30.0), 36.6 (+/-26.2; 16.5 to 56.7), 5.4 (+/-4.6; 1.5 to 9.2). The AFTER measures were 33.1 (+/-9.8; 28.2 to 38.0), 126.7 (+/-278.1; 0 to 265.0), 10.3 (+/-10.5; 5.1 to 15.4). The UNKNOWN measures were 28.0 (+/-13.5; 24.7 to 31.3), 37.1 (+/-21.8; 31.7 to 42.5), 6.5 (+/-4.3; 5.4 to 7.6). Only one "set" (glucose 49 mg/dL) had insulin <3.9 muIU/mL and C-peptide <1.4 ng/mL.. Insulin > or =3.9 muIU/mL, C-peptide > or =1.4 ng/mL, and glucose <49 mg/dl are consistent with sulfonylurea-induced hypoglycemia. BEFORE levels were lower, but they were consistent with sulfonylurea-induced hypoglycemia.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Infant, Newborn; Insulin; Male; Middle Aged; Sulfonylurea Compounds; Up-Regulation

Topics: Biomarkers; C-Peptide; Chromatography, Gel; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Factitious Disorders; Humans; Hypoglycemia; Immunoassay; Insulin Resistance; Insulin-Secreting Cells; Insulinoma; Kidney Diseases; Pancreatic Function Tests; Pancreatic Neoplasms; Proinsulin; Reference Values; Specimen Handling

The diagnosis of a hypoglycemic disorder requires a high level of suspicion, careful assessment of the patient for the presence of mediating drugs or a predisposing illness, and, where indicated, methodical evaluation on the basis of well-defined diagnostic criteria. The diagnostic burden is heaviest for healthy-appearing persons with episodes of confirmed neuroglycopenia. Our criteria for insulin mediation of hypoglycemia are: plasma insulin >or=18 pmol (ICMA [immunochemiluminometric assay]), C-peptide >or=200pmol/L (ICMA), proinsulin >or=5pmol/L (ICMA), betaOH butyrate,

Topics: Adult; Blood Glucose; C-Peptide; Child; Fasting; Humans; Hyperinsulinism; Hypoglycemia; Proinsulin

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diagnosis, Differential; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Reagent Kits, Diagnostic; Reference Values; Sensitivity and Specificity

Immune intervention seems to offer the prospect of preventing or reversing the hyperglycaemic phase of Type I (insulin-dependent) diabetes mellitus. A number of prevention trials have been undertaken before disease onset but the logistics of such trials are prohibitive. More rapid and less expensive means of testing new therapies are needed and the current emphasis is therefore on intervention after diagnosis to salvage residual beta-cell function. At present, because restoration of normal metabolism seems unattainable, such interventions are tested against their ability to maintain C-peptide production over the first months or years of diabetes.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Humans; Hypoglycemia; Immunotherapy; Islets of Langerhans

Optimal conditions for confirming the presence and accurately diagnosing the type of hypoglycemic disorder occur at the time of a spontaneous spell. Otherwise, dynamic testing to generate conducive conditions should be conducted in any patient with a history of neuroglycopenic symptoms, regardless of relation to meal ingestion. Specific criteria regarding beta-cell polypeptide concentrations are required to establish hyperinsulinemia. Sulfonylureas in plasma should be measured with sensitive assays. In complex cases, the selective arterial calcium test may be a useful dynamic test.

Topics: Antibodies; Blood Glucose; C-Peptide; Diagnosis, Differential; Fasting; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin

Topics: C-Peptide; Diabetes Mellitus; Diagnosis, Differential; Humans; Hypoglycemia

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Humans; Hypoglycemia; Immunoassay; Insulin; Proinsulin; Reagent Kits, Diagnostic

We report a case of severe hypoglycaemia following co-trimoxazole therapy. An 88-year-old woman was admitted with urinary tract infection and treated with co-trimoxazole (960 mg bid). Seven days after initiation of the treatment she became comatose. Blood sugar was 1.3 mmol/l and C-peptide at the upper limit of normal range. Glucose infusion restored normal consciousness and no hypoglycaemia recurred after interruption of co-trimoxazole therapy. Advanced aged was the only risk factor identified. Other risk factors described in previous case reports are renal failure, poor nutritional state and high doses of co-trimoxazole.

Topics: Aged; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hypoglycemia; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

Topics: Algorithms; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin

Topics: Animals; Blood Glucose; C-Peptide; Child; Female; Forensic Medicine; Homicide; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Munchausen Syndrome by Proxy; Reproducibility of Results

After beta-cell stimulation by carbohydrate or other secretagogues, insulin and C-peptide are secreted into the portal vein in a 1:1 molar ratio. A large fraction of endogenous insulin is cleared by the liver, whereas C-peptide, which is cleared primarily by the kidney and has a lower metabolic clearance rate than insulin, traverses the liver with essentially no extraction by hepatocytes. Hence, the molar ratio of insulin to C-peptide in peripheral venous blood (ICPR) should be less than 1.0 during fasting and feeding, unless exogenous insulin is introduced into the systemic circulation. Consequently, an ICPR in excess of 1.0 in a hypoglycemic patient argues persuasively for surreptitious or inadvertent insulin administration and against insulinoma (or sulfonylurea ingestion) as the cause of the hypoglycemia. This conclusion is supported by personal experience and by the literature.

Topics: Adult; Aged; C-Peptide; Diagnosis, Differential; Drug Overdose; Factitious Disorders; Female; Humans; Hypoglycemia; Infant; Insulin; Insulinoma; Male; Middle Aged; Osmolar Concentration; Pancreatic Neoplasms

Topics: C-Peptide; Humans; Hyperglycemia; Hypoglycemia; Insulin

Factitious hypoglycemia (FH) in a diabetic patient represents a difficult diagnostic and costly management problem. An adolescent diabetic with FH is reported. A literature search revealed 10 adolescent and 45 adult diabetic patients with FH. Tests currently available for diagnosis are evaluated. The role of psychiatric therapy in relation to overall management and prognosis is stressed.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Factitious Disorders; Humans; Hypoglycemia; Insulin; Male

Topics: Alcohol Drinking; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Eating; Evaluation Studies as Topic; Humans; Hypoglycemia; Insulin; Insulin Secretion

Topics: C-Peptide; Diagnosis, Differential; Fasting; Glipizide; Humans; Hypoglycemia; Insulin; Male; Medication Errors; Middle Aged

Artifactual hypoglycemia results from either improper collection of blood samples or interfering substances in the blood. Such artifacts should be easily detected and avoided. Factitious hypoglycemia, on the other hand, results from deliberate subterfuge by the patient and may thus elude proper diagnosis for some time. The most common cause of factitious hypoglycemia is surreptitious injection of insulin, and this is best diagnosed by the triad of hypoglycemia, inappropriately high insulin levels, and low C-peptide levels. Persons with diabetes may also intentionally misuse blood glucose strips to create the impression of hypoglycemia.

Topics: Adolescent; Adult; Blood Glucose; Blood Preservation; Blood Specimen Collection; C-Peptide; Diabetes Mellitus; Factitious Disorders; False Positive Reactions; Female; Glycolysis; Humans; Hypoglycemia; Insulin; Middle Aged; Sulfonylurea Compounds

Many other hypoglycemic states can be confused with an insulinoma. This article presents the diagnosis, localization, and therapy of these islet cell tumors. Also presented is a discussion of the role of nesidioblastosis in persistent hyperinsulinemic hypoglycemia in the neonate.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Humans; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin

Proinsulin is the single chain precursor of insulin. It consists of insulin, plus a peptide which connects the A and B chains of insulin. This peptide is termed C-peptide. C-peptide an insulin are secreted in equimolar amounts from pancreatic beta-cells, Hence, circulating C-peptide levels provide a measure of beta-cell secretory activity. C-peptide measurements are preferable to insulin measurements because of lack of hepatic extraction, slower metabolic clearance rate, and lack of cross reactivity with antibodies to insulin. This article reviews the methods for determination of C-peptide levels in body fluids, and discusses the applications of C-peptide measurement. These include the investigation of hypoglycemia and the assessment of insulin secretory function in insulin-treated and non-insulin-dependent diabetics. The contribution of C-peptide measurement to the understanding of the interrelationships between insulin secretory function and age, sex, obesity, blood lipids, and blood glucose concentrations will also be evaluated.

Topics: Amniotic Fluid; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Islets of Langerhans; Kidney; Liver; Male; Obesity; Pregnancy; Proinsulin; Radioimmunoassay; Reference Values

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Retinopathy; Glycated Hemoglobin; Glycosuria; Humans; Hypoglycemia; Insulin; Insulin Infusion Systems; Insulin Secretion; Time Factors

Appropriate use of test strategies requires not only an appreciation of analytic considerations and the ability of the tests to confirm or exclude the hypotheses, but also an understanding of the underlying pathophysiology and clinical features of the problems to be addressed. This discussion covers disease definition, pathophysiology, analytic considerations, and strategies for diagnosis and management.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Insulin; Male; Pregnancy; Proinsulin

Pancreatic beta-cell function is usually assessed by the measurement of plasma insulin concentration in various clinical situations. However, the advent of an assay for the measurement of connecting-peptide (C-peptide) concentration in plasma has provided a further method for the assessment of the secretory capacity of the pancreatic beta cell in clinical disorders, particularly in the investigation of hypoglycaemia. The metabolism and immunoassay methodology of C-peptide are reviewed, and its application in clinical practice is outlined.

Topics: C-Peptide; Drug Stability; Glucagon; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Peptides; Radioimmunoassay

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Glucagon; Humans; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Islets of Langerhans; Kidney Function Tests; Middle Aged; Peptides; Radioimmunoassay

Topics: C-Peptide; Carbohydrate Metabolism; Glucose Tolerance Test; Hepatitis, Viral, Human; Humans; Hypoglycemia; Insulin; Insulin Resistance; Liver Cirrhosis; Liver Diseases

Topics: Adenoma, Islet Cell; Angiography; Antineoplastic Agents; Benzothiadiazines; Blood Glucose; C-Peptide; Catheterization; Diagnosis, Differential; Diazoxide; Epinephrine; Hypoglycemia; Pancreas; Pancreatic Neoplasms; Portal Vein; Proinsulin; Somatostatin; Splenic Vein; Tomography, X-Ray Computed

Topics: Adenoma, Islet Cell; C-Peptide; Humans; Hypoglycemia; Insulin; Pancreatic Neoplasms; Proinsulin

Topics: Adolescent; Adult; Aged; C-Peptide; Child; Diabetes Mellitus; Female; Humans; Hypoglycemia; Insulin Antibodies; Male; Middle Aged; Pedigree; Peptides; Proinsulin

Topics: C-Peptide; Diabetes Mellitus; Humans; Hypoglycemia; Insulin; Radioimmunoassay

Topics: Artificial Organs; Blood Glucose; C-Peptide; Circadian Rhythm; Computers; Diabetes Mellitus, Type 1; Diabetic Coma; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Pancreas; Prostheses and Implants; Somatostatin; Sulfonylurea Compounds

Late preterm steroid administration can induce transient maternal and thus fetal hyperglycemia, which can increase production of fetal insulin and C-peptide. Infants delivered in this setting are subsequently at increased risk for hypoglycemia. Although maternal glycemic control before delivery is a key component of care for parturients with diabetes, this intervention has not been studied in the setting of late preterm steroid administration.. This study aimed to determine the effect of maternal screening for and treatment of hyperglycemia after late preterm steroid administration on fetal C-peptide levels and other metabolic markers.. This was a multicenter, randomized trial (NCT03076775) of nondiabetic parturients with a singleton gestation receiving betamethasone at 34 0/7 weeks to 36 5/7 weeks for anticipated preterm birth. Participants randomized to maternal glycemic control received fasting and 1-hour postprandial or serial intrapartum capillary blood glucose screening with insulin treatment as indicated. Those randomized to expectant management did not receive any glucose screening or treatment. The primary outcome was fetal C-peptide level measured from umbilical cord blood at delivery. Secondary outcomes included other fetal metabolic markers and neonatal hypoglycemia (glucose level <40 mg/dL). Baseline characteristics and outcomes were compared between the groups. We estimated that we would need a sample size of 144 to provide >90% power to show a 1 ng/mL decrease in C-peptide concentration (±1.5 ng/mL) at ⍺=0.05 using a 2-sample t test and 1 interim analysis. After the interim analysis, the trial was stopped for futility.. Of 491 screened parturients, 163 (33%) were deemed eligible and 86 (53%) were randomized to 1 of the treatment groups (June 2017 to February 2021). One person was lost to follow-up because of delivery at another hospital. Baseline characteristics were similar between groups. The median interval from betamethasone administration to delivery was 24 hours (interquartile range, 13-96 hours) and did not differ between groups (P=.82). Most (82%) randomized to maternal glycemic control had hyperglycemia: 80% had at least 1 fasting glucose level >95 mg/dL, 75% had at least one 1-hour postprandial glucose level >140 mg/dL, and 80% had at least 1 intrapartum glucose level >110 mg/dL. In addition, 15% had at least 1 glucose level >180 mg/dL. None had maternal hypoglycemia after insulin treatment. Compared with expectant management, maternal glycemic control did not affect the median fetal C-peptide level (1.02; interquartile range, 0.52-1.85 vs 1.09; interquartile range, 0.61-1.65; P=.97) or other metabolic markers. Maternal glycemic control also did not affect neonatal hypoglycemia (49% vs 51%; P=.83) or other secondary neonatal or maternal outcomes. There was no evidence of effect modification by gestational age or body mass index at randomization, indication for betamethasone, duration from betamethasone to delivery, maternal race or ethnicity, or neonatal sex. In addition, the results were unchanged in a sensitivity analysis using a per-protocol approach.. Maternal hyperglycemia was observed in most nondiabetic parturients after receiving late preterm betamethasone. However, there was no improvement in fetal metabolic status, neonatal hypoglycemia, or other neonatal or maternal outcomes with maternal glycemic control. Therefore, maternal glucose surveillance and treatment does not seem to be beneficial in nondiabetic parturients receiving late preterm steroids.

Topics: Betamethasone; C-Peptide; Female; Glucose; Humans; Hyperglycemia; Hypoglycemia; Infant, Newborn; Parturition; Pregnancy; Premature Birth

The effect of liraglutide in C-peptide-positive (C-pos) type 1 diabetes (T1D) patients during hypoglycemia remains unclear.. To investigate the effect of a 12-week liraglutide treatment on the body glucose fluxes during a hypoglycemic clamp in C-pos T1D patients and its impact on the alpha- and beta-cell responses during hypoglycemia.. This was a randomized, double-blind, crossover study. Each C-pos T1D patient was allocated to the treatment sequence liraglutide/placebo or placebo/liraglutide with daily injections for 12 weeks adjunct to insulin treatment, separated by a 4-week washout period.. Fourteen T1D patients with fasting C-peptide ≥ 0.1 nmol/L.. All patients underwent a hyperinsulinemic-stepwise-hypoglycemic clamp with isotope tracer [plasma glucose (PG) plateaus: 5.5, 3.5, 2.5, and 3.9 mmol/L] after a 3-month liraglutide (1.2 mg) or placebo treatment.. The responses of endogenous glucose production (EGP) and rate of peripheral glucose disposal (Rd) were similar for liraglutide and placebo treatment during the clamp.. The numbers of hypoglycemic events were similar in both groups. At the clamp, mean glucagon levels were significantly lower at PG plateau 5.5 mmol/L in the liraglutide than in the placebo group but showed similar responses to hypoglycemia in both groups. Mean C-peptide levels were significantly higher at PG-plateaus 5.5 and 3.5 mmol/L after liraglutide treatment, but this effect was not reflected in EGP and Rd. Hemoglobin A1c and body weight were lower, and a trend for reduced insulin was seen after liraglutide treatment.. The results indicate that 3 months of liraglutide treatment does not promote or prolong hypoglycemia in C-pos T1D patients.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Glucose; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Treatment Outcome

BACKGROUNDWe investigated residual β cell function in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study participants with an average 35-year duration of type 1 diabetes mellitus (T1DM).METHODSSerum C-peptide was measured during a 4-hour mixed-meal tolerance test. Associations with metabolic outcomes and complications were explored among nonresponders (all C-peptide values after meal <0.003 nmol/L) and 3 categories of responders, classified by peak C-peptide concentration (nmol/L) as high (>0.2), intermediate (>0.03 to ≤0.2), and low (≥ 0.003 to ≤0.03).RESULTSOf the 944 participants, 117 (12.4%) were classified as responders. Residual C-peptide concentrations were associated with higher DCCT baseline concentrations of stimulated C-peptide (P value for trend = 0.0001). Residual C-peptide secretion was not associated with current or mean HbA1c, HLA high-risk haplotypes for T1DM, or the current presence of T1DM autoantibodies. The proportion of subjects with a history of severe hypoglycemia was lower with high (27%) and intermediate (48%) residual C-peptide concentrations than with low (74%) and no (70%) residual C-peptide concentrations (P value for trend = 0.0001). Responders and nonresponders demonstrated similar rates of advanced microvascular complications.CONCLUSIONβ Cell function can persist in long-duration T1DM. With a peak C-peptide concentration of >0.03 nmol/L, we observed clinically meaningful reductions in the prevalence of severe hypoglycemia.TRIAL REGISTRATIONClinicalTrials.gov NCT00360815 and NCT00360893.FUNDINGDivision of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (DP3-DK104438, U01 DK094176, and U01 DK094157).

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Incidence; Insulin-Secreting Cells; Male; Middle Aged

This study aimed to investigate the influence of residual β-cell function on counterregulatory hormonal responses to hypoglycemia during acute physical exercise in people with type 1 diabetes (T1D). A secondary aim was to explore relationships between biomarkers of pancreatic β-cell function and indices of glycemia following acute exercise including the nocturnal period.. This study involved an exploratory, secondary analysis of data from individuals with T1D who partook in a four-peroid, randomized, cross-over trial involving a bout of evening exercise followed by an overnight stay in a clinical laboratory facility. Participants were split into two groups: (i) a stimulated C-peptide level of ≥30 pmol⋅L-1 (low-level secretors [LLS], n = 6) or (ii) <30 pmol⋅L-1 (microsecretors [MS], n = 10). Pancreatic hormones (C-peptide, proinsulin, and glucagon), catecholamines (epinephrine [EPI] and norepinephrine [NE]), and metabolic biomarkers (blood glucose, blood lactate, and β-hydroxybutyrate) were measured at rest, during exercise with and without a hypoglycemic (blood glucose ≤3.9 mmol⋅L-1) episode, and throughout a 13-h postexercise period. Interstitial glucose monitoring was used to assess indices of glycemic variability.. During in-exercise hypoglycemia, LLS presented with greater sympathoadrenal (EPI and NE P ≤ 0.05) and ketone (P < 0.01) concentrations. Glucagon remained similar (P = 0.09). Over exercise, LLS experienced larger drops in C-peptide and proinsulin (both P < 0.01) as well as greater increases in EPI (P < 0.01) and β-hydroxybutyrate (P = 0.03). LLS spent less time in the interstitial-derived hypoglycemic range acutely postexercise and had lower glucose variability throughout the nocturnal period.. Higher residual β-cell function was associated with greater sympathoadrenal and ketonic responses to exercise-induced hypoglycemia as well as improved glycemia leading into and throughout the nocturnal hours. Even a minimal amount of residual β-cell function confers a beneficial effect on glycemic outcomes during and after exercise in people with T1D.

Topics: Adult; Biomarkers; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Exercise; Female; Glucagon; Humans; Hypoglycemia; Insulin-Secreting Cells; Male; Middle Aged; Young Adult

Type 1 diabetes is an autoimmune disease characterized by progressive loss of pancreatic beta cells. Golimumab is a human monoclonal antibody specific for tumor necrosis factor. In this phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to receive subcutaneous golimumab or placebo for 52 weeks. The primary end point was endogenous insulin production, as assessed according to the area under the concentration-time curve for C-peptide level in response to a 4-hour mixed-meal tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end points included insulin use, the glycated hemoglobin level, the number of hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and response profile.. A total of 84 participants underwent randomization - 56 were assigned to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour C-peptide AUC at week 52 differed significantly between the golimumab group and the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per milliliter, P<0.001). A treat-to-target approach led to good glycemic control in both groups, and there was no significant difference between the groups in glycated hemoglobin level. Insulin use was lower with golimumab than with placebo. A partial-remission response (defined as an insulin dose-adjusted glycated hemoglobin level score [calculated as the glycated hemoglobin level plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the golimumab group and in 7% of those in the placebo group (difference, 36 percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did not differ between the trial groups. Hypoglycemic events that were recorded as adverse events at the discretion of investigators were reported in 13 participants (23%) in the golimumab group and in 2 (7%) of those in the placebo group. Antibodies to golimumab were detected in 30 participants who received the drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results for neutralizing antibodies.. Among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. (Funded by Janssen Research and Development; T1GER ClinicalTrials.gov number, NCT02846545.).

Topics: Adolescent; Antibodies, Monoclonal; Area Under Curve; C-Peptide; Child; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Proinsulin; Tumor Necrosis Factor-alpha; Young Adult

Topics: Adenosine Triphosphate; Blood Glucose; Brain; C-Peptide; Energy Metabolism; Hormones; Humans; Hydrogen-Ion Concentration; Hypoglycemia; Insulin; Lactic Acid; Male; Phosphocreatine; Young Adult

Postprandial hypoglycaemia (PPHG) is a complication of Roux-en-Y gastric bypass (RYGB) surgery in normoglycaemic individuals. In type 2 diabetes, RYGB improves glucose metabolism, but whether this improvement is related to the later development of PPHG is not known. We investigated the presence and mechanisms of PPHG in individuals with type 2 diabetes undergoing RYGB.. A total of 35 obese individuals with type 2 diabetes underwent an OGTT before and 24 months after surgery. PPHG was defined as a plasma glucose level of ≤3.3 mmol/l when not taking glucose-lowering agents. Insulin sensitivity was assessed by oral glucose insulin sensitivity index and beta-cell function by mathematical modelling of the plasma glucose, insulin and C-peptide concentrations.. After surgery, PPHG occurred in 11 of 35 individuals who underwent RYGB. Before surgery, BMI was lower, glycaemic control less good and time of glucose peak earlier in the PPHG vs No PPHG group, and the duration of diabetes was shorter with PPHG (all p ≤ 0.05). In addition, insulin sensitivity was greater in the PPHG than No PPHG group (p = 0.03). After surgery, BMI and fasting glucose and insulin levels decreased similarly in the two groups; insulin secretion during the first hour of the OGTT increased more in the PPHG than No PPHG group (p = 0.04). Beta-cell glucose sensitivity increased more in individuals with PPHG than those without (p = 0.002). Over the same time interval, the glucagon-like peptide 1 (GLP-1) response was lower in individuals with PPHG before surgery (p = 0.05), and increased more after surgery. At 2 h after glucose ingestion in the OGTT, postsurgery plasma glucagon level was significantly lower in the PPHG than No PPHG group.. In morbidly obese individuals with type 2 diabetes, spontaneous PPHG may occur after bariatric surgery independently of a remission of diabetes. Before surgery, individuals had a shorter duration and were more insulin sensitive. Two years after surgery, these individuals developed greater beta-cell glucose sensitivity, and showed greater insulin and GLP-1 release early in the OGTT.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucose Tolerance Test; Humans; Hypoglycemia; Male; Obesity, Morbid

Postprandial hypoglycemia is a risk after Roux-en-Y gastric bypass (RYGB).. We speculated that a carbohydrate-reduced, high-protein (CRHP) diet might reduce the risk of hypoglycemia and therefore compared the acute effects of a conventionally recommended (CR) diet and CRHP diet [55/30 energy percent (E%) carbohydrate and 15/30 E% protein, respectively] in RYGB patients.. Ten individuals (2 males, 8 females, mean ± SD age 47 ± 7 y; stable body mass index 31 ± 6 kg/m2; 6 ± 3 y post-RYGB) with recurrent postprandial hypoglycemia documented by plasma glucose (PG) ≤3.4 mmol/L were examined on 2 d with isoenergetic CRHP or CR diets comprising a breakfast and subsequent lunch meal.. Peak PG was significantly reduced on the CRHP diet after breakfast and lunch by 11% and 31% compared with the CR diet. Nadir PG increased significantly on CRHP (by 13% and 9%). Insulin secretion was reduced, and glucagon secretion increased on the CRHP diet after both meals. Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide secretion were lower after lunch but unaltered after breakfast on CRHP; β-cell function and insulin clearance were unchanged.. The CRHP diet lowered glucose excursions and reduced insulin secretion and incretin hormone responses, but enhanced glucagon responses compared with the CR diet. Taken together, the results may explain the decreased glucose variability and lower risk of postprandial hypoglycemia. This study was registered at clinicaltrials.gov as NCT02665715.

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Diet, High-Protein Low-Carbohydrate; Female; Gastric Bypass; Humans; Hypoglycemia; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Postoperative Care

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) causes postprandial insulin release and inhibits bone resorption assessed by carboxy-terminal collagen crosslinks (CTX).. To study if GIP affects bone homeostasis biomarkers independently of insulin release and glycemic level.. Randomized, double-blinded, crossover study with 5 study days.. Ten male C-peptide-negative patients with type 1 diabetes.. On 3 matched days with "low glycemia" (plasma glucose in the interval 3 to 7 mmol/L for 120 minutes), we administered intravenous (IV) GIP (4 pmol × kg-1 × min-1), glucagon-like peptide 1 (1 pmol × kg-1 × min-1), or placebo (saline), and on 2 matched days with "high glycemia" (plasma glucose 12 mmol/L for 90 minutes), we administered either GIP or saline.. CTX, procollagen type 1 N-terminal propeptide (P1NP), and parathyroid hormone (PTH).. During low glycemia: GIP progressively suppressed CTX from baseline by up to 59 ± 18% compared with 24 ± 10% during saline infusion (P < 0.0001). Absolute values of P1NP and PTH did not differ between days. During high glycemia: GIP suppressed CTX from baseline by up to 59 ± 19% compared with 7 ± 9% during saline infusion (P < 0.0001). P1NP did not differ between days. GIP suppressed PTH after 60 minutes compared with saline (P < 0.01), but this difference disappeared after 90 minutes.. Short-term GIP infusions robustly reduce bone resorption independently of endogenous insulin secretion and during both elevated and low plasma glucose, but have no effect on P1NP or PTH after 90 minutes.

Topics: Adult; Biomarkers; Blood Glucose; Bone Resorption; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Follow-Up Studies; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Humans; Hyperglycemia; Hypoglycemia; Male; Postprandial Period; Prognosis

Glucagon-like peptide-1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose-dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta-cell function (as measured by HOMA2-%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide-treated patients from AWARD-1, AWARD-3 and AWARD-6 clinical studies were categorised based on their homeostatic model assessment of beta-cell function (HOMA2-%B) tertiles. Changes in glycaemic measures in response to treatment with once-weekly dulaglutide were evaluated in each HOMA2-%B tertile. Patients with low HOMA2-%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P < .001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB-2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; -1.55% vs. -0.98% [-16.94 vs. -10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; -1.00 vs. -1.18% [-10.93 vs. -12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C-peptide were observed in the low tertile. Similar increases in HOMA2-%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta-cell function.

Topics: Aged; Biomarkers; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 2; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Recombinant Fusion Proteins

Fasting C-peptide levels are used to differentiate type 1 from type 2 diabetes (T2D), thereby determining eligibility for coverage of continuous subcutaneous insulin infusion (CSII) for patients with T2D.. A total of 168 patients (74 female/94 male, aged 55.5 ± 9.7 years) were randomized to CSII, and 163 patients (77 female/86 male, aged 56.4 ± 9.5 years) were randomized to multiple daily injections (MDI) of insulin and grouped by baseline C-peptide level: group A (≤183 pmol/L [≤0.55 ng/mL]); group B (>183 pmol/L [>0.55 ng/mL]). At 6 months, the MDI group crossed over to CSII. Within- and between-group comparisons were recorded at 6 and 12 months in the entire group and separately for those patients aged ≥65 years.. CSII reduced hemoglobin A1c (A1c) equally in groups A ( P = .0006, P = .0022) and B ( P<.0001, P<.0001) at 6 and 12 months, respectively. There was an increase in weight in group A versus group B at 6 months but not 12 months ( P<.03). CSII therapy reduced total daily dose (TDD) of insulin and improved treatment satisfaction similarly in groups A and B. The results for patients aged ≥65 years displayed a similar trend as the entire group.. A1c, TDD of insulin, and treatment satisfaction improved for T2D patients using CSII versus MDI therapy, irrespective of baseline C-peptide level. A subgroup of patients aged ≥65 years displayed a similar trend. These results support abandoning C-peptide as a criterion for reimbursing CSII therapy in patients with diabetes.. A1c = hemoglobin A1c; CMS = Centers for Medicare and Medicaid Services; CSII = continuous subcutaneous insulin infusion; DTSQ = Diabetes Treatment Satisfaction Questionnaire; MDI = multiple daily injections; RCT = randomized controlled trials; T1D = type 1 diabetes; T2D = type 2 diabetes; TDD = total daily dose.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Male; Middle Aged; Patient Satisfaction

Type-1 diabetes mellitus (T1DM) is caused by autoimmune insulitis. There are evidences that pregnancy and n-3 fatty acids exhibit suppressive effect on human inflammatory system.. Ninety pregnant women with T1DM were included in the prospective randomized placebo controlled clinical trial. Forty-seven of them were put on standard diabetic diet enriched with EPA and DHA twice a day (EPA 120 mg and DHA 616 mg; Study group) and 43 pregnant diabetic women were on standard diabetic diet with placebo (Control group). Duration of T1DM in all participants was between 5 to 30 years. Blood samples were analyzed from all pregnant women for fasting C-peptide (FC-peptide), fasting plasma glucose (FPG) and HbA1c in each trimester throughout pregnancy and after delivery. Umbilical vein blood was analyzed for fetal C-peptide level, glucose concentration and insulin resistance.. In the Study group FC-peptide concentration raised from 59.6±103.9 pmol/l in first trimester, to 67.7±101.3 pmol/l in the second trimester and to 95.1±152.7 pmol/l in the third trimester. Comparing the FC-peptide values during first and third trimester a statistically significant increase in third trimester was found (P<0.001). In the Control group FC-peptide concentration ranged from 41.7±91.6 pmol/l in the first trimester to 41.2±70.9 mmol/l in the second trimester while in the third trimester it reached 52.4±95.3 pmol/l. Comparing the FC-peptide values during first and third trimester the statistical difference was not significant.. Combining of LC n-3 PUFAs and pregnancy yields immunological tolerance and stimulates the production of endogenous insulin in women with T1DM.

Topics: Adult; Biomarkers; C-Peptide; Combined Modality Therapy; Diabetes Mellitus, Type 1; Diet, Diabetic; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Fetal Blood; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Maternal Nutritional Physiological Phenomena; Pregnancy; Pregnancy in Diabetics; Young Adult

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Epinephrine; Female; Glucose; Glucose Clamp Technique; Humans; Hydrocortisone; Hypoglycemia; Insulin; Male; Morphine; Norepinephrine; Receptors, Opioid

We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus.. We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint.. At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference -0.92% [95% confidence interval -1.07%, -0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups.. Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.

Topics: Adamantane; Aged; Blood Glucose; C-Peptide; Deoxyglucose; Diabetes Mellitus, Type 2; Dipeptides; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Male; Middle Aged; Placebo Effect; Treatment Outcome

To investigate the effect of initial insulin dosage on blood glucose (BG) dynamics, β-cell protection, and oxidative stress in type 1 diabetes mellitus.. Sixty newly diagnosed type 1 diabetes mellitus patients were randomly assigned to continuous subcutaneous insulin infusions of 0.6 ± 0.2 IU/kg/d (group 1), 1.0 ± 0.2 IU/kg/d (group 2), or 1.4 ± 0.2 IU/kg/d (group 3) for 3 wk. BG was monitored continuously for the first 10 d and the last 2 d of wk 2 and 3. A total of 24-hour urinary 8-iso-PGF2α was assayed on days 8, 9, and 10. The occurrence and duration of the honeymoon period were recorded. Fasting C-peptide and glycosylated hemoglobin (HbA1c) were assayed after 1, 6, and 12 months of insulin treatment.. BG decreased to the target range by the end of wk 3 (group 1), wk 2 (group 2), or wk 1 (group 3). The actual insulin dosage over the 3 wk, frequency of hypoglycemia on wk 1 and 2, and median BG at the end of wk 1 differed significantly, but not 8-iso-PGF2α and the honeymoon period in the three groups. No severe hypoglycemia event was observed in any patient, but there was significant difference in the first occurrence of hypoglycemia.. Differences in initial insulin dosage produced different BG dynamics in wk 1, equivalent BG dynamics on wk 2 and 3, but had no influence on short- and long-term BG control and honeymoon phase. The wide range of initial insulin dosage could be chosen if guided by BG monitoring.

Topics: Biomarkers; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Dinoprost; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Insulin Secretion; Insulin-Secreting Cells; Male; Monitoring, Ambulatory; Oxidative Stress

Gemigliptin is a new dipeptidyl peptidase-IV inhibitor. We investigated the efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes (T2D).. A total of 433 T2D patients with a glycosylated haemoglobin (HbA1c) level of 7.5% to 11.0% and a fasting plasma glucose (FPG) concentration <270 mg/dL were randomly assigned to 3 groups: (1) gemigliptin 50 mg qd + metformin 1000 to 2000 mg qd (titrated individually), (2) gemigliptin 50 mg qd, or (3) metformin 1000 to 2000 mg qd. The primary end-point was the change in HbA1c level after 24 weeks. Secondary end-points were the changes in FPG, insulin, proinsulin and C-peptide levels. The percentages of responders who achieved an HbA1c level <7% (or <6.5%) were compared between treatment groups.. Baseline HbA1c levels were 8.7% in all groups. The mean changes in HbA1c level from baseline to week 24 were -2.06%, -1.24% and -1.47% in the combination, gemigliptin monotherapy and metformin monotherapy groups, respectively. The 95% confidence intervals for between-group differences in HbA1c changes were -1.02 to -0.63 in the combination group vs the gemigliptin group and -0.82 to -0.41 vs the metformin group, which confirmed the superiority of combination therapy. A significantly higher percentage of patients in the combination therapy group reached the target HbA1c level <7% (or <6.5%) compared with the monotherapy groups. No severe side effects were observed.. In T2D patients, the initial combination of gemigliptin and metformin had superior efficacy without safety concerns compared with monotherapy with either drug.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Piperidones; Proinsulin; Pyrimidines; Republic of Korea; Thailand; Treatment Outcome

To investigate the dose-response relationship of subcutaneous (s.c.) glucagon administration on plasma glucose and on counter-regulatory hormone responses during s.c. insulin-induced mild hypoglycaemia in patients with type 1 diabetes treated with insulin pumps.. Eight insulin pump-treated patients completed a blinded, randomized, placebo-controlled study. Hypoglycaemia was induced in the fasting state by an s.c. insulin bolus and, when plasma glucose reached 3.4 mmol/l [95% confidence interval (CI) 3.2-3.5], an s.c. bolus of either 100, 200, 300 µg glucagon or saline was administered. Plasma glucose, counter-regulatory hormones, haemodynamic variables and side effects were measured throughout each study day. Peak plasma glucose level was the primary endpoint.. Plasma glucose level increased significantly by a mean (95% CI) of 2.3 (1.7-3.0), 4.2 (3.5-4.8) and 5.0 (4.3-5.6) mmol/l to 6.1 (4.9-7.4), 7.9 (6.4-9.3) and 8.7 (7.8-9.5) vs 3.6 (3.4-3.9) mmol/l (p < 0.001) after the three different glucagon doses as compared with saline, and the increase was neither correlated with weight nor insulin levels. Area under the plasma glucose curve, peak plasma glucose, time to peak plasma glucose and duration of plasma glucose level above baseline were significantly enhanced with increasing glucagon doses; however, these were not significantly different between 200 and 300 µg glucagon. Free fatty acids and heart rates were significantly lower initially after glucagon than after saline injection. Other haemodynamic variables, counter-regulatory hormones and side effects did not differ between interventions.. An s.c. low-dose glucagon bolus effectively restores plasma glucose after insulin overdosing. Further research is needed to investigate whether low-dose glucagon may be an alternative treatment to oral carbohydrate intake for mild hypoglycaemia in patients with type 1 diabetes.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Female; Glucagon; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin Antagonists; Insulin Aspart; Insulin Infusion Systems; Male; Middle Aged; Severity of Illness Index; Single-Blind Method; Young Adult

Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment.. This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant.. The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients.. Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Immunosuppression Therapy; Islets of Langerhans Transplantation; Male; Middle Aged; North America; Young Adult

In natural history studies, maintenance of higher levels of C-peptide secretion (a measure of endogenous insulin production) correlates with a lower incidence of major hypoglycemic events in patients with type 1 diabetes mellitus (T1D), but it is unclear whether this is also true for drug-induced C-peptide preservation.. We analyzed hypoglycemic events and glycemic control data from the T1DAL (Inducing Remission in New-Onset T1D with Alefacept) study, a trial of alefacept in new-onset T1D, which found significant C-peptide preservation at 1 and 2 years. We performed a post hoc analysis using mixed models of the association between the meal-stimulated 4-hour C-peptide AUC (4-hour AUC) and rates of major hypoglycemia, measures of glycemic control (glycosylated hemoglobin [HbA1c]; mean glucometer readings), and variability (glucometer SDs; highest and lowest readings), and an index of partial remission (insulin dose-adjusted HbA1c[ IDAA1c]).. Data from 49 participants (33 in the alefacept group and 16 in the placebo group) were analyzed at baseline and 12 and 24 months. We found that the 4-hour AUC at baseline and at 1 year was a significant predictor of the number of hypoglycemic events during the ensuing 12-month interval (p = 0.030). There was a strong association between the 4-hour AUC and glucometer SDs (P < 0.001), highest readings (p < 0.001), and lowest readings (p = 0.03), all measures of glycemic variability. There was a strong inverse correlation between the 4-hour AUC and 2 measures of glycemic control: HbA1c and mean glucometer readings (both p < 0.001). There was also a strong inverse correlation between the 4-hour AUC and IDAA1c values (p < 0.001), as well as a strong correlation between IDAA1c values and glucometer SDs (p < 0.001), suggesting that reduced glycemic variability is associated with a trend toward partial remission. None of these analyses found a significant difference between the alefacept and placebo groups.. Measures of glycemic variability and control, including rates of hypoglycemia, are significantly correlated with preservation of C-peptide regardless of whether this is achieved by immune intervention with alefacept or natural variability in patients with new-onset T1D. Thus, preservation of endogenous insulin production by an immunomodulatory drug may confer clinical benefits similar to those seen in patients with higher C-peptide secretion due to slow disease progression.

Topics: Adolescent; Adult; Alefacept; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immune Tolerance; Insulin; Male; Recombinant Fusion Proteins; Young Adult

To examine the efficacy and safety of add-on ipragliflozin in Japanese patients with type 2 diabetes in the early stage of insulin therapy.. Patients treated with insulin (bolus component <30% of total daily dose) with/without a dipeptidyl peptidase-4 (DPP-4) inhibitor were randomized to receive placebo (n = 87) or ipragliflozin (n = 175) for 16 weeks. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline. Secondary endpoints included changes in fasting plasma glucose (FPG) and metabolic hormones. Safety endpoints were also examined.. The changes in HbA1c were 0.27% and -0.79% (2.9 and -8.7 mmol/mol) in the placebo and ipragliflozin groups, respectively (baseline: 8.62% vs 8.67% [70.8 vs 71.2 mmol/mol]), corresponding to an adjusted mean difference of -1.07% (95% confidence interval -1.24, -0.91) or -11.7 mmol/mol (-13.5, -9.9), p < .001. Ipragliflozin reduced FPG and serum C-peptide levels and body weight (all p < .001), and increased serum adiponectin levels (p = .022). There was a statistically significant interaction for use/non-use of a DPP-4 inhibitor × treatment group for the change in HbA1c (p = .042). Hypoglycaemia was the only treatment-related adverse event reported in >5% of patients (14.9% vs 29.1%). Events consistent with urinary tract infection (placebo 1.1% vs ipragliflozin 2.3%) or genital infection (0.0% and 4.0%, respectively) occurred in <5% of patients.. Ipragliflozin was well tolerated and effective in insulin-treated patients, especially when used with a DPP-4 inhibitor.

Topics: Adiponectin; Aged; Asian People; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Male; Middle Aged; Reproductive Tract Infections; Thiophenes; Treatment Outcome; Urinary Tract Infections

Glucose-dependent insulinotropic polypeptide (GIP) is glucagonotropic, and glucagon-like peptide-1 (GLP-1) is glucagonostatic. We studied the effects of GIP and GLP-1 on glucagon responses to insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Ten male subjects with T1DM (C-peptide negative, age [mean ± SEM] 26 ± 1 years, BMI 24 ± 0.5 kg/m(2), HbA1c 7.3 ± 0.2%) were studied in a randomized, double-blinded, crossover study, with 2-h intravenous administration of saline, GIP, or GLP-1. The first hour, plasma glucose was lowered by insulin infusion, and the second hour constituted a "recovery phase." During the recovery phase, GIP infusions elicited larger glucagon responses (164 ± 50 [GIP] vs. 23 ± 25 [GLP-1] vs. 17 ± 46 [saline] min ⋅ pmol/L, P < 0.03) and endogenous glucose production was higher with GIP and lower with GLP-1 compared with saline (P < 0.02). On the GIP days, significantly less exogenous glucose was needed to keep plasma glucose above 2 mmol/L (155 ± 36 [GIP] vs. 232 ± 40 [GLP-1] vs. 212 ± 56 [saline] mg ⋅ kg(-1), P < 0.05). Levels of insulin, cortisol, growth hormone, and noradrenaline, as well as hypoglycemic symptoms and cognitive function, were similar on all days. Our results suggest that during hypoglycemia in patients with T1DM, exogenous GIP increases glucagon responses during the recovery phase after hypoglycemia and reduces the need for glucose administration.

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Synergism; Fatty Acids, Nonesterified; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycerol; Hormones; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Treatment Outcome

In patients with diabetes, intensive glycaemic control reduces microvascular complications. However, severe hypoglycaemia frequently complicates intensive glycaemic control. Blood biomarkers that predict successful intensification of glycaemic control in patients with type 2 diabetes without the development of severe hypoglycaemia would advance patient care. In patients who received intensive treatment for type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesised that insulin deficiency and islet autoantibodies would be associated with severe hypoglycaemia and failure to achieve near-normal glycaemia (HbA1c <6.0% [42 mmol/mol]).. A nested case-control design was used. Cases (n = 326) were defined as participants having severe hypoglycaemia and failure to achieve an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death. Controls (n = 1,075) were those who achieved an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death without severe hypoglycaemia. Each case was matched (for race, age and BMI) by up to four controls. Baseline insulin deficiency (fasting C-peptide ≤0.15 nmol/l) and islet autoantibodies (glutamic acid decarboxylase [GAD], tyrosine phosphatase-related islet antigen 2 [IA2], insulin [IAA] and zinc transporter 8 [ZnT8]) were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used on the full cohort and after removal of patients who died and their respective controls.. Severe hypoglycaemia accompanied by an inability to achieve an HbA1c level of <6.0% (42 mmol/mol) was associated with insulin deficiency (adjusted OR 23.2 [95% CI 9.0, 59.5], p < 0.0001), the presence of IAA autoantibodies or baseline insulin use (adjusted OR 3.8 [95% CI 2.7, 5.3], p < 0.0001), GAD autoantibodies (OR 3.9 [95% CI 2.5, 6.0], p < 0.0001), IA2 autoantibodies (OR 16.7 [95% CI 3.9, 71.6], p = 0.0001) and ZnT8 autoantibodies (adjusted OR 3.9 [95% CI 1.2, 12.4], p = 0.02).. C-peptide and islet autoantibodies may serve as biomarkers to predict the risk of severe hypoglycaemia during intensification of type 2 diabetes treatment.. ClinicalTrials.gov NCT00000620 (original ACCORD study).

Topics: Aged; Autoantibodies; Biomarkers; Body Mass Index; C-Peptide; Cardiovascular Diseases; Case-Control Studies; Cation Transport Proteins; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glutamate Decarboxylase; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Male; Microcirculation; Middle Aged; Receptor-Like Protein Tyrosine Phosphatases, Class 8; Zinc Transporter 8

Reported rates of hypoglycemia in patients with type 2 diabetes mellitus are lower with glimepiride as compared to glyburide. The aim of this study was to determine whether physiologic differences in counterregulatory neuroendocrine and metabolic mechanisms during hypoglycemia provide a basis for the observed clinical differences between glimepiride and glyburide.. Non-diabetic volunteers (age 38±2years, BMI 26±1kg/m(2)) were studied in a single-blind fashion during separate 2day randomized protocols consisting of 2h hyperinsulinemic (9pmol/kg/min) euglycemic (4.9±0.1mmol) and hypoglycemic (2.9±0.1mmol/L) clamps. Individuals received biologically equivalent doses of glimepiride (4mg) or glyburide (10mg) 1h prior to each glucose clamp (n=11) as well as a control group of placebo studies. Glucose kinetics were calculated using D-Glucose-6-6d2.. Insulin and C-peptide levels were increased (p<0.05) during euglycemia in both sulfonylurea groups as compared to placebo. However, despite equivalent hypoglycemia, insulin and C-peptide levels were higher (p<0.05) only after glyburide. Glucagon responses and endogenous glucose production (EGP) were decreased (p<0.05) during hypoglycemia following glyburide administration as compared to glimepiride. Glyburide reduced (p<0.05) norepinephrine responses during euglycemic clamps. In addition combined epinephrine and norepinephrine responses during hypoglycemia were reduced (p<0.05) following glyburide as compared to placebo. Leptin levels fell by a greater amount (p<0.05) during hypoglycemia with both sulfonylureas as compared to placebo.. In summary, glimepiride and glyburide can both similarly increase insulin and C-peptide levels during hyperinsulinemic euglycemia. However, during moderate hyperinsulinemic hypoglycemia (2.9mmol/L) glyburide resulted in increased C-peptide and insulin, but blunted glucagon, sympathetic nervous system and EGP responses. We conclude that glyburide can acutely reduce key neuroendocrine and metabolic counterregulatory defenses during hypoglycemia in healthy individuals.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucagon; Glucose Clamp Technique; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Leptin; Male; Pancreatic Polypeptide; Single-Blind Method; Sulfonylurea Compounds

We compared the effects of insulin degludec (IDeg; Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin) and insulin glargine (IGlar; A21Gly,B31Arg,B32Arg human insulin) on the day-to-day variability of fasting plasma glucose (FPG) levels in individuals with type 1 diabetes treated with basal-bolus insulin injections.. The effects of basal-bolus insulin therapy for 4 weeks with either IDeg or IGlar as the basal insulin in adult C-peptide-negative outpatients with type 1 diabetes were investigated in an open-label, multicentre, randomised, crossover trial. Randomisation was conducted using a centralised allocation process. The primary endpoints were the SD and CV of FPG during the final week of each treatment period. Secondary endpoints included serum glycoalbumin level, daily dose of insulin, intraday glycaemic variability and frequency of severe hypoglycaemia.. Thirty-six randomised participants (17 in the IDeg/IGlar and 19 in the IGlar/IDeg groups) were recruited, and data for 32 participants who completed the trial were analysed. The mean (7.74 ± 1.76 vs 8.56 ± 2.06 mmol/l; p = 0.04) and SD (2.60 ± 0.97 vs 3.19 ± 1.36 mmol/l; p = 0.03) of FPG were lower during IDeg treatment than during IGlar treatment, whereas the CV did not differ between the two treatments. The dose of IDeg was smaller than that of IGlar (11.0 ± 5.2 vs 11.8 ± 5.6 U/day; p < 0.01), but other secondary endpoints did not differ between the treatments.. IDeg yielded a lower FPG level and smaller day-to-day variability of FPG at a lower daily dose compared with IGlar in participants with type 1 diabetes. IDeg serves as a good option for basal insulin in the treatment of type 1 diabetes.. University Hospital Medical Information Network 000009965.. This research recieved no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Secretion; Insulin, Long-Acting; Insulin, Regular, Human; Male; Middle Aged; Reproducibility of Results

To assess the pharmacokinetics (PK) and glucodynamics (GD) of LY2605541 in patients with type 2 diabetes mellitus.. This parallel-group, open-label, dose-escalation study examined the PK and GD of basal insulin LY2605541 after single and multiple-dose administration. Fixed doses of LY2605541 (0.33-1.00 U/kg) were given once-daily (QD) for 14 days to insulin-treated patients with type 2 diabetes. A 24-h euglycaemic glucose clamp was conducted on days 1 and 14.. PK steady state was achieved within 7-10 days and the peak-to-trough fluctuation was <2, translating to a nearly 'peakless' glucose infusion rate at steady state and with a duration of action of at least 24 h. Across dose levels t1/2 ranged from 44.7 to 75.5 h (~2-3 days). As steady state was achieved, there were dose-dependent reductions in the prandial insulin dose and in fasting blood glucose, which decreased to 60-100 mg/dl across dose levels. Within-patient variability was <14 and <26% for the area under the concentration versus time curve (AUC) of the 8-point blood glucose profile and fasting blood glucose, respectively. The nocturnal glucose control between 03:00 and 09:00 hours was relatively unchanged. Mild hypoglycaemia was the most common adverse event.. In this Phase I study of fixed LY2605541 doses without titration, LY2605541 was well-tolerated and demonstrated a flat PK and GD profile accompanied by glucose normalization, prandial insulin dose reduction and no severe hypoglycaemia.

Topics: Adolescent; Adult; Aged; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Lispro; Male; Middle Aged; Polyethylene Glycols; Treatment Outcome

The aim of present study is to assess whether if basal insulin, glargine, could improve insulin secretory function of β-cells compared with glimepiride when metformin alone was failed. This was an open-label and multi-center study for 52 weeks in Korean patients with uncontrolled type 2 diabetes by metformin monotherapy. Subjects were randomized to glargine or glimepiride groups (n = 38 vs. 36, respectively). The primary endpoint was to compare changes in c-peptide via glucagon test after 48 weeks. Glycemic efficacy and safety endpoints (glycated hemoglobin (HbA1c), HOMA-B, fasting plasma glucose (FPG), lipid profiles, and hypoglycemic events) were also checked. The mean disease duration of all subjects was 88.2 months. Changes in C-peptide was no significant different between groups (P = 0.73), even though insulin secretion was not worsened in both groups at the endpoint. Glargine was not superior to glimepiride in other β-cell function indexes such as HOMA-B (P = 0.28). HbA1c and FPG reduced significantly in each groups but not different between two groups. Although, severe hypoglycemia did not occur, symptomatic hypoglycemia was more frequent in glimepiride group (P = 0.01). Insulin glargine was as effective as glimepiride in controlling hyperglycemia and maintaining β-cell function in Korean patients with type 2 diabetes during 48 weeks study period, after failure of metformin monotherapy. Hypoglycemic profile was favorable in the insulin glargine group and less weight gain was observed in the glimepiride group. Our results suggest that glargine and glimepiride can be considered after failure of metformin monotherapy.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Chi-Square Distribution; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Republic of Korea; Sulfonylurea Compounds; Young Adult

Basal-supported oral therapy (BOT) is often used to treat poorly controlled type 2 diabetes. However, patients sometimes experience nocturnal and early morning hypoglycemia. Thus, maintaining targeted glycemic control by BOT is limited in some patients. We assessed the efficacy and safety of replacing basal insulin by sitagliptin therapy in Japanese type 2 diabetes patients on BOT. Forty-nine subjects were sequentially recruited for the 52-week, prospective, single arm study. Patients on BOT therapy were switched from basal insulin to sitagliptin. The primary endpoint was change in HbA1c in 52 weeks. The secondary endpoints were dropout rate, changes in body weight, frequency of hypoglycemia, and relationship between change in HbA1c and insulin secretion capacity evaluated by glucagon loading test. The average dose of basal insulin was 15.0±8.4 units. Sixteen subjects (31.3%) were dropped because replacement by sitagliptin was less effective for glycemic control. In these subjects, diabetes duration was longer, FPG and HbA1c at baseline were higher, and insulin secretion capacity was lower. Change in HbA1c in 52 weeks was - 4 mmol/mol (95% CI - 5 to - 4 mmol/mol) (p<0.05). Change in body weight was - 0.71 kg (95% CI - 1.42 to - 0.004 kg) (p<0.05). Frequency of hypoglycemia was decreased from 1.21±1.05 to 0.06±0.24 times/month. HbA1c level was improved if C-peptide index (CPI) was over 1.19. In conclusion, basal insulin in BOT can be replaced by sitagliptin with a decrease in HbA1c level and frequency of hypoglycemia in cases where insulin secretion capacity was sufficiently preserved.

Topics: Aged; Asian People; Body Mass Index; Body Weight; C-Peptide; Demography; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Male; Pyrazines; ROC Curve; Sitagliptin Phosphate; Treatment Outcome; Triazoles

To compare the ability of customized versus normalized population fetal growth norms in identifying neonates at risk for adverse perinatal outcomes (APOs) associated with fetal overgrowth and gestational diabetes (GDM).. Secondary analysis of a multicenter treatment trial of mild GDM. The primary outcome was a composite of neonatal outcomes associated with fetal overgrowth and GDM. Birth weight percentiles were calculated using ethnicity- and gender-specific population and customized norms (Gardosi).. Two hundred three (9.8%) and 288 (13.8%) neonates were large for gestational age by population (LGApop) and customized (LGAcust) norms, respectively. Both LGApop and LGAcust were associated with the primary outcome and neonatal hyperinsulinemia, but neither was associated with hypoglycemia or hyperbilirubinemia. The ability of customized and population birth weight percentiles for predicting APOs were poor (area under the receiver operating characteristic curve < 0.6 for six of eight APOs).. Neither customized nor normalized population norms better identify neonates at risk of APOs related to fetal overgrowth and GDM.

Topics: Adult; Area Under Curve; Birth Weight; Blood Glucose; C-Peptide; Confidence Intervals; Diabetes, Gestational; Female; Fetal Macrosomia; Gestational Age; Humans; Hyperbilirubinemia, Neonatal; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Odds Ratio; Pregnancy; Pregnancy Outcome; Reference Values; ROC Curve; Young Adult

Glucokinase is expressed in the hypothalamus, but effects of glucokinase activators (GKAs) on counterregulatory responses to hypoglycemia are unknown.. Two separate studies assessed the counterregulatory hormone responses to hypoglycemia induced by the GKAs, AZD6370 and AZD1656, compared with insulin infusion.. Both studies were randomized, open, two-way crossover studies, conducted in separate clinical research centers.. Both studies involved 12 healthy adult male volunteers.. Each subject received two treatments in randomized order, separated by a washout. In the AZD6370 study, overnight-fasted subjects received either a single oral AZD6370 dose (300 mg) or insulin infusion (0.8 mU/kg · min). In the AZD1656 study, overnight-fasted subjects received either a single oral dose of AZD1656 (80 mg) plus supporting insulin (1 mU/kg · min) or insulin alone (1 mU/kg · min). Insulin was added to support AZD1656 because AZD1656 alone did not produce the desired hypoglycemia. Plasma glucose was lowered during a stepwise hypoglycemic clamp with a glycemic nadir of 2.7 mmol/liter for 30 min.. Epinephrine, norepinephrine, GH, cortisol, and glucagon plasma levels were assessed.. No safety issues were raised. AZD6370 and AZD1656 had no effect on counterregulatory responses for norepinephrine, GH, or cortisol, but epinephrine increased slightly with AZD1656. Glucagon responses were reduced by approximately 30% with both GKAs vs. insulin.. These data suggest the central nervous system-mediated counterregulatory response during GKA-induced hypoglycemia was preserved, whereas the glucagon response was attenuated; the latter was possibly mediated by a local pancreatic effect (intraislet hyperinsulinemia) rather than by impairment of the central nervous system-mediated response.

Topics: Adult; Azetidines; Benzamides; Body Mass Index; C-Peptide; Cross-Over Studies; Enzyme Activators; Epinephrine; Glucagon; Glucokinase; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Norepinephrine; Pyrazines; Sulfones; Young Adult

For the last 10 yr, continuous glucose monitoring (CGM) has brought up new insights into the accuracy of blood glucose analysis.. Our objective was to determine how islet graft function was able to influence the various components of dysglycemia after islet transplantation (IT).. We conducted a single-arm open-labeled study with a 3-yr follow-up in a referral center (ClinicalTrial.gov identifiers NCT00446264 and NCT01123187).. Twenty-three consecutive patients with type 1 diabetes (14 islet alone, nine islet after kidney) received IT within 3 months using the Edmonton protocol.. INTERVENTION included 72-h CGM before and 3, 6, 9, 12, 24, and 36 months after transplantation.. Graft function was estimated via β-score, a previously validated index (range 0-8) based on treatment requirements, C-peptide, blood glucose, and glycated hemoglobin.. At the 3-yr visit, graft function persisted in 19 patients (82%), and 10 (43%) remained insulin independent. Glycated hemoglobin decreased in the whole cohort from 8.3% (7.3-9.0%) at baseline to 6.7% (5.9-7.7%) at 3 yr [median (interquartile range), P < 0.01]. Mean glucose, glucose sd, and time spent with glycemia above 10 mmol/liter (hyperglycemia) and below 3 mmol/liter (hypoglycemia) were significantly lower after IT (P < 0.05 vs. baseline). The four CGM outcomes were related to β-score (P < 0.001). However, partial function (β-score >3) was sufficient to abrogate hypoglycemia; suboptimal function (β-score >5) was necessary to significantly improve mean glucose, glucose sd, and hyperglycemia; and optimal function (β score >7) was necessary to normalize them.. The four components of dysglycemia were not equally affected by the degree of islet graft function, which could have important implications for future development of β-cell replacement. A β-score above 3 dramatically reduced the occurrence of hypoglycemia.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Islets of Langerhans Transplantation; Male; Middle Aged; Treatment Outcome

Intensive insulin therapy (IIT) improved outcome in the adult and pediatric intensive care unit (PICU) compared with conventional insulin therapy (CIT). IIT did not increase the anabolic hormone IGF-I in critically ill adults, but feeding in critically ill children and pediatric hormonal responses may differ. Twenty-five percent of the children with IIT experienced hypoglycemia, which may have evoked counterregulatory responses.. We hypothesized that IIT reactivates the somatotropic axis and anabolism in PICU patients.. This was a preplanned subanalysis of a randomized controlled trial on IIT.. We studied 369 patients who stayed in PICU for at least 3 d (study 1) and 126 patients in a nested case-control study (study 2).. Circulating insulin, C-peptide, GH, IGF-I, bioavailable IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit were analyzed upon admission and d 3. In the nested case-control study, the somatotropic axis, cortisol, and glucagon were analyzed before and after hypoglycemia.. On d 3, C-peptide was more than 10-fold lower (P < 0.0001) in the IIT group than in the CIT group. IIT increased circulating GH (P = 0.04) and lowered bioavailable IGF-I (P = 0.002). IIT also decreased IGFBP-3 (P = 0.0005) and acid-labile subunit (P = 0.007), while increasing IGFBP-1 (P = 0.04) and the urea/creatinine ratio, a marker of catabolism (P = 0.03). In the nested case-control study, IGFBP-1 was increased after hypoglycemia, whereas the somatotropic axis and the counterregulatory hormones cortisol and glucagon did not change.. Despite improved PICU outcome, IIT did not counteract the catabolic state of critical illness. Suppression of portal insulin may have resulted in lower bioavailable IGF-I.

Topics: Adolescent; C-Peptide; Case-Control Studies; Child; Child, Preschool; Critical Illness; Female; Glucagon; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Infant; Infant, Newborn; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Intensive Care Units, Pediatric; Male; Prospective Studies

It is uncertain whether the ability to avoid hypoglycaemia during fasting is preserved, and the risk of reactive hypoglycaemia after an oral glucose stimulus following a prolonged fasting period is increased at augmented glucagon-like peptide-1 (GLP-1) levels.. A randomized, double-blind placebo-controlled cross-over study in eight healthy men to assess the safety, in terms of hypoglycaemia, of a continuously infused pharmacological dose of native GLP-1 during long-term fasting. After an overnight fast the fasting period continued for 48 h and was followed by a 3-h oral glucose tolerance test (OGTT). GLP-1(7-36 amide) or placebo was continuously infused subcutaneously and titrated to a dose of 4.8 pmol/kg per min.. Two subjects in the GLP-1 group and one subject in the placebo group were withdrawn due to protocol specified plasma glucose (PG) < or = 2.8 mm and neuroglycopaenic symptoms. The infusion of GLP-1 resulted in pharmacological levels of intact GLP-1. During the fasting period PG, insulin and C-peptide levels declined and glucagon, GH and free fatty acid (FFA) levels increased with no differences between GLP-1 and placebo. During OGTT circulating levels of insulin and C-peptide were higher with GLP-1 infusion. However, PG was similar during GLP-1 vs. placebo infusions. GLP-1 infusion increased norepinephrine and cortisol levels during OGTT.. The counter-regulatory response during 48 h of subcutaneous GLP-1 infusion was preserved despite long-term fasting with no apparent increased risk of hypoglycaemic episodes. No reactive hypoglycaemia was observed when the fast was followed by an OGTT. Thus use of long-acting GLP-1 analogues may not increase the risk of hypoglycaemia.

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Fasting; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucose Tolerance Test; Human Growth Hormone; Humans; Hypoglycemia; Infusions, Subcutaneous; Insulin; Male; Norepinephrine; Peptide Fragments

OBJECTIVE Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump has been available for the past 25 years. CIPII, with its specific pharmacodynamic properties, may be a viable treatment alternative to improve glycemic control in patients with type 1 diabetes for whom other therapies have failed. There have been few studies in which CIPII was compared with subcutaneous insulin treatment for patients with type 1 diabetes with poor glycemic control. RESEARCH DESIGN AND METHODS In an open-label, prospective, crossover, randomized, 16-month study, the effects of CIPII and subcutaneous insulin were compared in 24 patients. The primary outcome measure was the incidence of hypoglycemia. Secondary outcome measures were A1C, and glucose profile, including time in euglycemia, as measured by continuous glucose monitoring. RESULTS The incidence of grade 1 hypoglycemic events was 4.0 +/- 2.6 per week with subcutaneous insulin compared with 3.5 +/- 2.3 per week during CIPII (P = 0.13). The absolute mean difference in A1C with CIPII compared with subcutaneous treatment was -0.76% (95% CI -1.41 to -0.11) (P = 0.03). Baseline time spent in euglycemia was 45.2 +/- 12.6% and increased 10.9% (4.6-17.3) with CIPII compared with subcutaneous treatment (absolute value; P = 0.003). There were no differences in the occurrence rate for severe hypoglycemic events, daily insulin use, or BMI. No pump or catheter malfunction was observed during the study. CONCLUSIONS Although we did not observe a significant reduction in hypoglycemic events, improved glycemic control was achieved with the use of CIPII. We saw a 0.8% decrease in A1C and an 11% increase in the time spent in euglycemia.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemia; Incidence; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Middle Aged; Patient Selection; Young Adult

To compare blood glucose control when using biphasic insulin aspart (BIAsp) three times a day (using 70/30 high-mix before breakfast and lunch), with biphasic human insulin (BHI, 30/70) twice daily in adults with type 2 diabetes already treated with insulin.. In a 60-day, open-label, crossover study, people with insulin-treated type 2 diabetes [n = 38, baseline haemoglobin A1c 8.3 +/- 0.9 (s.d.) %] were randomized to BIAsp three times a day before meals, as BIAsp 70 (70% insulin aspart and 30% protamine-complexed insulin aspart) before breakfast and lunch and BIAsp 30 (30/70 free and protamine-complexed insulin aspart) before dinner, or to human premix insulin (BHI) 30/70 twice a day before meals. A 24-h in-patient plasma glucose profile was performed at the end of each 30-day treatment period. The total daily insulin dose of BIAsp regimen was 110% of BHI and the doses were not changed during the study.. There was no difference between BIAsp and BHI in geometric weighted average serum glucose over 24 h [7.3 vs. 7.7 mmol/l, BIAsp/BHI ratio 0.95 (95% CI 0.88-1.02), not significant (NS)], but daytime geometric weighted average glucose concentration was significantly lower with the BIAsp regimen than with BHI [8.3 vs. 9.2 mmol/l, BIAsp/BHI ratio 0.90 (0.84-0.98), p = 0.014]. The mealtime serum glucose excursion was also lower with BIAsp than with BHI with statistically significant differences at lunchtime [difference -4.9 (-7.0 to -2.7) mmol/l, p = 0.000); the difference in glucose excursions above 7.0 mmol/l was also significant [-5.8 (-8.3 to -3.2) mmol/l, p = 0.000). The proportion of participants experiencing confirmed hypoglycaemic episodes was similar between regimens (42 vs. 43%, NS).. An insulin regimen using high-mix BIAsp (BIAsp 70) before breakfast and lunch and BIAsp 30 before dinner can achieve lower blood glucose levels during the day through reduced mealtime glucose excursions in particular at lunchtime than a twice-daily premix regimen.

Topics: Adult; Aged; Biphasic Insulins; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; England; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Aspart; Insulin, Isophane; Male; Middle Aged; Treatment Outcome; Young Adult

This trial evaluated the effects of 16 weeks of consumption of 1000mg rebaudioside A (n=60) a steviol glycoside with potential use as a sweetener, compared to placebo (n=62) in men and women (33-75 years of age) with type 2 diabetes mellitus. Mean+/-standard error changes in glycosylated hemoglobin levels did not differ significantly between the rebaudioside A (0.11+/-0.06%) and placebo (0.09+/-0.05%; p=0.355) groups. Changes from baseline for rebaudioside A and placebo, respectively, in fasting glucose (7.5+/-3.7mg/dL and 11.2+/-4.5mg/dL), insulin (1.0+/-0.64microU/mL and 3.3+/-1.5microU/mL), and C-peptide (0.13+/-0.09ng/mL and 0.42+/-0.14ng/mL) did not differ significantly (p>0.05 for all). Assessments of changes in blood pressure, body weight, and fasting lipids indicated no differences by treatment. Rebaudioside A was well-tolerated, and records of hypoglycemic episodes showed no excess vs. placebo. These results suggest that chronic use of 1000mg rebaudioside A does not alter glucose homeostasis or blood pressure in individuals with type 2 diabetes mellitus.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Diterpenes, Kaurane; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Lipids; Male; Middle Aged; Placebos; Sweetening Agents

The acylated long-acting insulin analog detemir is more lipophilic than human insulin and likely crosses the blood-to-brain barrier more easily than does human insulin. The aim of these studies was to assess the brain/hypothalamus responses to euglycemia and hypoglycemia in humans during intravenous infusion of equipotent doses of detemir and human insulin.. Ten normal, nondiabetic subjects (six men, age 36+/-7 years, and BMI 22.9+/-2.6 kg/m(2)) were studied on four occasions at random during intravenous infusion of either detemir or human insulin in euglycemia (plasma glucose 90 mg/dl) or during stepped hypoglycemia (plasma glucose 90, 78, 66, 54, and 42 mg/dl steps).. Plasma counterregulatory hormone response to hypoglycemia did not differ between detemir and human insulin. The glycemic thresholds for adrenergic symptoms were higher with detemir (51 +/- 7.7 mg/dl) versus human insulin (56 +/- 7.8 mg/dl) (P = 0.029). However, maximal responses were greater with detemir versus human insulin for adrenergic (3 +/- 2.5 vs. 2.4 +/- 1.8) and neuroglycopenic (4 +/- 3.9 vs. 2.7+/-2.5) symptoms (score, P < 0.05). Glycemic thresholds for onset of cognitive dysfunction were lower with detemir versus human insulin (51 +/- 8.1 vs. 47 +/- 3.6 mg/dl, P = 0.031), and cognitive function was more deteriorated with detemir versus human insulin (P < 0.05).. Compared with human insulin, responses to hypoglycemia with detemir resulted in higher glycemic thresholds for adrenergic symptoms and greater maximal responses for adrenergic and neuroglycopenic symptoms, with an earlier and greater impairment of cognitive function. Additional studies are needed to establish the effects of detemir on responses to hypoglycemia in subjects with diabetes.

Topics: 3-Hydroxybutyric Acid; Adult; Alanine; Blood Glucose; Brain; C-Peptide; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Glucose; Glycerol; Humans; Hypoglycemia; Insulin; Insulin Detemir; Insulin, Long-Acting; Lactic Acid; Male; Middle Aged; Time Factors

Sleep loss has immediate effects on metabolic function that in the long run may contribute to the development of obesity and type 2 diabetes.. Our objective was to explore the neuroendocrine mechanisms mediating the acute effects of sleep deprivation on blood glucose regulation under basal and hypoglycemic conditions.. In a randomized, crossover study in 10 healthy young men, plasma concentrations of relevant hormones were examined during basal rest, a subsequent stepwise hypoglycemic clamp after one night of total sleep deprivation (SD) and one night of regular sleep.. Basal glucagon concentrations were decreased (P = 0.022) and C-peptide levels were slightly reduced after SD (P = 0.085), compared with regular sleep. During hypoglycemia after SD, the glucagon increase relative to baseline was enhanced (P = 0.034) and the relative decrease in C-peptide was reduced (P = 0.013). Also, the relative increase in norepinephrine was reduced (P = 0.031). SD did not affect epinephrine, ACTH, cortisol, lactate, beta-hydroxybutyrate, or nonesterified fatty acids during hypoglycemia, but overall, plasma nonesterified fatty acid levels were reduced after SD (P = 0.009). SD markedly increased rated hunger during basal rest (P < 0.008), resulting in a dampened relative increase during hypoglycemia (P < 0.009). Unexpectedly, despite distinct alterations in basal secretory activity, the absolute amplitude of hormonal counterregulation and hunger responses to hypoglycemia was not affected by SD.. Short-term SD distinctly alters hormonal glucose regulation, affecting especially pancreatic islet secretion, and also increases hunger. Immediate perturbations in the dynamic regulation of energy metabolism caused by acute sleep curtailment may contribute to the association between chronic sleep loss and metabolic disorders.

Topics: 3-Hydroxybutyric Acid; Adrenocorticotropic Hormone; Adult; C-Peptide; Cross-Over Studies; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Glucose; Glucose Clamp Technique; Hormones; Human Growth Hormone; Humans; Hunger; Hydrocortisone; Hypoglycemia; Lactic Acid; Male; Neurosecretory Systems; Norepinephrine; Sleep Deprivation

We evaluated the respective value of insulin, C-peptide and proinsulin levels in 33 patients with endogenous hyperinsulinism and in 67 controls to determine the best parameters and thresholds to make or to rule out the diagnosis of endogenous hyperinsulinism.. When blood glucose levels were below 2.5 mmol/l, insulin was <21 pmol/l in 8-35% of the patients and in all controls; C-peptide was >0.2 nmol/l in all insulinomas but not in the nesidioblastosis or in the controls; proinsulin was >5 pmol/l in all patients but not in the controls. When fasting blood glucose levels reached 2.5-3.3 mmol/l, proinsulin was <22 pmol/l in all the controls and >22 pmol/l in 74% of the patients. Proinsulin after an overnight fast was below 22 pmol/l in all non-obese controls and above 22 pmol/l in 73% of non-obese patients.. Proinsulin levels above 5 pmol/l with blood glucose levels below 2.5 mmol/l during a 72 h fast test represent the best criterion for the diagnosis of endogenous hyperinsulinism, reaching 100% diagnostic specificity and sensitivity. Concomitant C-peptide levels above 0.2 nmol/l also make the diagnosis of all our insulinoma patients, not the diagnosis of nesidioblastosis, while insulin levels have much less diagnostic accuracy. Whether proinsulin levels above 22 pmol/l could also make the diagnosis of endogenous hyperinsulinism in part of the patients at the time of fasting blood glucose levels between 2.5 and 3.3 mmol/l or after an overnight fast in non-obese subjects needs further study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; C-Peptide; Circadian Rhythm; Diagnostic Techniques, Endocrine; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Middle Aged; Proinsulin; Sensitivity and Specificity; Time Factors

Inhibition of dipeptidyl peptidase 4 by vildagliptin enhances the concentrations of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The present study asked whether vildagliptin accentuates glibenclamide-induced hypoglycemia or affects endogenous secretion of GLP-1 and GIP after an oral glucose tolerance test.. There were 16 healthy male subjects studied on four occasions after an overnight fast in a double-blind, four-way crossover study. In random order, vildagliptin (100 mg) or placebo, with and without glibenclamide (5 mg), was administered 30 min before 75 g oral glucose. Blood was sampled to measure glucose, and total (sum of active and inactive) GLP-1 and GIP. Statistical evaluation was done using repeated-measures ANOVA.. Glibenclamide provoked hypoglycemia (

Topics: Adamantane; Adult; Algorithms; C-Peptide; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glyburide; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Nitriles; Pyrrolidines; Vildagliptin

Severe hypoglycemia, the most serious side effect of sulfonylurea therapy, has been reported to occur more frequently with glyburide than glimepiride. The present studies were undertaken to test the hypothesis that a differential effect on glucagon secretion may be involved. We performed hyperinsulinemic hypoglycemic (approximately 2.5 mmol/L) clamps in 16 healthy volunteers who received in randomized order placebo, glyburide (10 mg), and glimepiride (4 mg) just before beginning the insulin infusion and measured plasma glucagon, insulin, C-peptide, glucagon, epinephrine, cortisol, and growth hormone levels during the clamp and during a 3-hour recovery period after discontinuation of the insulin infusion. Neither sulfonylurea altered glucagon responses or those of other counterregulatory hormones (except cortisol) during the clamp. However, glyburide delayed plasma glucose recovery from hypoglycemia (plasma glucose at end of recovery period: control, 4.9 +/- 0.2 mmol/L; glyburide, 3.7 +/- 0.2 mmol/L; P = .0001; glimepiride, 4.5 +/- 0.2 mmol/L; P = .08). Despite lower plasma glucose levels, glyburide stimulated insulin secretion during this period (0.89 +/- 0.13 vs 1.47 +/- 0.15 pmol x kg(-1) x min(-1), control vs glyburide; P = .001), whereas glimepiride did not (P = .08). Short-term administration of glyburide or glimepiride did not alter glucagon responses during hypoglycemia. In contrast, during recovery from hypoglycemia, glyburide but not glimepiride inappropriately stimulates insulin secretion at low plasma glucose levels. This differential effect on insulin secretion may be an important factor in explaining why glyburide causes severe hypoglycemia more frequently than glimepiride.

Topics: Adult; Blood Glucose; C-Peptide; Epinephrine; Female; Glucose; Glyburide; Hormones; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Kinetics; Male; Sulfonylurea Compounds

To study the effect of the short-acting insulin secretagogue nateglinide in patients with maturity-onset diabetes of the young type 3 (MODY3), which is characterized by a defective insulin response to glucose and hypersensitivity to sulfonylureas.. We compared the acute effect of nateglinide, glibenclamide, and placebo on prandial plasma glucose and serum insulin, C-peptide, and glucagon excursions in 15 patients with MODY3. After an overnight fast, they received on three randomized occasions placebo, 1.25 mg glibenclamide, or 30 mg nateglinide before a standard 450-kcal test meal and light bicycle exercise for 30 min starting 140 min after the ingestion of the first test drug.. Insulin peaked earlier after nateglinide than after glibenclamide or placebo (median [interquartile range] time 70 [50] vs. 110 [20] vs. 110 [30] min, P = 0.0002 and P = 0.0025, respectively). Consequently, compared with glibenclamide and placebo, the peak plasma glucose (P = 0.031 and P < 0.0001) and incremental glucose areas under curve during the first 140 min of the test (P = 0.041 and P < 0.0001) remained lower after nateglinide. The improved prandial glucose control with nateglinide was achieved with a lower peak insulin concentration than after glibenclamide (47.0 [26.0] vs. 80.4 [71.7] mU/l; P = 0.023). Exercise did not induce hypoglycemia after nateglinide or placebo, but after glibenclamide six patients experienced symptomatic hypoglycemia and three had to interrupt the test.. A low dose of nateglinide prevents the acute postprandial rise in glucose more efficiently than glibenclamide and with less stimulation of peak insulin concentrations and less hypoglycemic symptoms.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cross-Over Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise Test; Female; Glucagon; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

Animal and in vitro studies indicate that a decrease in beta-cell insulin secretion, and thus a decrease in tonic alpha-cell inhibition by intraislet insulin, may be an important factor for the increase in glucagon secretion during hypoglycemia. However, in humans this role of decreased intraislet insulin is still unclear.. We studied glucagon responses to hypoglycemia in 14 nondiabetic subjects on two separate occasions. On both occasions, insulin was infused from 0 to 120 min to induce hypoglycemia. On one occasion, somatostatin was infused from -60 to 60 min to suppress insulin secretion, so that the decrement in intraislet insulin during the final 60 min of hypoglycemia would be reduced. On the other occasion, subjects received an infusion of normal saline instead of the somatostatin.. During the 2nd h of the insulin infusion, when somatostatin or saline was no longer being infused, plasma glucose ( approximately 2.6 mmol/l) and insulin levels ( approximately 570 pmol/l) were comparable in both sets of experiments (both P > 0.4). In the saline experiments, insulin secretion remained unchanged from baseline (-90 to -60 min) before insulin infusion and decreased from 1.20 +/- 0.12 to 0.16 +/- 0.04 pmol . kg(-1) . min(-1) during insulin infusion (P < 0.001). However, in the somatostatin experiments, insulin secretion decreased from 1.18 +/- 0.12 pmol . kg(-1) . min(-1) at baseline to 0.25 +/- 0.09 pmol . kg(-1) . min(-1) before insulin infusion so that it did not decrease further during insulin infusion (-0.12 +/- 0.10 pmol . kg(-1) . min(-1), P = 0.26) indicating the complete lack of a decrement in intraislet insulin during hypoglycemia. This was associated with approximately 30% lower plasma glucagon concentrations (109 +/- 7 vs. 136 +/- 9 pg/ml, P < 0.006) and increments in plasma glucagon above baseline (41 +/- 8 vs. 67 +/- 11 pg/ml, P < 0.008) during the last 15 min of the hypoglycemic clamp. In contrast, increases in plasma growth hormone were approximately 70% greater during hypoglycemia after somatostatin infusion (P < 0.007), suggesting that to some extent the increases in plasma glucagon might have reflected a rebound in glucagon secretion.. These results provide direct support for the intraislet insulin hypothesis in humans. However, the exact extent to which a decrement in intraislet insulin accounts for the glucagon responses to hypoglycemia remains to be established.

Topics: Adult; Blood Glucose; C-Peptide; Epinephrine; Female; Glucagon; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; Somatostatin

Despite the demonstrated benefits of glycemic control, patient acceptance of basal/bolus insulin therapy for type 1 diabetes has been slow. We investigated whether a basal/bolus insulin regimen involving rapid-acting, dry powder, inhaled insulin could provide glycemic control comparable with a basal/bolus subcutaneous regimen.. Patients with type 1 diabetes (ages 12-65 years) received twice-daily subcutaneous NPH insulin and were randomized to premeal inhaled insulin (n = 163) or subcutaneous regular insulin (n = 165) for 6 months.. Mean glycosylated hemoglobin (A1C) decreased comparably from baseline in the inhaled and subcutaneous insulin groups (-0.3 and -0.1%, respectively; adjusted difference -0.16% [CI -0.34 to 0.01]), with a similar percentage of subjects achieving A1C <7%. Although 2-h postprandial glucose reductions were comparable between the groups, fasting plasma glucose levels declined more in the inhaled than in the subcutaneous insulin group (adjusted difference -39.5 mg/dl [CI -57.5 to -21.6]). Inhaled insulin was associated with a lower overall hypoglycemia rate but higher severe hypoglycemia rate. The overall hypoglycemia rate (episodes/patient-month) was 9.3 (inhaled) vs. 9.9 (subcutaneous) (risk ratio [RR] 0.94 [CI 0.91-0.97]), and the severe hypoglycemia rate (episodes/100 patient-months) was 6.5 vs. 3.3 (RR 2.00 [CI 1.28-3.12]). Increased insulin antibody serum binding without associated clinical manifestations occurred in the inhaled insulin group. Pulmonary function between the groups was comparable, except for a decline in carbon monoxide-diffusing capacity in the inhaled insulin group without any clinical correlates.. Inhaled insulin may provide an alternative for the management of type 1 diabetes as part of a basal/bolus strategy in patients who are unwilling or unable to use preprandial insulin injections.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin; Male; Middle Aged; Respiratory Function Tests

This study assessed whether glucose-dependent insulin secretion and overall counterregulatory response are preserved during hypoglycemia in the presence of exenatide. Twelve healthy fasted volunteers were randomized in a triple-blind crossover study to receive either intravenous exenatide (0.066 pmol. kg(-1). min(-1)) or placebo during a 270-min stepwise hyperinsulinemic-hypoglycemic clamp (insulin infusion 0.8 mU. kg(-1). min(-1)). Plasma glucose was clamped sequentially at 5.0 (0-120 min), 4.0 (120-180 min), 3.2 (180-240 min), and 2.7 mmol/l (240-270 min). At 270 min, insulin infusion was terminated and plasma glucose increased to approximately 3.2 mmol/l. The time to achieve plasma glucose >/=4 mmol/l thereafter was recorded. Insulin secretory rates (ISRs) and counterregulatory hormones were measured throughout. Glucose profiles were superimposable between the exenatide and placebo arms. In the presence of euglycemic hyperinsulinemia, ISRs in the exenatide arm were approximately 3.5-fold higher than in the placebo arm (353 +/- 29 vs. 100 +/- 29 pmol/min [least-square means +/- SE]). However, ISRs declined similarly and rapidly at all hypoglycemic steps (

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Exenatide; Fatty Acids, Nonesterified; Glucagon; Humans; Hydrocortisone; Hypoglycemia; Infusions, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Peptides; Venoms

A double-blind, prospective, randomised, cross-over clinical trial was performed comparing a glibenclamide (G) 5.0 mg/metformin (M) 400 mg combination with a G 2.5 mg/M 400 mg formulation to evaluate whether a higher dose of glibenclamide was able to improve glycaemia in poorly controlled Type 2 diabetic patients. One hundred and ninety-eight patients with poorly controlled Type 2 diabetes mellitus were randomised to receive one of the two trial drugs for a first 3-month period, and were then assigned to the alternative combination for further 3 months. The starting dose (2 tablets/day, 30 min before breakfast and dinner) was to be up-titrated to 3 tablets/day when required. A standard dietary regimen was kept constant for the total trial duration. Fasting plasma glucose, HbA1c, C-peptide, insulin and lactate levels, haematology and blood chemistry were measured at the start/end of each cycle. Patients' self-assessment of the glycaemic profile (at fasting and 2 hr after the main meals) was performed weekly. Patients were constantly monitored for adverse events and episodes of hypoglycaemia, and all events were recorded. Decrease of mean fasting glucose levels measured in the first cycle was more pronounced in the group treated with G 5.0 mg/M 400 (p<0.01) compared to baseline, although the difference was not significant--no changes were observed in the second 3-month period. Results of patients' self-assessment of the glycaemic profile in the overall 6-month period show that the two trial drugs produced similar effects on fasting glucose, but the decrease of post-prandial glycaemic levels was markedly higher with G 5 mg/M 400 mg than with G 2.5 mg/M 400 mg at both main meals. A similar significant decrease (p<0.01) of HbA1c was observed in both sequence groups at the end of the first 3-month treatment period, and mean levels remained unchanged at 6 months. Drug-related adverse events were observed in 2 patients during treatment with G 2.5 mg/M 400 mg and in 5 with G 5 mg/M 400 mg, while 14 and 22 episodes of hypoglycaemia occurred with the two trial drugs, respectively (p=NS between treatments). Metformin-induced increases of lactate levels were similar in the two sequence groups. No differences between groups were found either in the number of up-titrated patients or in all the other laboratory parameters. In conclusion, the new combination containing 5-mg glibenclamide produced a greater improvement in post-prandial glycaemic control compared with the s

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Food; Glyburide; Glycated Hemoglobin; History, 18th Century; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Lactic Acid; Male; Metformin; Middle Aged; Prospective Studies

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic-sympathetic neural and adrenomedullary response and the resulting neurogenic [autonomic] symptom responses) and thus causes a vicious cycle of recurrent hypoglycemia. To assess the suggestion that it is the cortisol response to antecedent hypoglycemia that mediates HAAF, we tested the hypothesis that plasma cortisol elevations during euglycemia that are comparable to those that occur during hypoglycemia reduce sympathoadrenal and neurogenic symptom responses to subsequent hypoglycemia. To do this, 12 healthy subjects were studied with hyperinsulinemic-stepped hypoglycemic clamps the day after saline or cortisol (1.3 +/- 0.2 micro g. kg(-1) x min(-1)) infusions from 0930 to 1200 and from 1330 to 1600. Compared with saline, antecedent cortisol elevations did not reduce the sympathoadrenal (e.g., final plasma epinephrine levels of 674 +/- 84 vs. 606 +/- 80 pg/ml and final plasma norepinephrine levels of 332 +/- 26 vs. 304 +/- 26 pg/ml) or neurogenic symptom (e.g., final scores of 9.3 +/- 1.1 vs. 13.2 +/- 1.3) responses to subsequent hypoglycemia. Thus, these data do not support the suggestion that cortisol mediates HAAF.

Topics: Adult; Anti-Inflammatory Agents; Autonomic Nervous System Diseases; C-Peptide; Diabetic Neuropathies; Epinephrine; Female; Glucose Clamp Technique; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Male; Norepinephrine; Sodium Chloride

Glucagon-like peptide 1 (GLP-1) is a proglucagon derivative secreted primarily from the L-cells of the small intestinal mucosa in response to the ingestion of meals. GLP-1 stimulates insulin secretion and inhibits glucagon secretion. It has previously been shown that intravenous or subcutaneous administration of GLP-1 concomitant with intravenous glucose results in hypoglycemia in healthy subjects. Because GLP-1 is also effective in type 2 diabetic patients and is currently being evaluated as a therapeutic agent, it is important to investigate whether GLP-1 may cause hypoglycemia in such patients. We have previously shown that GLP-1 does not cause hypoglycemia in obese type 2 diabetic patients with insulin resistance amounting to 5.4 +/- 1.1 according to homeostasis model assessment (HOMA). In this study, we investigated diabetic patients with normal or close to normal insulin sensitivity.. Eight lean type 2 diabetic patients (group 1) aged 60 years (range 50-72) with BMI 23.1 kg/m(2) (20.3-25.5) and HbA(1c) 8.0% (6.9-11.4) and eight patients with type 2 diabetes secondary to chronic pancreatitis (group 2) aged 52 years (41-62) with BMI 21.9 kg/m(2) (17.6-27.3) and HbA(1c) 7.8% (6.2-12.4) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body wt. Then, 15 min later, at the time of peak GLP-1 concentration, plasma glucose (PG) was raised to 15 mmol/l with an intravenous glucose bolus. HOMA (mean +/- SEM) showed insulin resistance amounting to 1.9 +/- 0.3 and 1.7 +/- 0.5 in the two groups, respectively.. In both groups, PG decreased rapidly and stabilized at 7.5 mmol/l (range 3.9-10.1) and 7.2 mmol/l (3.1-10.9) in groups 1 and 2, respectively, after 90 min. Neither symptoms of hypoglycemia nor biochemical hypoglycemia were observed in any patient.. We conclude that a GLP-1-based therapy would not be expected to be associated with an increased risk of hypoglycemia in insulin-sensitive type 2 diabetic patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin; Kinetics; Middle Aged; Pancreatitis; Peptide Fragments; Protein Precursors

The finding of insulin levels above a minimum threshold at the time of symptomatic hypoglycaemia is crucial in the diagnosis of endogenous hyperinsulinism. The aim of this study was to evaluate insulin levels at the time of hypoglycaemia with an insulin-specific assay in such patients.. We measured insulin levels in 15 patients with fasting hypoglycaemia related to endogenous hyperinsulinism using an insulin-specific immunoradiometric assay (IRMA) without any significant cross-reaction with intact proinsulin.. Insulin levels were below 6 mIU/l in all the samples taken at the time of symptomatic hypoglycaemia in 6/15 patients, and in some of the samples in three patients; insulin levels were below 3 mIU/l in samples from 5 patients. C-peptide levels were above 0.6 ng/ml in all these samples. The lowest proinsulin level was 35 pmol/l. Insulin levels were measured with a less specific RIA (40% cross-reaction with proinsulin) in 8/15 patients and were above 6 mIU/l in all samples in seven patients, and all but one sample in the 8th patient. Mean concomitant C-peptide and insulinoma size were lower in those patients with insulin-IRMA levels below 6 mIU/l.. Symptomatic hypoglycaemia below 0.45 g/l can result from insulin levels below 6 or even 3 mIU/l; lower insulin levels and secretion could be observed preferentially in small insulinomas. If an insulin assay devoid of any significant cross-reaction with intact proinsulin is employed, measuring C-peptide (and/or proinsulin) levels at the time of symptomatic hypoglycaemia is mandatory to make the diagnosis of endogenous hyperinsulinism.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Immunoradiometric Assay; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin

In a pilot study, the metabolic effects of continuous subcutaneous insulin infusion (CSII) versus intensive subcutaneous insulin therapy (ISIT) started at diagnosis in patients with Type 1 diabetes and continued for a 2-year period were evaluated and compared. Twenty-three patients (between 12 and 35 years old, mean +/- SD 18.4 +/- 9 years) were randomized into two treatment groups (CSII vs. ISIT), and both received supplemental nicotinamide (NA), 25 mg/kg of body weight. CSII was started immediately after admission to the hospital. Parameters of metabolic control [insulin dose, hemoglobin A1c (HbA1c), and C-peptide] were evaluated for a 2-year follow-up period. Data are presented for a total of 19 patients who remained in the study for its duration. Two years after diagnosis, mean +/- SD HbA1c was 6.3 +/- 0.5% and 6.2 +/- 0.3% for the CSII and ISIT groups, respectively (p=not significant). Compared with baseline values, an increase of baseline C-peptide of 38% for the CSII group and 27% for the ISIT group was observed; however, the difference between the groups was not significant. The insulin requirement for the entire duration of the study, but not at entry and 3 months, was significantly higher in CSII compared with ISIT patients (0.62 +/- 0.4 IU/kg/day vs. 0.3 +/- 0.4 IU/kg/day, respectively; p<0.01). After trial completion patients on CSII continued with this mode of therapy. Implementation of CSII as well as ISIT at diagnosis of Type 1 diabetes and continuation for 2 years thereafter achieved similar and optimal metabolic control, but more insulin was required with the CSII group. Both types of intensive insulin therapy combined with NA are able to preserve C-peptide secretion or even increase baseline levels for up to 2 years after diagnosis.

Topics: Analysis of Variance; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Pilot Projects; Reproducibility of Results; Treatment Outcome

This study compared the effects of acarbose plus glibenclamide combination therapy with acarbose or glibenclamide treatment alone on postprandial blood glucose, serum insulin and C-peptide levels, and the tendency to develop hypoglycaemia. A total of 84 patients with Type 2 diabetes (fasting blood glucose: 120-180 mg/dl; postprandial blood glucose: 140-240 mg/dl) was included in this two-centre, double-blind, double-dummy, placebo-controlled study. Patients were randomised to one of 4 treatment groups: acarbose (100 mg); glibenclamide (3.5 mg); acarbose plus glibenclamide; or placebo. Treatment was administered before a standard breakfast, and fasting (07.30 h, 08.00 h) and postprandial (09.00, 10.00, 11.00, 12.00 h) blood glucose, serum insulin and C-peptide levels were determined. Acarbose plus glibenclamide treatment significantly reduced the mean increase in postprandial blood glucose levels (23.7+/-17.3 mg/dl) compared with either acarbose (58.4+/-31.6 mg/dl), glibenclamide (56.9+/-42.8 mg/dl) or placebo (101.6+/-49.2 mg/dl) (p<0.05 for all). Serum insulin levels (mean AUC(7.30-12 h)) observed with acarbose plus glibenclamide combination therapy were significantly lower than those observed with glibenclamide monotherapy (243.5+/-161.1 vs 383.4+/-215.8 hr x microU/ml; p=0.02), and comparable with the values seen with placebo (226.0+/-166.6 hr x microU/ml), suggesting that acarbose modifies the insulin secretion induced by glibenclamide. Glibenclamide monotherapy resulted in a significantly higher rate of decrease in blood glucose level than with acarbose plus glibenclamide (71.8+/-29.9 vs 46.2+/-18.0 mg/dl x h(-1); p=0.0003), and blood glucose levels at 11.00 h were also markedly lower with glibenclamide (84.4+/-29 mg/dl) than acarbose plus glibenclamide (102.0+/-41 mg/dl), suggesting a reduced tendency for hypoglycaemic episodes with acarbose plus glibenclamide than with glibenclamide alone. In all, 6 (29%) hypoglycaemic episodes occurred with glibenclamide, 2 (10%) with acarbose plus glibenclamide and none with acarbose. Acarbose plus glibenclamide combination therapy results in an additive glucose lowering effect and reduced risk for hypoglycaemia. Acarbose modifies the insulin secretion induced by glibenclamide, which explains the lower risk of hypoglycaemia compared with glibenclamide monotherapy.

Topics: Acarbose; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Food; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kinetics; Male; Placebos

Hypoglycemia-associated autonomic failure (HAAF)-reduced autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia caused by recent antecedent hypoglycemia-plays a key role in the pathogenesis of defective glucose counterregulation and hypoglycemia unawareness and thus iatrogenic hypoglycemia in type 1 diabetes. On the basis of the findings that cortisol infusion mimics and deficient or inhibited cortisol secretion minimizes this phenomenon, it has been suggested that the cortisol response to antecedent hypoglycemia mediates HAAF. We tested the hypothesis that any stimulus that releases cortisol, such as exercise, reduces autonomic and symptomatic responses to subsequent hypoglycemia. Thirteen healthy young adults (four women) were studied on three occasions in random sequence: 1) cycle exercise ( approximately 70% peak oxygen consumption) from 0830 to 0930 h and from 1200 to 1300 h on day 1 and hyperinsulinemic (2.0 mU x kg(-1) x min(-1)) stepped hypoglycemic (85, 75, 65, 55, and 45 mg/dl) clamps on day 2, 2) rest on day 1 and identical hypoglycemic clamps on day 2, and 3) hyperinsulinemic-euglycemic clamps. Exercise raised plasma cortisol concentrations to 16.9 +/- 1.9 (0930 h) and 16.6 +/- 1.6 microg/dl (1300 h) on day 1. Compared with rest on day 1, exercise on day 1 was associated with reduced epinephrine (P = 0.0113) responses-but not norepinephrine (P = 0.6270), neurogenic symptom (P = 0.6470), pancreatic polypeptide (P = 0.0629), or glucagon (P = 0.0436, but higher) responses-to hypoglycemia on day 2. However, the effect was small. (The final day 2 hypoglycemia epinephrine values were 765 +/- 106 pg/ml after rest on day 1 and 550 +/- 94 pg/ml after exercise on day 1 compared with 30 +/- 6 pg/ml during euglycemia.) These data are consistent with the hypothesis that the cortisol response to hypoglycemia mediates in part the reduced epinephrine response to subsequent hypoglycemia, one key component of HAAF in type 1 diabetes. However, the small effect suggests that an additional factor or factors may well be involved. These data do not support the hypothesis that the cortisol response to hypoglycemia mediates the reduced neurogenic symptom response to subsequent hypoglycemia, another key component of HAAF in type 1 diabetes.

Topics: Adult; Autonomic Nervous System; Blood Glucose; C-Peptide; Epinephrine; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemia; Male; Norepinephrine; Physical Exertion; Rest

Available basal insulin formulations do not provide a constant and reliable 24-h insulin supply. We compared the efficacy and safety of glargine (a long-acting insulin analog) and NPH insulins in insulin-naive type 2 diabetic patients treated with oral antidiabetic agents.. There were 426 type 2 diabetic patients (age 59 +/- 9 years, BMI 28.9 +/- 4.3 kg/m2, mean +/- SD) with poor glycemic control on oral antidiabetic agents randomized to treatment for 1 year with bedtime insulin glargine or bedtime NPH insulin. Oral agents were continued unchanged. The fasting blood glucose (FBG) target was 6.7 mmol/l (120 mg/dl).. Average glycemic control improved similarly with both insulins (HbA(1c), [reference range <6.5%] 8.3 +/- 0.1 vs. 8.2 +/- 0.1% at 1 year, glargine vs. NPH, mean +/- SEM, P < 0.001 vs. baseline for both). However, there was less nocturnal hypoglycemia (9.9 vs. 24.0% of all patients, glargine vs. NPH, P < 0.001) and lower post-dinner glucose concentrations (9.9 +/- 0.2 vs. 10.7 +/- 0.3 mmol/l, P < 0.02) with insulin glargine than with NPH. Insulin doses and weight gain were comparable. In patients reaching target FBG, HbA(1c) averaged 7.7 and 7.6% in the glargine and NPH groups at 1 year.. Use of insulin glargine compared with NPH is associated with less nocturnal hypoglycemia and lower post-dinner glucose levels. These data are consistent with peakless and longer duration of action of insulin glargine compared with NPH. Achievement of acceptable average glucose control requires titration of the insulin dose to an FBG target < or =6.7 mmol/l. These data support use of insulin glargine instead of NPH in insulin combination regimens in type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Cholesterol, HDL; Circadian Rhythm; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Antibodies; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Male; Middle Aged; Postprandial Period; Triglycerides

Non-obese type 2 diabetic subjects in good metabolic control (n=6, HbA1c 7.0 +/- 0.3%, mean diabetes duration: 5.7 +/- 1 years) and matched non-diabetic subjects (control; n = 6) were studied during hyperinsulinemic (approximately 3 nmol/l)-hypoglycemic (approximately 3.1 mmol/l) clamp tests (0-120 min) and the subsequent recovery period (120-240 min). Plasma glucagon rose gradually but not significantly, whereas norepinephrine and epinephrine similarly increased approximately 2 and approximately 25-fold in both groups. Islet amyloid polypeptide (IAPP) decreased to approximately 41% and approximately 24% of basal values during hypoglycemia and rapidly rose approximately 4.7-fold during the recovery period, while plasma C-peptide remained suppressed in both groups. Within 140 min, plasma free fatty acids similarly decreased to approximately 70 micromol/l (p < 0.05), but then rose to values being approximately 50% higher in diabetic than in control subjects (240 min: 907 +/- 93 vs. 602 +/- 90 micromol/l; p < 0.05). Glucose infusion rates were comparable during hypoglycemia, but approximately 40% lower during recovery in diabetic patients (1.88 +/- 0.27 vs. 3.44 +/- 0.27 mg x kg(-1) x min(-1), p < 0.001). These results demonstrate that (i) hypoglycemia induced by high-dose insulin largely abolishes the counterregulatory response of glucagon, but not of catecholamines in nondiabetic and well-controlled type 2 diabetic subjects, (ii) the rapid posthypoglycemic increase of plasma IAPP occurs independently of plasma insulin, and (iii) the superior rise in plasma free fatty acids may account at least in part for the posthypoglycemic insulin resistance of type 2 diabetic patients.

Topics: Adult; Amyloid; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Epinephrine; Fatty Acids, Nonesterified; Glucose Clamp Technique; Hormones; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Male; Norepinephrine

To determine the safety and efficacy of the long-acting insulin analog, insulin glargine, as a component of basal bolus therapy in patients with type 1 diabetes.. Patients with type 1 diabetes receiving basal-bolus insulin treatment with NPH human insulin and insulin lispro were randomized to receive insulin glargine (HOE 901), a long-acting basal insulin analog, once a day (n = 310) or NPH human insulin (n = 309) as basal treatment with continued bolus insulin lispro for 16 weeks in an open-label study NPH insulin patients maintained their prior schedule of administration once or twice a day, whereas insulin glargine patients received basal insulin once a day at bedtime.. Compared with all NPH insulin patients, insulin glargine patients had significant decreases in fasting blood glucose measured at home (means +/- SEM, -42.0 +/- 4.7 vs. -12.4 +/- 4.7 mg/dl [-2.33 +/- 0.26 vs. -0.69 +/- 0.26 mmol/l]; P = 0.0001). These differences were evident early and persisted throughout the study More patients in the insulin glargine group (29.6%) than in the NPH group (16.8%) reached a target fasting blood glucose of 119 mg/dl (< 6.6 mmol/l). However, there were no differences between the groups with respect to change in GHb. Insulin glargine treatment was also associated with a significant decrease in the variability of fasting blood glucose values (P = 0.0124). No differences in the occurrence of symptomatic hypoglycemia, including nocturnal hypoglycemia, were observed. Overall, adverse events were similar in the two treatment groups with the exception of injection site pain, which was more common in the insulin glargine group (6.1%) than in the NPH group (0.3%). Weight gain was 0.12 kg in insulin glargine patients and 0.54 kg in NPH insulin patients (P = 0.034).. Basal insulin therapy with insulin glargine once a day appears to be as safe and at least as effective as using NPH insulin once or twice a day in maintaining glycemic control in patients with type 1 diabetes receiving basal-bolus insulin treatment with insulin lispro.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Therapy, Combination; Ethnicity; Fasting; Female; Humans; Hypoglycemia; Insulin; Insulin Glargine; Insulin Lispro; Insulin, Isophane; Insulin, Long-Acting; Male; United States

Glargine, a product of recombinant technology, has different structural and physicochemical properties compared with native human insulin. We determined whether such differences are associated with alterations in the responses to hypoglycaemia induced by glargine.. Nineteen adults (six healthy and 13 with type 1 diabetes) underwent a 5-h hyperinsulinaemic (2 mU/kg/min(-1)) stepped hypoglycaemic clamps (hourly targets of 4.7, 4.2, 3.6, 3.1 and 2.5 mmol/l, respectively) on two occasions using intravenous infusion of regular human insulin or glargine, in random sequence. Hypoglycaemic symptoms, counter-regulatory hormones and glucose disposal rates were assessed at intervals throughout the clamps. A 1-week 'wash out' period was observed between studies.. The peak total symptoms scores (mean +/- s.e.m.) at nadir blood glucose (2.5 mmol/1) were 18.83 +/- 2.68 (healthy) and 17.46 +/- 3.62 (diabetic) during regular insulin, and 18.50 +/- 3.20 (healthy) and 19.08 +/- 3.83 (diabetic) during glargine infusion. The peak epinephrine levels during hypoglycaemia were 767.8 +/- 140.4 pg/ml (regular insulin) and 608.8 +/- 129.9 pg/ml (glargine) among healthy subjects, and 332.5 +/- 54.8 pg/ml (regular insulin) and 321.8 +/- 67.4 pg/ml (glargine) in diabetic patients. Diabetic patients had blunted glucagon responses during hypoglycaemia with either insulin. Both insulins also elicited similar rates of glucose disposal.. We conclude that insulin glargine and regular human insulin elicit comparable symptomatic and counter-regulatory hormonal responses during hypoglycaemia in healthy or diabetic subjects, and induce similar rates of glucose disposal. Since glargine is designed for subcutaneous (s.c.) use, it is possible (though unlikely) that our findings obtained using an intravenous protocol could differ from responses to hypoglycaemia induced by the s.c. route.

Topics: Adult; Blood Glucose; Blood Pressure; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Heart Rate; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Norepinephrine; Recombinant Proteins; Reference Values

An extrapancreatic effect of sulfonylureas has been postulated. However, in vivo results have been disputed because the amelioration of insulin action that follows sulfonylurea may represent the relief from glucose toxicity rather than a direct effect of the drug. Therefore, we studied the hypoglycemic action of gliclazide acutely and after 2 months of therapy in seven type 2 diabetic patients. All patients received a 240-minute i.v. glucose infusion with [3-3H]glucose. In a random order, 160 mg gliclazide (study 1) or placebo (study 2) was given orally before glucose infusion. Finally, the effect of 160 mg gliclazide was reassessed after a two-month treatment with the same sulfonylurea (80 mg t.i.d.). Basal plasma glucose, insulin, C-peptide and endogenous glucose production (EGP) were similar before the two initial studies. During glucose infusion, EGP was more suppressed after gliclazide in spite of comparable increase in plasma insulin and C-peptide. After the two-month therapy, basal plasma glucose levels and HbA1c were lower while plasma insulin and C-peptide were higher with respect to baseline (p < 0.05). Gliclazide further reduced plasma glucose, the incremental area above baseline, and EGP during glucose infusion, while plasma insulin and C-peptide achieved higher plateaus (p < 0.05). When data were pooled, plasma glucose concentration and EGP correlated both in the basal state (r = 0.71) and during the last hour of glucose infusion (r = 0.84; both p < 0.05). These data suggest that gliclazide enhances the suppression of EGP induced by insulin and that this effect is greater with chronic treatment because of concomitant improvement of insulin secretion.

Topics: Acute Disease; Blood Glucose; C-Peptide; Chronic Disease; Diabetes Mellitus, Type 2; Gliclazide; Gluconeogenesis; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kinetics; Middle Aged; Placebos; Regression Analysis; Time Factors; Tritium

Regular insulin given with the evening meal could contribute to the risk of nocturnal hypoglycemia in adolescents with type 1 diabetes using a multiple injection regimen. To test this hypothesis, we compared glucodynamics and free insulin levels on two separate study nights.. A total of 14 adolescents were recruited. On both nights, identical doses of regular insulin or insulin lispro were administered 30 min or 10 min, respectively, before the evening meal, using a double-blind randomized crossover study design. Doses of NPH insulin and carbohydrate content of the evening meal and snack were kept identical. Blood samples were taken every 15 min for blood glucose and every 60 min for free insulin and ketones.. After insulin lispro administration, glucose levels were significantly lower between the evening meal and the bedtime snack (analysis of variance [ANOVA] P = 0.02), and four hypoglycemic episodes were recorded. This corresponded to a higher (458 +/- 48 vs. 305 +/- 33 pmol/l, P = 0.02), earlier (64 +/- 4.6 vs. 103 +/- 12 min, P = 0.01), and shorter-lasting (245 +/- 21 vs. 365 +/- 39 min, P = 0.01) insulin peak in contrast to regular insulin. After the bedtime snack, glucose levels increased dramatically during the lispro night and stayed higher, up to 0300 in the morning (ANOVA P = 0.01), corresponding to lower mean insulin levels (146 +/- 20 vs. 184 +/- 27 pmol/l, P = 0.04). No differences were seen in glucose and insulin levels between 0300 and 0800. Four episodes of nocturnal hypoglycemia were documented after the bedtime snack during the regular insulin night, in contrast to one episode after insulin lispro. No differences in ketone levels were observed.. The replacement of regular insulin with insulin lispro may reduce the risk of late hypoglycemia, but redistribution of the evening carbohydrate may be needed to ensure good metabolic control and prevent early postprandial hypoglycemia.

Topics: Activity Cycles; Adolescent; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Drug Administration Schedule; Eating; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Lispro; Insulin, Isophane; Ketones; Life Tables; Male; Postprandial Period

Unmodified regular insulin has a long absorption tail, unlike the fast-acting insulin analog lispro, and may contribute to hypoglycemia in the early part of the night. A randomized crossover double-blind study was performed to compare blood glucose concentrations in the early part of the night in type 1 diabetic patients receiving lispro or unmodified regular human insulin, in random order, on 2 separate study days.. We studied 23 C-peptide-negative patients; 12 were using a premeal plus basal insulin regimen, and 11 were using twice-daily insulin injections. Patients were admitted to the investigation unit at 5:00 P.M. and received a single dose of lispro or unmodified regular human insulin before the evening meal. In both groups, the NPH insulin dose remained unchanged. Identical meals and snacks were eaten at the same time during both study days.. Average postprandial (6:00-10:00 P.M.) blood glucose concentrations were significantly lower after lispro therapy compared with human insulin (7.1 +/- 0.4 [SE] vs. 8.5 +/- 0.4 mmol/l, P = 0.0002). Nighttime (midnight to 4:00 A.M.) blood glucose concentrations were significantly higher after lispro compared with human insulin (10.3 +/- 0.4 vs. 9.1 +/- 0.4 mmol/l, P = 0.02). This difference was greatest in patients on the premeal plus basal insulin regimen (11.6 +/- 0.5 vs. 8.7 +/- 0.4 mmol/l, P < 0.001). The incidence of nocturnal hypoglycemia (midnight to 4:00 A.M., blood glucose < 3.5 mmol/l) was less with lispro compared with unmodified insulin (1 vs. 6 patients, P = 0.04). Nighttime (midnight to 4:00 A.M.) 3-hydroxybutyrate (102 +/- 13 vs. 51 +/- 7 mumol/l, P = 0.000) and glycerol (52 +/- 3 vs. 42 +/- 2 mumol/l, P < 0.01) were significantly higher after lispro therapy compared with human insulin in patients on the premeal plus bolus insulin regimen.. Lispro can improve postprandial blood glucose control and reduce the incidence of nocturnal hypoglycemia at the expense of nocturnal hyperglycemia and hyperketonemia in patients using a premeal plus basal insulin regimen.

Topics: Adult; Blood Glucose; C-Peptide; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Administration Schedule; Eating; Fasting; Female; Human Growth Hormone; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Lispro; Male; Postprandial Period

This study tested a simple algorithm for beginning insulin for obese patients with type 2 diabetes after sulfonylurea failure, comparing suppertime 70/30 insulin plus continued glimepiride with insulin alone.. This was a multicenter ambulatory randomized double-masked parallel comparison. There were 208 subjects with secondary failure to sulfonylureas who took glimepiride titrated to 8 mg b.i.d. for 8 weeks; 145 subjects with fasting plasma glucose (FPG) 180-300 mg/dl (10-16.7 mmol/l) on this treatment were randomized to placebo plus insulin (PI) or glimepiride plus insulin (GI) for 24 weeks. A dosage of 70/30 insulin before supper was titrated, seeking fasting capillary blood glucose (FBG) 120 mg/dl (6.7 mmol/l), equivalent to FPG 140 mg/dl (7.8 mmol/l). Outcome measures included FPG, HbA1c, insulin dosage, weight, serum insulin and lipids, and adverse events.. FPG and HbA1c were equivalent at baseline: 261 vs. 250 mg/dl (14.5 vs. 13.9 mmol/l), and 9.9 vs. 9.7%. At 24 weeks, the FPG target was achieved in both groups (136 vs. 138 mg/dl, 7.6 vs. 7.6 mmol/l), and HbA1c values were equal (7.7 vs. 7.6%). However, with GI, control improved faster and fewer subjects dropped out (3 vs. 15%, P < 0.01), and less insulin was needed (49 vs. 78 U/d, P < 0.001). The outcomes were alike in other respects. No subject had severe hypoglycemia.. Injection of 70/30 insulin before supper safely restored glycemic control of type 2 diabetes not controlled by glimepiride alone. Control was restored more rapidly and with less injected insulin when glimepiride was continued.

Topics: Aged; Blood Glucose; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Patient Dropouts; Sulfonylurea Compounds; Treatment Outcome; Triglycerides

Hypoglycemia is a serious complication of therapy for diabetes. Chronic hypoglycemia and the attendant decrease in quality of life have been rationales for advocating pancreas transplantation as an alternative treatment. However, reports have appeared that suggest that as high as 30-50% of pancreas transplant recipients have occasional symptoms of mild hypoglycemia. Therefore, we studied glucose and hormone levels in transplant recipients and healthy control subjects.. We studied glucose and hormone levels in transplant recipients reporting frequent symptoms of hypoglycemia (n = 10), transplant recipients without symptoms of hypoglycemia (n = 9), and healthy control subjects (n = 8) after a mixed meal and during a subsequent 24-h modified fast. All transplant recipients were insulin-independent; were receiving prednisone, cyclosporine, and azothioprine; and had functioning grafts with systemic venous drainage.. No significant differences were observed in the fasting glucose, insulin, C-peptide, or glucagon levels when comparing the symptomatic with the asymptomatic groups of patients who had undergone successful pancreas transplantation. Similarly, no significant differences were found in the immediate postprandial period after a mixed meal. However, during the subsequent 24-h fast, glucose levels fell lower in the symptomatic than in the asymptomatic group of patients receiving a transplanted pancreas (71+/-2 vs. 81+/-2 mg/dl, P < 0.002). During the fast, no significant differences were found in insulin, C-peptide, or glucagon levels when comparing asymptomatic to symptomatic groups. Of 10 symptomatic recipients of pancreas transplantation, 5 reported symptoms of hypoglycemia during the study. In four of these five subjects, the onset of symptoms corresponded to nadirs in serum glucose, which occurred at values 2 SD or more below the mean glucose observed for the control and the asymptomatic pancreas recipient groups. The serum glucose levels at the time of symptoms in these four subjects were 55, 66, 51, and 57 mg/dl. In each of these four subjects, symptoms abated and the glucose levels rose spontaneously without intervention. One of these four subjects had elevated insulin binding activity in his serum consistent with endogenous insulin antibodies. This individual had a serum glucose value of 55 mg/dl at the conclusion of the 24-h fast without symptoms.. Among a group of pancreas transplant recipients reporting frequent symptoms of hypoglycemia, some individuals demonstrated transient, symptomatic postprandial hypoglycernia. With the exception of one recipient with insulin antibodies, no evidence was found for hypoglycemia during fasting. Although postprandial hypoglycemia may occur in some pancreas transplant recipients, it does not appear to be a highly significant clinical problem.

Topics: Activities of Daily Living; Adult; Autoantibodies; Blood Glucose; C-Peptide; Diabetes Mellitus; Fasting; Female; Humans; Hypoglycemia; Insulin; Male; Pancreas Transplantation; Postprandial Period; Quality of Life

Lys(B28)Pro(B29) human insulin analogue (Lispro) is a newly developed monomeric insulin analogue with a rapid onset and short duration of action. The aim of the study was to compare the thresholds for the counterregulatory responses during a stepwise euglycaemic/hypoglycaemic clamp for insulin lispro (LP), human (H), and porcine (P) insulin in a randomized order in 12 healthy male volunteers (age 22.4 +/- 1.7 years, BMI 21.9 +/- 1.7 kg m-2). A euglycaemic period of 2 h was followed by three hypoglycaemic levels of 60 min each; from 150-210 min at 3.5 mmol l-1, 240-300 min at 3.0 mmol l-1 and 330-390 min at 2.5 mmol l-1. Plasma insulin levels during the 50 mU kg-1 h-1 infusions and blood glucose levels were not significantly different. The glucose requirements (mean +/- SD) during the last part of the euglycaemic period (90-120 min) tended to be higher during LP compared to those during H and P; 2239 +/- 702 and 1929 +/- 769, 1957 +/- 725 mg kg-1, P = 0.067, respectively. The thresholds (blood glucose level at which a sustained elevation of the counterregulatory hormones as compared to the mean at normoglycaemia level 4.0 mmol l-1, occurs) for the various hormones were very similar during LP, H, and P insulin infusions and occurred at 253.8 +/- 56.7, 256.3 +/- 55.3 and 257.5 +/- 70.0 min for adrenaline; 241.4 +/- 80.3, 260.5 +/- 82.5 and 225.0 +/- 75.9 min for noradrenaline; 307.5 +/- 65.5, 304.1 +/- 74.1 and 322.5 +/- 40.4 min for cortisol; 263.8 +/- 50.3, 255.0 +/- 63.6 and 249.6 +/- 50.9 min for growth hormone; 236.3 +/- 78.2, 200.0 +/- 73.1 and 226.3 +/- 65.5 for pancreatic polypeptide. The autonomic and neuroglycopenic symptoms were elicited at 240 and 300 min, respectively. In conclusion, our data indicate a tendency to a higher biological activity of approximately 10% for Lispro insulin. During a stepwise euglycaemic/hypoglycaemic clamp, the counterregulatory hormone responses to insulin lispro, human insulin, and porcine insulin were similar.

Topics: Adult; Animals; Blood Glucose; Blood Pressure; C-Peptide; Epinephrine; Glucose Clamp Technique; Heart Rate; Homeostasis; Hormones; Human Growth Hormone; Humans; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Lispro; Male; Norepinephrine; Pancreatic Polypeptide; Recombinant Proteins; Reference Values; Swine; Time Factors

This study compared the effect of mild exercise while fasting on plasma glucose concentrations in subjects with NIDDM treated with extended-release glipizide and subjects not taking an oral hypoglycemic agent.. Twenty-five moderately obese subjects with NIDDM were randomized to treatment with extended-release glipizide or placebo. After 9 weeks of treatment, they fasted overnight, took their study drug, omitted breakfast, and exercised on a treadmill for 90 min. Glucose, insulin, and C-peptide concentrations were measured before, during, and after exercise.. On the fasting-exercise day, fasting glucose concentrations were lower (153 vs. 241 mg/dl, P < 0.01) and insulin and C-peptide concentrations higher in the extended-release glipizide group. The decrement of glucose from the fasting baseline was modest and equivalent in the two groups: 17 vs. 21 mg/dl at the end of exercise and 28 vs. 27 mg/dl after 2 h of recovery. No subject had hypoglycemic symptoms.. Chronic use of extended-release glipizide does not enhance the hypoglycemic effect of fasting plus mild exercise for people with NIDDM. Routine lifestyle treatments for NIDDM may be continued during ongoing use of this agent.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise; Exercise Test; Female; Glipizide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Time Factors

The hormonal responses to, and symptoms of, hypoglycaemia were investigated in 19 diabetic children (mean age 14.2 (SD 1.4) years, mean HbA1c 9.8 (SD 1.2)%) and 16 non-diabetic children (14.4(1.0) years) during a gradual reduction in plasma glucose with the glucose clamp technique. Plasma glucose was reduced from approximately 5.7 to approximately 2.6 mmol l(-1) in the diabetic children and from approximately 5.7 to approximately 2.9 mmol l(-1) in the non-diabetic children over 200 min. The mean glycaemic thresholds for adrenaline, and for autonomic and total symptom score, were similar in the diabetic and non-diabetic groups, and were found at plasma glucose levels between 3.4 and 3.7 mmol l(-1). The mean glucose levels which elicited increase of cortisol, growth hormone, and glucagon were lower (p < 0.01), and the mean incremental responses of adrenaline, cortisol, and glucagon were smaller in the diabetic than in the non-diabetic children. In the diabetic children, a correlation was found between Body Mass Index (BMI) and the hypoglycaemic thresholds for autonomic and total symptom scores (r = 0.64, p < 0.01 and r = 0.72, p = 0.001, respectively). We conclude that counterregulatory hormone responses are attenuated in diabetic as compared to non-diabetic children, whereas recognition of autonomic symptoms is similar in the two groups. Diabetic children with a higher BMI seem to have increased awareness of a declining plasma glucose level.

Topics: Adolescent; Blood Glucose; Body Mass Index; C-Peptide; Child; Diabetes Mellitus; Diabetes Mellitus, Type 1; Epinephrine; Female; Glucagon; Glucose; Glucose Clamp Technique; Glycated Hemoglobin; Growth Hormone; Hormones; Humans; Hydrocortisone; Hypoglycemia; Insulin; Male; Norepinephrine; Time Factors

The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range = 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4. 55+/-0.06 vs. 4.75+/-0.06 mM; P = 0.038) and endogenous glucose production (11.3+/-0.4 vs. 12.9+/-0.5 micromol/[kg.min]; P = 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83+/-5 and 92+/-5% of basal), but it did not in LTx subjects (66+/-7%; P < 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1) suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulin-induced glucagon suppression detectable in CU and

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Central Nervous System; Denervation; Glucagon; Glucose Clamp Technique; Growth Hormone; Homeostasis; Humans; Hydrocortisone; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Resistance; Liver; Liver Transplantation; Middle Aged; Models, Biological; Somatostatin; Time Factors

Recent studies indicate that C-peptide, when given to patients with insulin-dependent (Type 1) diabetes mellitus (IDDM), exerts significant effects on microvascular and neuronal functions. Adjuvant therapy with C-peptide has been advocated in the treatment of IDDM patients. Since endogenous insulin secretion is believed to be of importance for the alpha-cell function, we addressed the issue whether C-peptide given acutely interferes with the responses to hypoglycaemia. Seven IDDM patients were randomly exposed to hypoglycaemia with and without exogenous C-peptide. Insulin and and C-peptide were given intravenously in equimolar amounts for 3 hours. The decrease of blood glucose was faster and more pronounced during C-peptide infusion, yielding a significantly lower AUC 0-180 min of blood glucose (38.5 +/- 1.6 vs 44.4 +/- 2.2 mmol l(-1)h(-1); p = 0.032). No difference between the two experiments was found concerning glucagon when the AUC, delta-values or levels at separate points of time were calculated. In conclusion, the main finding of this study was that exogenous C-peptide, given acutely, gave rise to a more rapid onset of hypoglycaemia yielding no detectable differences with respect to the response of glucagon and other counterregulatory hormones.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Epinephrine; Female; Glucagon; Humans; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Male; Pilot Projects; Radioimmunoassay

To test the hypothesis that glycemic thresholds for hypoglycemic cognitive dysfunction, like those for neuroendocrine responses to and symptoms of hypoglycemia, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia, 16 healthy young adult subjects (7 women and 9 men) were studied on two separate occasions in random sequence, once with hyperinsulinemic hypoglycemia (2.6 +/- 0.1 mmol/l, 47 +/- 1 mg/dl) and once with otherwise identical hyperinsulinemic euglycemia (4.8 +/- 0.1 mmol/l, 86 +/- 5 mg/dl) between 1430 and 1630. Neuroendocrine, symptomatic, and cognitive responses to hyperinsulinemic stepped hypoglycemic (4.7, 4.2, 3.6, 3.0, 2.8, 2.5, and 2.2 mmol/l; 85, 75, 65, 55, 50, 45, and 40 mg/dl) clamps were quantitated the following morning on both occasions. Cognitive function tests included measures of information processing (Serial Addition), attention (Stroop Arrow Word), pattern recognition and memory (Delayed Non-Match to Sample), and declarative memory (Paragraph Recall). As expected, plasma glucagon (P = 0.0094), epinephrine (P = 0.0063), and pancreatic polypeptide (P = 0.0046) responses to stepped hypoglycemia were reduced significantly, and symptomatic responses tended to be reduced after afternoon hypoglycemia. Performance on the cognitive function tests deteriorated (P < 0.0001) during stepped hypoglycemic clamps, but there were no significant overall effects of antecedent hypoglycemia on hypoglycemic cognitive dysfunction. Although deterioration was reduced (P < 0.05) from the 2.8 mmol/l (50 mg/dl) to the 2.5 mmol/l (45 mg/dl) steps on the Serial Addition and Delayed Non-Match to Sample tasks after afternoon hypoglycemia, comparable differences were not found on the Stroop Arrow Word or Paragraph Recall tasks. Thus, glycemic thresholds for hypoglycemic cognitive dysfunction, unlike those for neuroendocrine responses to and symptoms of hypoglycemia, do not seem to shift to substantially lower plasma glucose concentrations after recent antecedent hypoglycemia in nondiabetic humans.

Topics: Adolescent; Adult; Blood Glucose; Body Composition; C-Peptide; Circadian Rhythm; Cognition; Female; Glucagon; Humans; Hypoglycemia; Insulin; Male; Norepinephrine; Pancreatic Polypeptide; Time Factors

We report on the results of a one-year, multicenter, randomized, double-blind, parallel-group titration study of the new sulfonylurea agent, glimepiride, versus use of non-micronized glyburide to treat 577 patients with non-insulin dependent diabetes mellitus (NIDDM). Similar decreases in both fasting plasma glucose and HbA1C were found using glimepiride and glyburide. There was a lower incidence of hypoglycemia with glimepiride than glyburide.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Sulfonylurea Compounds

The effects of exercise on metabolic control in type II diabetic patients given glimepiride or glibenclamide were studied in a multinational phase II clinical trial (14 centers in 4 countries). A total of 167 type II diabetic out-patients (117 men, 50 women) completed the trial as planned. The study was of parallel group, 2 x 2 factorial design: patients were first stabilized in a randomized, double-blind manner on 3 mg of glimepiride or 10 mg of glibenclamide treatment once daily over 14-28 days and were then assigned in randomized open fashion to a group with or without exercise. Exercise consisted of riding a bicycle ergometer for 1 hour at pulse rate 120 beats per minute. Three-hour blood glucose, insulin, and C-peptide profiles were made after the stabilization phase (baseline profiles) and 7 days later with or without exercise (endpoint profiles). Pairwise comparisons of changes in blood glucose AUC/1-3 h revealed a statistically significant decrease in patients who exercised vs those who did not, which was comparable for both sulfonylureas used. There was a statistically significant decrease in C-peptide AUC/1-3 h and insulin AUC/1-3 h in the glimepiride exercise group vs the glimepiride group without exercise. Physical exercise did not lead to statistically significant changes in C-peptide AUC/1-3 h and insulin AUC/1-3 h under glibenclamide treatment. In conclusion, a blood-glucose-lowering response to acute exercise was demonstrated in type II diabetic patients treated with either sulfonylurea, but a significant suppression of endogenous insulin secretion was observed for glimepiride only.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise; Female; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Sulfonylurea Compounds

Arginine vasopressin (AVP) hypersecretion in response to metoclopramide or to insulin-induced hypoglycaemia has been described in type I diabetes mellitus. In the present study, we examined whether residual endogenous insulin secretion may play a role in the control of this abnormal AVP secretory pattern. For this purpose, 21 insulin-dependent diabetic men and 10 age- and weight-matched normal men were tested with MCP (20 mg in an i.v. bolus). On a different occasion, subjects were tested with insulin (0.15 IU kg-1). The diabetic patients were subdivided into C-peptide negative patients (CpN, 11 patients without detectable endogenous pancreatic beta cell activity) (group I) and C-peptide positive patients (CpP, 10 patients with residual endogenous insulin secretion) (group II). Experiments started after optimization of the metabolic status of the diabetic men by 3 days of treatment with continuous subcutaneous insulin infusion. The basal concentrations of AVP were similar in all groups. The administration of MCP induced a striking elevation in plasma AVP levels in the normal controls and in the diabetic subjects of groups I and II. However, the AVP rise was significantly higher in group I and group II than in normal controls. Furthermore, group I diabetics showed higher AVP increments than group II. Insulin induced a similar hypoglycaemic nadir in all subjects at 30 min, even though the diabetic subjects of groups I and II had a delayed recovery in blood glucose levels. The hypoglycaemic pattern was similar in group I and II. Hypoglycaemia induced a striking AVP increase in the normal controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Antiemetics; Arginine Vasopressin; C-Peptide; Diabetes Mellitus, Type 1; Humans; Hypoglycemia; Insulin; Male; Metoclopramide

Combination therapy with insulin and sulphonylurea has gained acceptance in management of subjects with Type 2 (non-insulin-dependent) diabetes mellitus. However, its role in management of Type 1 (insulin-dependent) diabetes mellitus remains controversial. In this study, the effect of combination therapy with insulin and glibenclamide on metabolic control, daily insulin dosage, and insulin sensitivity was assessed in subjects with Type 1 diabetes mellitus. Ten men with Type 1 diabetes mellitus participated in a randomized, double-blind, crossover, clinical trial with three treatment regimens, namely (1) insulin alone, (2) insulin and placebo, (3) insulin and glibenclamide, each lasting 3 months. Combination therapy induced: (1) reduction in daily insulin dosage; (2) more uniform blood glucose control as reflected by a lower average 24 h blood glucose level, a smaller difference between mean preprandial and 2 h postprandial blood glucose concentrations, decreased 24 h urine glucose excretion, and a decline in number of hypoglycaemic events; (3) improved insulin sensitivity as expressed by more rapid plasma glucose disappearance rate, without a significant alteration in fasting plasma glucagon and 1h postprandial serum C-peptide levels; when compared with treatment with either insulin alone or with insulin and placebo. Therefore, it is apparent that the addition of glibenclamide to insulin reduces daily insulin dosage and renders a greater uniformity to diurnal blood glucose control, most probably secondary to enhancement of insulin sensitivity.

Topics: Adult; Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Drug Therapy, Combination; Glucagon; Glyburide; Glycated Hemoglobin; Glycosuria; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Placebos; Triglycerides

The relationship between the increase in adrenomedullary catecholamine secretion and the sympathetic response to hypoglycemia is not well understood in humans. To explore this relationship more closely, we directly muscle sympathetic nerve activity (MSNA) in control subjects and in insulin-dependent diabetes mellitus (IDDM) subjects without clinically evident diabetic complications.. Twelve IDDM subjects (22.5 +/- 3.9 years of age, diabetes duration of 9.8 +/- 8.3 years) and 12 age-matched control subjects were studied. MSNA was measured during insulin infusion (720 pM.m-2.min-1) with 30-min periods of 1) euglycemia, 2) hypoglycemia (target plasma glucose, 2.8 mM), and 3) recovery. The effect of increased insulin dose (1,440 pM.m-2.min-1) was studied in six subjects in each group, and the effect of prolonged hypoglycemia (1 h) was studied in five IDDM subjects and four control subjects.. MSNA levels increased in IDDM and control subjects, 31 +/- 8 and 29 +/- 6%, respectively, above euglycemia during hypoglycemia and returned to euglycemic levels during recovery. MSNA levels during hypoglycemia were lower in IDDM subjects than in control subjects (26 +/- 3 vs. 35 +/- 2 bursts/min, P < 0.01). Importantly, no relationships were found between the MSNA and epinephrine responses to hypoglycemia in either group. Increasing the insulin infusion rate did not alter the MSNA response to hypoglycemia. During prolonged hypoglycemia, MSNA remained elevated above euglycemic levels throughout hypoglycemia.. These results demonstrate that insulin-induced hypoglycemia increases muscle sympathetic neural outflow in IDDM and control subjects. The lack of correlation between the MSNA and epinephrine responses to hypoglycemia indicates that the adrenomedullary and peripheral sympathetic responses to hypoglycemia are independently mediated.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemia; Muscles; Reference Values; Sympathetic Nervous System; Time Factors

To test the hypothesis that differing physiological insulin levels can modify the counter-regulatory response to prolonged hypoglycemia, experiments were carried out in 10 healthy male subjects. Insulin was infused subcutaneously for 8 h in two separate randomized protocols, so that steady-state levels of 132 +/- 6 pM (low) and 402 +/- 18 pM (high) were obtained. The fall in plasma glucose was controlled by the glucose-clamp technique. Plasma glucose fell slowly and similarly in both groups, reaching an identical steady-state (final 120 min of each study) level of 3.4 +/- 0.1 mM. Steady-state plasma epinephrine (2.5 +/- 0.4 vs. 1.5 +/- 0.2 nM) and norepinephrine (1.5 +/- 0.2 vs. 1.1 +/- 0.1 nM) were significantly (P < 0.05) greater during high- compared with low-dose insulin infusions. Plasma glucagon was reduced during high compared with low infusions (104 +/- 9 vs. 150 +/- 19 ng/l, P < 0.05). Growth hormone, cortisol, and pancreatic polypeptide increased significantly but were not different during the two insulin infusions. Hepatic glucose production (HGP) was equal during the steady-state period (8.4 +/- 1.0 mumol.kg-1.min-1) of each infusion. Blood lactate levels (1,255 +/- 73 vs. 788 +/- 69 mumol/l, P < 0.02) were increased in high compared with low, but nonesterified fatty acid (205 +/- 43 vs. 579 +/- 65 mumol/l) and 3-hydroxybutyrate (40 +/- 36 vs. 159 +/- 51 mumol/l) were reduced (P < 0.002) during the high-compared with low-dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Cardiovascular System; Glucose; Glucose Clamp Technique; Hormones; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Kinetics; Liver; Male

Suspected postprandial (reactive or idiopathic) hypoglycemia is characterized by predominantly adrenergic symptoms appearing after meals rich in carbohydrates and by their rare association with low blood glucose level (< 2.77 mmol/L). We studied heart rate, blood pressure, plasma insulin, C-peptide, and catecholamine responses during a 5-h oral glucose tolerance test in eight patients with suspected postprandial hypoglycemia and eight age-, sex-, and body mass index-matched healthy controls. We also evaluated beta-adrenergic sensitivity by using the isoproterenol sensitivity test. Psychological profile was assessed by the Symptom Checklist (SCL-90R) self-report symptom inventory. Patients with suspected postprandial hypoglycemia had higher beta-adrenergic sensitivity (defined as the dose of isoproterenol required to increase the resting heart rate by 25 beats/min) than controls (mean +/- SEM, 0.8 +/- 0.13 vs. 1.86 +/- 0.25 microgram isoproterenol; P = 0.002). After administration of glucose (75 g) blood glucose, plasma C-peptide, plasma epinephrine, and plasma norepinephrine responses were identical in the two groups, but plasma insulin was higher in the patients (group effect, P = 0.02; group by time interaction, P = 0.0001). Both heart rate and systolic blood pressure were significantly higher (but remained in the normal range) after glucose administration in patients with suspected postprandial hypoglycemia than in controls (group by time interactions, P = 0.004 and 0.0007, respectively). After glucose intake, seven patients had symptoms (palpitations, headache, tremor, generalized sweating, hunger, dizziness, sweating of the palms, flush, nausea, and fatigue), whereas in the control group, one subject reported flush and another palpitations, tremor, and hunger. Analysis of the SCL-90R questionnaire revealed that patients had emotional distress and significantly higher anxiety, somatization, depression, and obsessive-compulsive scores than controls. We may conclude that patients with suspected postprandial hypoglycemia have normal glucose tolerance, increased beta-adrenergic sensitivity, and emotional distress.

Topics: Adult; Blood Glucose; Blood Pressure; C-Peptide; Catecholamines; Eating; Female; Glucose; Glucose Tolerance Test; Heart Rate; Humans; Hypersensitivity; Hypoglycemia; Insulin; Isoproterenol; Male; Receptors, Adrenergic, beta; Stress, Psychological

Hypoglycemic symptoms have been reported by more than half of pancreas transplantation (PTX) recipients. To better understand the mechanism for the hypoglycemia documented in some of these patients, we studied the glucose and pancreatic hormone response to Sustacal in patients with and without hypoglycemia following PTX.. Twelve patients with established, repeated episodes of hypoglycemia following PTX (hypo) were case-matched to PTX recipients without hypoglycemic symptoms (control; n = 7). On the day of the study, fasting glucose, free and total immunoreactive insulin (IRI), C-peptide, proinsulin, and glucagon were drawn (time 0); Sustacal was administered; and glucose, free and total IRI, and C-peptide were assayed at 15, 30, 45, 75, 120, 150, 180, and 240 min. Based on the glucose response to Sustacal, the hypo group was further divided into those whose glucose rose after Sustacal (hypo-high; n = 7) and those with no increase in glucose from baseline concentration (hypo-flat; n = 5).. Before the administration of Sustacal, the hypo-high group had a lower fasting free/total IRI (0.26 +/- 0.06, mean +/- SE) than the hypo-flat (0.51 +/- 0.02) or control (0.52 +/- 0.04) groups (both P < 0.05 compared with hypo-high). The glucose response to Sustacal was greatest in the hypo-high group as defined. Area under the curve (AUC) for total IRI following Sustacal was also greatest in the hypo-high group (P < 0.05 compared with both control and hypo-flat groups), but there was no significant difference in free IRI AUC following Sustacal between the three groups. Two individuals developed hypoglycemia during the Sustacal challenge, both in the hypo-high group.. The lower fasting free/total IRI ratio and greater increase in glucose and total IRI in response to Sustacal in the hypo-high group compared with either the hypo-flat or control groups are consistent with the presence of significant quantities of anti-insulin antibodies in the hypo-high group. Because anti-insulin antibodies are, in turn, an established cause of episodic hypoglycemia, this study provides the first data to support the hypothesis that significant quantities of anti-insulin antibodies are a cause of symptomatic hypoglycemia following PTX in some recipients.

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Female; Food, Formulated; Glucagon; Humans; Hypoglycemia; Insulin Antibodies; Male; Pancreas Transplantation; Precipitin Tests; Proinsulin; Sucrose

Topics: Biological Availability; Blood Glucose; C-Peptide; Carrier Proteins; Humans; Hydrocortisone; Hypoglycemia; Injections, Subcutaneous; Insulin; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Pituitary Gland, Anterior; Pituitary Hormones

New treatment options are needed for glycemic control in NIDDM. We evaluated the effects of bedtime or morning insulin treatment, combined with daytime glyburide or given alone.. Twenty-nine male patients with NIDDM, mean age 63 +/- 1.7 yr, body weight 124 +/- 2.98% of DBW, received a maximum glyburide dose (20 mg/day) for a minimum of 6 wk, to confirm sulfonylurea failure. Human lente insulin was added for 12 wk either AM (n = 14) or HS (n = 15) and adjusted to obtain fasting euglycemia (FPG; combination treatment phase). Glyburide was then stopped, and insulin was continued for 6 wk, aiming for normal FPG (insulin phase).. After combination treatment phase, FPG decreased (P < 0.02) from 12.43 +/- 0.68 to 5.73 +/- 0.65 mM (AM) and from 12.68 +/- 0.76 to 5.51 +/- 0.48 mM (HS) (AM vs. HS, NS). Postbreakfast, presupper, and 0200 AM plasma glucose levels fell equally (P < 0.02) except for 1-h postprandial (AM 12.46 +/- 0.51 mM, HS 10.88 +/- 0.62 mM, AM vs. HS, P < 0.1). Mean HBA1c fell similarly in both AM and HS groups. At 2 wk of the insulin phase, FPG was higher in AM than HS, 9.8 +/- 0.76 vs. 7.56 +/- 0.7 mM (P < 0.1). At the end of insulin phase, plasma glucose levels were similar to the end of combination treatment phase, but the insulin dose had to be raised in AM by 39% (P < 0.02) and HS by 30% (P < 0.05). After the combination treatment phase, fasting C-peptide was significantly suppressed in HS group only, from 1.22 +/- 0.12 to 0.82 +/- 0.09 nM (P < 0.02). At the end of insulin phase, fasting C-peptide was further suppressed in both groups, but 2-h postprandial C-peptide levels decreased significantly in AM group only, from 1.85 +/- 0.23 to 1.42 +/- 0.13 nM (P < 0.02). Triglycerides and total and HDL cholesterol did not change significantly after either combination treatment phase or insulin phase. Mean weight gain was 6.5 lb during combination treatment phase (NS from baseline), without further change during insulin phase. Hypoglycemic reactions, all mild, were recorded at a rate of 1.35/patient in the AM group and 0.4/patient in the HS group (P < 0.025).. Normal fasting glycemia and near-normal postprandial glucose profile could be obtained with combination therapy in NIDDM. Results were similar if insulin, alone or in combination with glyburide, was given before breakfast or at bedtime, but hypoglycemic reactions were more common with conventional morning insulin injections.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Fasting; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin, Long-Acting; Male; Middle Aged; Recombinant Proteins; Time Factors

To test the hypothesis that, in contrast to administration of glucose or glucagon, administration of the amino acid Ala or of the beta 2-adrenergic agonist terbutaline produces sustained glucose recovery from hypoglycemia.. We developed a model of clinical hypoglycemia using subcutaneous injection of insulin (0.15 U/kg) in patients with IDDM. In comparison with nondiabetic subjects, patients with IDDM exhibited reduced glucagon (P = 0.0001), epinephrine (P = 0.0060), and pancreatic polypeptide (P = 0.0001) responses to hypoglycemia. In addition to placebos, the following were administered during hypoglycemia (2 h after insulin injection) in IDDM patients: oral glucose, 10 and 20 g; subcutaneous glucagon, 1.0 mg; oral Ala, 40 g; oral terbutaline, 5.0 mg; and subcutaneous terbutaline, 0.25 mg.. Glucose (10 and 20 g) and glucagon raised plasma glucose (P = 0.0163, 0.0060, and 0.0001, respectively) from 3.0-3.3 mM to peaks of 5.4 +/- 0.4, 6.8 +/- 0.7, and 11.8 +/- 0.8 mM within 30, 45, and 60 min, respectively, but the responses were transient. Oral Ala raised glucose levels (P = 0.0401) to 4.0 +/- 0.4 mM within 30 min; glucose levels then rose gradually to a 6-h value of only 7.1 +/- 0.9 mM. Oral terbutaline raised glucose levels (P = 0.0294) to 4.3 +/- 0.3 mM within 30 min; glucose levels then rose substantially. In contrast, subcutaneous terbutaline raised glucose levels (P = 0.0249) to 3.7 +/- 0.1 mM within 15 min; the levels plateaued at 5.0 mM from approximately 60-150 min and then paralleled the placebo curve.. Ala and terbutaline produce sustained glucose recovery from hypoglycemia in IDDM and are therefore potentially useful agents for the treatment of mild or moderate iatrogenic hypoglycemia, or the prevention of iatrogenic hypoglycemia, when food intake is not anticipated over the following several hours.

Topics: 3-Hydroxybutyric Acid; Administration, Oral; Alanine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Humans; Hydroxybutyrates; Hypoglycemia; Injections, Subcutaneous; Insulin; Lactates; Pancreatic Polypeptide; Terbutaline; Time Factors

1. To assess the influence of counterregulatory hormones, independently of neuroglycopaenia, on higher cerebral (cognitive) function, 'hypoglycaemic' warning symptoms and glucose kinetics, 10 healthy subjects participated in two hyperinsulinaemic (2 m-units min-1 kg-1) glucose clamp studies. After 100 min of euglycaemia (plasma glucose level 5 mmol/l), the plasma glucose level was either (a) maintained at 5 mmol/l for 120 min by glucose infusion with concomitant replacement of counterregulatory hormones (continuous infusions of glucagon, adrenaline, noradrenaline, cortisol and growth hormone) to mimic the hormonal milieu normally associated with hypoglycaemia (hormone infusion study) or (b) lowered to 2.8 mmol/l for 120 min (hypoglycaemia study). Assessments were made of cognitive function (P300 auditory evoked responses), symptoms (visual analogue scales) and glucose kinetics (3-[3H]glucose). 2. Hypoglycaemia was associated with an increase in all symptoms (facial flushing, palpitations, tingling, trembling, sweating, hunger, light-headedness and sleepiness, P < 0.01) and all subjects were aware that blood glucose levels had fallen. P300 evoked potential latency increased from 280 +/- 6 to 312 +/- 5 ms (mean +/- SEM, P < 0.01). In contrast, P300 latency and several individual symptoms (hunger, facial flushing, sweating and light-headedness) did not change from baseline during the hormone infusion study (P < 0.05 versus hypoglycaemia). Hepatic glucose production was lower (1.5 +/- 0.4 versus 2.3 +/- 0.3 mg min-1 kg-1, P < 0.05) and peripheral glucose uptake was higher (7.4 +/- 1.0 versus 5.6 +/- 0.6 mg min-1 kg-1, P < 0.01) during infusion of the hormones compared with during hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Awareness; Blood Glucose; C-Peptide; Cognition; Female; Glucose; Hormones; Humans; Hypoglycemia; Insulin; Kinetics; Liver; Male

In order to prevent nocturnal hypoglycaemia in patients with insulin-dependent diabetes mellitus with complex carbohydrates a pilot-study was designed with nine children with ages of 9-18 years. The children were admitted twice to the hospital (control and test) and remained the evening, night and morning the following day. The standard evening snack, given on the control day, was replaced on the test day by a test snack which contained a solution of uncooked cornstarch as a source of complex carbohydrates. The carbohydrate content of the test snack was maintained but did not contain mono- and disaccharides. Blood samples were collected and when the child had blood glucose concentrations of < or = 3.0 mmol/l or showed clinical symptoms of impending hypoglycaemia, intervention occurred with extra carbohydrates. Six out of nine children needed intervention after the standard snack (blood glucose concentrations were 1.8, 2.7, 3.0, 3.6 and 3.7 mmol/l). After the test snack this was four out of nine (blood glucose concentrations were 2.3, 2.6, 3.2 and 3.2). Three children needed a second intervention after the standard snack versus two after the test snack. One child needed a third intervention after the standard snack. The time of intervention ranged from 11 p.m. to 4 a.m. and from 10 p.m. to 12 a.m., respectively, on the day of the standard and test snack. Raw cornstarch, as a source of complex carbohydrates, did not prevent nocturnal hypoglycaemia in the dose used but blood glucose levels dropped more slowly than those after the standard snack.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Child Nutritional Physiological Phenomena; Diabetes Mellitus, Type 1; Dietary Carbohydrates; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Male; Starch; Time Factors

The problem of fasting hyperglycaemia remains unresolved on currently used twice-daily injection regimens. Human ultralente insulin is of longer duration than human lente and differs from it only in the nature of the zinc-insulin complex. In a 6-month double-blind crossover study these insulins were compared in 66 patients who were randomized to human ultralente or human lente insulin given together with human soluble insulin in a twice-daily injection regimen. Patients were seen monthly and crossed over after 3 months treatment. Fasting blood glucose concentrations on the ultralente regimen were considerably lower than on the lente regimen, the difference being statistically significant (6.6 +/- 0.5 vs 8.2 +/- 0.5 mmol l-1, p less than 0.05), but only present in those patients with fasting concentrations below the median. Glycosylated haemoglobin was identical on both regimens (9.3 +/- 0.2%). The evening ultralente dose was slightly but significantly lower than the evening lente dose (14.9 +/- 0.8 vs 15.5 +/- 0.8 U, p less than 0.05) thus endorsing the lowering effect of ultralente on the fasting blood glucose concentration. However, the incidence of serious hypoglycaemic events was higher on the ultralente regimen (0.38 +/- 0.10 vs 0.09 +/- 0.04 events per patient-month, p less than 0.02), the majority of nocturnal events occurring between 0500 h and breakfast. We conclude that ultralente insulin can give an improved fasting blood glucose concentration but that in those patients with more marked fasting hyperglycaemia or with a nocturnal hypoglycaemia problem it offers no clinical advantage over human lente insulin in a twice-daily injection regimen.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin, Long-Acting; Male; Middle Aged; Recombinant Proteins

Since ultralente insulin pharmacokinetics suggest faster absorption by human insulin when compared with bovine insulin using the subcutaneous route, the safety and efficacy of human ultralente in the outpatient setting was evaluated. Twenty type I patients participated in a randomized study using a crossover design of four six-week phases: (a) one daily injection of human ultralente; (b) two daily injections of human ultralente; (c) one daily injection of bovine ultralente and (d) two daily injections of bovine ultralente. Pre-meal human regular insulin was used with ultralente insulins and comprised 39 +/- 2% of the total daily insulin dose. Total and ultralente daily insulin doses were lower with human ultralente insulin (51.3 +/- 3.0 total and 30.9 +/- 3.4 ultra lente u/day) when compared to bovine ultralente insulin (57.8 +/- 4.4 and 36.1 +/- 4.4 u/day, p less than 0.01), yet the metabolic control achieved was virtually identical during both phases: (hemoglobin Alc 8.6 +/- 0.2% human vs. 8.4 +/- 0.4 bovine, p = NS). The frequency of mild hypoglycemia was 3.0 +/- 0.5 events per week vs 2.0 +/- 0.3 (p = NS). No severe hypoglycemia occurred. There were no differences between blood glucose daily profiles, insulin doses, hemoglobin Alc (8.6 +/- 0.4% BID vs. 8.4 +/- 0.3% QD injections) and occurrence of hypoglycemia between the single and two-dose long-acting regimens. These data indicate that long-acting semi-synthetic human insulin (a) can be effectively used as a once daily injection, (b) may be more biologically active than bovine, and (c) can be associated with safe and effective diabetes control.

Topics: Adult; Animals; C-Peptide; Cattle; Delayed-Action Preparations; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin, Long-Acting; Male; Recombinant Proteins

To determine if chromium (Cr) is involved in hypoglycemia, eight female patients with symptoms of hypoglycemia were supplemented with 200 micrograms of Cr as chromic chloride for three months in a double-blind crossover experimental design study. Chromium supplementation alleviated the hypoglycemic symptoms and significantly raised the minimum serum glucose values observed two to four hours following a glucose load. Insulin binding to red blood cells and insulin receptor number also improved significantly during Cr supplementation. These data suggest that impaired Cr nutrition and/or metabolism may be a factor in the etiology of hypoglycemia.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chromium; Double-Blind Method; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Middle Aged; Receptor, Insulin

We have studied the effect of the combination of a sulfonylurea (Hb 420 or glibenclamide) with insulin in 22 type II diabetic patients, treated with insulin and with residual insulin secretion (fasting plasma C peptide level greater than 0.2 pmol/ml). After a 3 week run-in period, the patients received either glibenclamide (7 mg of Hb 420 before breakfast and 3.5 mg before supper) or placebo in double blind fashion. Clinical and biological parameters (body weight, number of hypoglycemic episodes, daily insulin dose, fasting and postprandial glucose and C peptide levels after a standard meal) were collected during the basal (run-in) period and after 8 and 16 weeks of treatment. In the glibenclamide group, a significant increase in the number of hypoglycemic episodes was observed in spite of a 8 to 10% reduction in insulin requirements. A 18% reduction of both fasting and postprandial plasma glucose levels was found after 8 and 16 weeks of glibenclamide therapy. Concomitantly, a 35% increase of fasting and postprandial plasma C peptide levels occurred. The data suggest that the use of combined sulfonylurea and insulin therapy may be beneficial to type II diabetic patients with residual insulin secretion and poor glycemic control under insulin therapy alone.

Topics: Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glyburide; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Triglycerides

In order to study the effect of the calcium antagonist, verapamil, on glibenclamide stimulated insulin release, nine healthy fasted male volunteers were given 5 mg oral glibenclamide with either 120 mg oral verapamil or placebo in a double-blind crossover manner 1 week apart. Blood was withdrawn at intervals for drug, hormonal and glucose estimations. Concomitant administration of verapamil resulted in higher levels of glibenclamide at each time point (P less than 0.01) suggesting that verapamil interferes with glibenclamide metabolism. However, levels of plasma glucose, C-peptide, insulin and glucagon did not differ between the verapamil and placebo studies.

Topics: Adult; C-Peptide; Glucagon; Glucose; Glyburide; Humans; Hypoglycemia; Insulin; Insulin Secretion; Male; Verapamil

Two-hundred and two pregnant women with impaired glucose tolerance were randomized to treatment with diet or diet and insulin by stratified selection. Self-monitoring of blood glucose was performed six times a day, 3 days/wk. Dietary treatment was considered inappropriate if fasting and postprandial blood glucose values exceeded 7 and 9 mmol/L, respectively, in which case insulin therapy was instituted. Insulin doses were adjusted according to blood glucose values, aiming at fasting and postprandial values below 5 and 6.5 mmol/L, respectively. There were no perinatal deaths. The two treatment regimens disclosed no differences regarding achieved degree of maternal blood glucose control, hemoglobin A1c at delivery, obstetric or neonatal complications, infant's size at birth including skin-fold thickness, or C-peptide concentration in cord serum. Routine treatment of pregnant women with mild carbohydrate intolerance with insulin seems unnecessary. However, 15 patients (14%) in the diet group needed insulin to achieve acceptable blood glucose control, underlining the importance of monitoring blood glucose to detect those who are at risk of developing overt diabetes.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Evaluation Studies as Topic; Female; Fetal Blood; Glycated Hemoglobin; Humans; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Middle Aged; Pregnancy; Pregnancy in Diabetics; Random Allocation

1 The effects of oral doses of pindolol (15 mg), metoprolol (200 mg) and propranolol (160 mg) on the response to insulin-induced hypoglycaemia and an oral glucose load were investigated. 2 Serum insulin and serum C-peptide secretion in response to a glucose load were inhibited (2P less than 0.01) by metoprolol and propranolol but not by pindolol. 3 During hypoglycaemia metoprolol and propranolol inhibited the clearance of insulin (2P less than 0.01) and caused a delay of glucose nadirs. 4 Adrenaline secretion during hypoglycaemia was markedly increased by metoprolol and propranolol but not by pindolol. 5 The counterregulatory response of growth hormone, ACTH and cortisol was increased following metoprolol and propranolol but not after pindolol. 6 The hypoglycaemic symptoms and signs showed a prevalence of sweating and prolonged changes in skin conductivity whereas palpitations were not observed during beta-adrenoceptor blockade. Asymptomatic hypoglycaemia did not occur. 7 The absence of unphysiological rises in adrenaline, growth hormone, ACTH and cortisol supports the use of a beta-adrenoceptor blocker with intrinsic sympathomimetic activity.

Topics: Adrenergic beta-Antagonists; Adult; Blood Glucose; C-Peptide; Catecholamines; Glucose Tolerance Test; Heart Rate; Hormones; Humans; Hyperglycemia; Hypoglycemia; Insulin; Male; Sympathomimetics

Topics: Adult; C-Peptide; Catecholamines; Clinical Trials as Topic; Glucagon; Growth Hormone; Half-Life; Humans; Hydrocortisone; Hypertension; Hypoglycemia; Insulin; Male; Metoprolol; Middle Aged; Peptides; Proinsulin; Propanolamines

Exogenous insulin antibody syndrome (EIAS) can lead to unexpected and potentially life-threatening recurrent hypoglycemia.. We aimed to better define autoimmune hypoglycemia caused by EIAS in patients with diabetes and shed light on the improvements in the identification and intervention for this rare but possibly life-threatening condition.. We summarized the clinical characteristics of autoimmune hypoglycemia caused by EIAS in 23 patients with diabetes. Furthermore, we performed human leukocyte antigen (HLA) genotyping of 10 patients.. We identified a high frequency of autoimmune comorbidities (21.7%), food or drug allergy (48%), insulin allergy (30%), lipodystrophy at the insulin injection sites (22%), and antinuclear antibodies (25%) in the patients. Alternation between hyperglycemia and hypoglycemia was observed in more than 90% of the patients. Most patients showed a high insulin autoantibody titer (>90%) and inappropriately increased insulin concentration (insulin/C-peptide molar ratio >7, >85%). We detected similar frequencies of DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 compared with previously reported frequencies in type 1 diabetes, and a lower frequency of DRB1*0406 compared with insulin autoimmune syndrome. The spontaneous remission rate exceeded 70%.. Predisposing factors for autoimmune hypoglycemia caused by EIAS include a strong autoimmune background. Susceptible HLA genotypes for type 1 diabetes or insulin autoimmune syndrome might not explain susceptibility to this condition. Additionally, insulin autoantibodies and the insulin/C-peptide molar ratio are reliable screening options. The prognosis for this condition is favorable. Monitoring of insulin and insulin autoantibodies may contribute to treatment effectiveness.

Topics: Autoantibodies; Autoimmune Diseases; C-Peptide; China; Diabetes Mellitus, Type 1; HLA-DRB1 Chains; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Syndrome

C-peptide levels are a key measure of beta-cell mass following islet transplantation, but threshold values required to achieve clinically relevant patient-centered outcomes are not yet established.. We conducted a cross-sectional retrospective cohort study evaluating patients undergoing islet transplantation at a single center from 1999 to 2018. Cohorts included patients achieving insulin independence without hypoglycemia, those with insulin dependence without hypoglycemia, and those with recurrent symptomatic hypoglycemia. Primary outcome was fasting C-peptide levels at 6 to 12 mo postfirst transplant; secondary outcomes included stimulated C-peptide levels and BETA-2 scores. Fasting and stimulated C-peptide and BETA-2 cutoff values for determination of hypoglycemic freedom and insulin independence were evaluated using receiver operating characteristic curves.. We analyzed 192 patients, with 122 (63.5%) being insulin independent without hypoglycemia, 61 (31.8%) being insulin dependent without hypoglycemia, and 9 (4.7%) experiencing recurrent symptomatic hypoglycemia. Patients with insulin independence had a median (interquartile range) fasting C-peptide level of 0.66 nmol/L (0.34 nmol/L), compared with 0.49 nmol/L (0.25 nmol/L) for those being insulin dependent without hypoglycemia and 0.07 nmol/L (0.05 nmol/L) for patients experiencing hypoglycemia ( P < 0.001). Optimal fasting C-peptide cutoffs for insulin independence and hypoglycemia were ≥0.50 nmol/L and ≥0.12 nmol/L, respectively. Cutoffs for insulin independence and freedom of hypoglycemia using stimulated C-peptide were ≥1.2 nmol/L and ≥0.68 nmol/L, respectively, whereas optimal cutoff BETA-2 scores were ≥16.4 and ≥5.2.. We define C-peptide levels and BETA-2 scores associated with patient-centered outcomes. Characterizing these values will enable evaluation of ongoing clinical trials with islet or stem cell therapies.

Topics: Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Follow-Up Studies; Humans; Hypoglycemia; Insulin; Islets of Langerhans Transplantation; Patient-Centered Care; Retrospective Studies

A 69-year-old female patient and a 70-year-old male patient were admitted to hospital with recurrent, severe hypoglycemic episodes and a typical manifestation of Whipple's triad. In the female, elevated levels of insulin, C‑peptide and pro-insulin together with pathological findings during a fasting test proved the presence of an insulinoma, which could be detected by Ga-68-DOTATOC-PET-CT in the pancreas. There was a very rare co-existence of a neuroendocrine Merkel cell carcinoma. In the male, levels of insulin and C‑peptide were suppressed and a diagnosis of paraneoplastic hypoglycemia by IGF‑2 secretion was made with increased glucose disposal in skeletal muscle proven by. Eine 69-jährige Patientin und ein 70-jähriger Patient wurden mit rezidivierenden, schweren Hypoglykämien und klinischer Whipple-Trias aufgenommen. Bei der Patientin ließen erhöhte Spiegel an Insulin und C‑Peptid, ein pathologischer insulinogener Index und ein Fastentest an ein Insulinom denken, welches im

Topics: Aged; C-Peptide; Female; Gallium Radioisotopes; Humans; Hypoglycemia; Insulin; Insulin, Regular, Human; Male; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography

Diagnosis of endogenous hyperinsulinism relies on the occurrence of a hypoglycemia, concomitant with inadequate high insulin and C-peptide levels. However, diagnostic cutoffs are not consensual among the different learned societies. The objective of this work was to propose optimized cutoffs for these three parameters for the diagnosis of endogenous hyperinsulinism.. All the patients having performed a fasting trial in Cochin Hospital Endocrinology Department between February 2012 and August 2022 were included. The results of glycemia, insulin and C-peptide levels during fasting trial were collected and analyzed.. One hundred and fifty-nine patients were included: 26 with endogenous hyperinsulinism and 133 without endogenous hyperinsulinism. ROC analysis of glycemia nadir during fasting trial identified the value of 2.3 mmol/L as the optimal cutoff, ensuring a sensitivity of 100% associated with a specificity of 81%. ROC analysis of insulin and C-peptide levels concomitant with hypoglycemia <2.3 mmol/L showed very good diagnostic performances of both parameters with respective cutoffs of 3.1 mUI/L (=21.5 pmol/L; sensitivity = 96%; specificity = 92%) and 0.30 nmol/L (sensitivity = 96%; specificity = 100%). Insulin to glycemia ratio as well as C-peptide to glycemia ratio (in pmol/mmol) at the time of glycemia nadir did not show better diagnostic performances than C-peptide alone.. A C-peptide level 0.3 nmol/L concomitant with a hypoglycemia <2.3 mmol/L appears as the best criterion to make the diagnosis of endogenous hyperinsulinism. Insulin level can be underestimated on hemolyzed blood samples, frequently observed in fasting trial, and thus shows lower diagnostic performances.

Topics: Blood Glucose; C-Peptide; Fasting; Humans; Hyperinsulinism; Hypoglycemia; Insulin

Factitious hypoglycemia is a factitious disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), referring to intentionally covertly induced hypoglycemia, with potentially severe consequences. Knowledge of factitious hypoglycemia relies on case reports, and evidence-based information and guidelines are lacking. Diagnosing factitious hypoglycemia in insulin-treated diabetic persons is therefore challenging and often requires a long and costly process. Moreover, the typical metrics proposed to differentiate insulin-induced factitious hypoglycemia from insulinoma (i.e., high insulin and low C-peptide versus high insulin and high C-peptide, respectively) are not always applicable, depending on whether the insulin quantification method can detect the insulin analog. When factitious hypoglycemia is suspected, an emerging trend from recent publications advocates a combination of two insulin quantification methods with different cross-reactivity for insulin analogs, early on in the diagnostic process.

Topics: C-Peptide; Diabetes Mellitus; Factitious Disorders; Humans; Hypoglycemia; Insulin; Pancreatic Neoplasms

We examined the associations of GAD antibodies (GADA) and C-peptide (CP) with insulin initiation, glycemic responses, and severe hypoglycemia in type 2 diabetes (T2D).. In 5,230 Chinese patients (47.6% men) with T2D (mean ± SD age: 56.5 ± 13.9 years; median diabetes duration: 6 [interquartile range 1, 12] years), enrolled consecutively in 1996-2012 and prospectively observed until 2019, we retrospectively measured fasting CP and GADA in stored serum and examined their associations with aforementioned outcomes.. At baseline, 28.6% (n = 1,494) had low CP (<200 pmol/L) and 4.9% (n = 257) had positive GADA (GADA+). In the low-CP group, 8.0% had GADA+, and, in the GADA+ group, 46.3% had low CP. The GADA+ group had an adjusted hazard ratio (aHR) of 1.46 (95% CI 1.15-1.84, P = 0.002) for insulin initiation versus the GADA- group, while the low-CP group had an aHR of 0.88 (0.77-1.00, P = 0.051) versus the high-CP group. Following insulin initiation, the GADA+ plus low-CP group had the largest decrements in HbA1c (-1.9% at month 6; -1.5% at month 12 vs. -1% in the other three groups). The aHR of severe hypoglycemia was 1.29 (95% CI 1.10-1.52, P = 0.002) in the low-CP group and 1.38 (95% CI 1.04-1.83, P = 0.024) in the GADA+ group.. There is considerable heterogeneity in autoimmunity and β-cell dysfunction in T2D with GADA+ and high CP associated with early insulin initiation, while GADA+ and low CP, increased the risk of severe hypoglycemia. Extended phenotyping is warranted to increase the precision of classification and treatment in T2D.

Topics: Adult; Aged; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glutamate Decarboxylase; Humans; Hypoglycemia; Insulin; Insulin, Regular, Human; Male; Middle Aged; Retrospective Studies

Diabetes Mellitus is a silent epidemic affecting >500 million, which claimed 6.7 million lives in 2021, a projected increase of >670% in <20 years old in the next two decades but insulin is unaffordable for the large majority of the globe. Therefore, we engineered proinsulin in plant cells to facilitate oral delivery. Stability of the proinsulin gene and expression in subsequent generations, after removal of the antibiotic-resistance gene, was confirmed using PCR, Southern and western blots. Proinsulin expression was high (up to 12 mg/g DW or 47.5% of total leaf protein), stable up to one year after storage of freeze-dried plant cells at ambient temperature and met FDA regulatory requirements of uniformity, moisture content and bioburden. GM1 receptor binding, required for uptake via gut epithelial cells was confirmed by pentameric assembly of CTB-Proinsulin. IP insulin injections (without C peptide) in STZ mice rapidly decreased blood glucose level leading to transient hypoglycemia, followed by hepatic glucose compensation. On the other hand, other than the 15-min lag period of oral proinsulin (transit time required to reach the gut), the kinetics of blood sugar regulation of oral CTB-Proinsulin in STZ mice was very similar to naturally secreted insulin in healthy mice (both contain C-peptide), without rapid decrease or hypoglycemia. Elimination of expensive fermentation, purification and cold storage/transportation should reduce cost and increase other health benefits of plant fibers. The recent approval of plant cell delivery of therapeutic proteins by FDA and approval of CTB-ACE2 for phase I/II human clinical studies augur well for advancing oral proinsulin to the clinic.

Topics: Adult; Animals; Blood Glucose; C-Peptide; Humans; Hypoglycemia; Insulin; Mice; Plant Cells; Proinsulin; Young Adult

The destruction of pancreatic β cells causes type 1 diabetes mellitus (T1D), an autoimmune disease. Studies have demonstrated that there is heterogeneity in residual β-cell function in Caucasians; therefore, we aimed to evaluate β-cell function in Chinese autoimmune T1D patients.. β-cell function was determined using oral glucose tolerance testing or standardized steamed bread meal tolerance test in 446 participants with autoantibody-positive T1D. Clinical factors, such as age onset, sex, duration, body mass index, autoantibodies, other autoimmune diseases, diabetic ketoacidosis, hypoglycemia events, glycosylated hemoglobin, and insulin dose, were retrieved. We also analyzed single nucleotide polymorphism (SNP) data for C-peptides from 144 participants enrolled in the Chinese-T1D genome-wide association study.. Of 446 T1D patients, 98.5%, 97.4%, 86.9%, and 42.6% of individuals had detectable C-peptide values (≥ 0.003 nmol/L) at durations of < 1 year, 1 to 2 years, 3 to 6 years, and ≥ 7 years, respectively. A total of 60.7% of patients diagnosed at ≥ 18 years old and 15.8% of those diagnosed at < 18 years had detectable C-peptide after ≥ 7 years from the diagnosis. Furthermore, the patients diagnosed at ≥ 18 years old had higher absolute values of stimulated C-peptide (≥ 0.2 nmol/L). Diabetic ketoacidosis, hypoglycemia events, and insulin doses were shown to be associated with β-cell function. SNPs rs1770 and rs55904 were associated with C-peptide levels.. Our results have indicated that there are high residuals of β-cell mass in Chinese patients with autoimmune T1D. These findings may aid in the consideration of therapeutic strategies seeking prevention and reversal of β-cell function among Chinese T1D patients.

Topics: Adolescent; Autoantibodies; Autoimmune Diseases; C-Peptide; China; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Disease Progression; Genome-Wide Association Study; Humans; Hypoglycemia; Insulin

Islet transplantation represents an established therapeutic option for people with type 1 diabetes who have hypoglycemia unawareness syndrome and frequent problematic hypoglycemic episodes when other methods comprising diabetes education and use of technological support fail. Because the current standard method of islet infusion into the liver has some limitations, novel approaches are under investigation.. We report our first results with 2 cases of islet transplantation into an omental pouch using a biocompatible plasma-fibrin gel. The recipients received 12,350 and 5,350 islet equivalents per kilogram that were mixed with autologous plasma, seeded during a laparoscopic procedure on the omentum, overlaid with human thrombin solution, and fixed by flapping the omentum over.. During a 9-month follow-up, neither patient experienced any moderate or severe hypoglycemia. Their glucose control significantly improved, insulin dose decreased by approximately 50%, and C-peptide at 1 year was 0.22 and 0.14 pmol/mL, respectively. The postoperative course was uneventful, but C-peptide production in the first patient progressively declined at 1 year and hypoglycemic episodes recurred.. Though the results for these first 2 cases are not fully satisfactory, we have demonstrated the feasibility, safety, and ability of this novel method to restore insulin production. Further refinements to improve immediate islet survival seem necessary.

Topics: Biomedical Research; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Omentum; Thrombin

Little is known about changes in the pancreas as the course of type 1 diabetes progresses. Recently, shear wave elastography (SWE) emerged as a tool for assessing pancreatic stiffness in chronic pancreatitis and pancreatic cancer with a few studies assessing it in diabetes.. To compare pancreatic SWE in children with recent-onset and long-standing type 1 diabetes to healthy controls and to correlate it with diabetes duration, glycated hemoglobin (HbA1C), functional B cell reserve (fasting C-peptide) and diabetic complications.. Fifty children with type 1 diabetes (25 with recent-onset and 25 with long-standing type 1 diabetes) and 50 controls were enrolled. Diabetes duration, insulin therapy, fundoscopic examination of the eyes and the neuropathy disability score were assessed. Fasting C-peptide, lipids, HbA1C and urinary albumin-creatinine ratio were measured. Pancreatic SWE was measured using the General Electric Logiq P9 ultrasound system.. The mean SWE of the studied children with recent-onset type 1 diabetes was 4.81±0.62 kilopascals (Kpa), those with long-standing type 1 diabetes was 7.10±1.56Kpa and for controls was 5.57±0.27 Kpa (P<0.001). SWE was positively correlated to diabetes duration (P<0.001) and negatively correlated to fasting C-peptide (P<0.001). Regarding diabetes complications, SWE was positively correlated to frequency of severe hypoglycemia (P=0.005), HbA1C (P=0.03), low-density lipoproteins (P<0.001) and cholesterol (P<0.001) and significantly related to diabetic neuropathy (P=0.04) and nephropathy (P=0.05). Diabetes duration, fasting C-peptide, HbA1C and frequency of severe hypoglycemia were the significant independent variables related to SWE increase by multivariable regression analysis.. Pancreatic SWE changes significantly with duration of type 1 diabetes, being lowest in those with recent-onset type 1 diabetes and highest in those with long-standing type 1 diabetes, particularly those with diabetic nephropathy and neuropathy.

Topics: C-Peptide; Child; Diabetes Complications; Diabetes Mellitus, Type 1; Elasticity Imaging Techniques; Fasting; Glycated Hemoglobin; Glycemic Index; Humans; Hypoglycemia; Pancreas

Insulin antibodies (IAs) induced by exogenous insulin rarely cause hypoglycemia. However, insulin autoantibodies (IAAs) in insulin autoimmune syndrome (IAS) can cause hypoglycemia. The typical manifestations of IAS are fasting or postprandial hypoglycemia, elevated insulin level, decreased C-peptide levels, and positive IAA. We report a 45-year-old male with type 1 diabetes mellitus (T1DM) treated with insulin analogues suffering from recurrent hypoglycemic coma and diabetic ketoacidosis (DKA). His symptoms were caused by exogenous insulin and were similar to IAS. A possible reason was that exogenous insulin induced IA. IA titers were 61.95% (normal: < 5%), and the concentrations of insulin and C-peptide were > 300 mU/L and < 0.02 nmol/L when hypoglycemia occurred. Based on his clinical symptoms and other examinations, he was diagnosed with hyperinsulinemic hypoglycemia caused by IA. His symptoms improved after changing insulin regimens from insulin lispro plus insulin detemir to recombinant human insulin (Gensulin R) and starting prednisone.

Topics: Autoimmune Diseases; C-Peptide; Coma; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Antibodies; Male; Middle Aged

A 50-year-old woman was hospitalized for fainting caused by hypoglycemia. Her blood glucose level was low (40 mg/dL), immunoreactive insulin was 16.9 μU/mL, and C-peptide level was high (4.8 ng/mL). Computed tomography and magnetic resonance imaging revealed a 7-mm tumor in the uncinate process of the pancreas. A selective arterial calcium injection test indicated an increase in the superior mesenteric artery. Insulinoma of the uncinate process of the pancreas was diagnosed, and tumor enucleation was planned using an artificial pancreas for intraoperative and postoperative blood glucose control. Hypoglycemia (blood glucose, 38 mg/dL) was observed from the onset of surgery. An artificial pancreas cannot be used if the blood glucose level is ≤ 70 mg/dL; thus, continuous glucose infusion was administered. The sudden rise in blood glucose prompted insulin infusion from the device, causing hypoglycemia. Controlling blood glucose levels is challenging when introducing the artificial pancreas. However, altering the device's blood glucose control algorithm controlled the fluctuating blood glucose level, and, intraoperative average blood glucose was raised to 94.8 ± 21.1 mg/dL, thereby avoiding hypoglycemia, that is, a blood glucose level of ≤ 70 mg/dL. We report a case in which an artificial pancreas was used for glycemic control during surgery for an insulinoma.

Topics: Blood Glucose; C-Peptide; Calcium; Female; Glucose; Humans; Hypoglycemia; Insulin; Insulinoma; Middle Aged; Pancreas, Artificial; Pancreatic Neoplasms

Pancreatic β-cells have an extraordinary ability to adapt to acute fluctuations in glucose levels by rapid changing insulin production to meet metabolic needs. Although acute changes have been characterised, effects of prolonged metabolic stress on β-cell dynamics are still unclear. Here, the aim was to investigate pancreatic β-cell dynamics and function during and after prolonged hypoglycaemia. Hypoglycaemia was induced in male and female rats by infusion of human insulin for 8 weeks, followed by a 4-week infusion-free recovery period. Animals were euthanized after 4 or 8 weeks of infusion, and either 2 days and 4 weeks after infusion-stop. Total volumes of pancreatic islets and β-cell nuclei, islet insulin and glucagon content, and plasma c-peptide levels were quantified. Prolonged hypoglycaemia reduced c-peptide levels, islet volume and almost depleted islet insulin. Relative β-cell nuclei: total pancreas volume decreased, while being unchanged relative to islet volume. Glucagon: total pancreas volume decreased during hypoglycaemia, whereas glucagon: islet volume increased. Within two days after infusion-stop, plasma glucose and c-peptide levels normalised and all remaining parameters were fully reversed after 4 weeks. In conclusion, our findings indicate that prolonged hypoglycaemia inactivates β-cells, which can rapidly be reactivated when needed, demonstrating the high plasticity of β-cells even following prolonged suppression.

Topics: Animals; Blood Glucose; C-Peptide; Female; Glucagon; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Male; Rats

This is a case study of a 25-year-old female, Ashkenazy Jewish, previously healthy, presented with a complaint of weakness. Her sugar level on the glucometer was 50 mg% and she felt better after ingestion of a small amount of sugar. Two weeks earlier, while traveling in Peru, she developed thyrotoxicosis and began taking Mercaptizol 30 mg a day and Atenolol 100 mg. She didn't drink iodine (iodinated preparations for water purification) while traveling and had no pain or fever. Her physical examination showed no goiter or exophthalmos. While I saw her she was already euthyroid and felt quite good except for fatigue. In the literature, we found a few case reports of Mercaptizol and PTU-induced insulin autoantibodies which cause symptomatic hypoglycemia. Most cases were described in the Asian population (especially Japanese people) and resolved a few weeks after stopping intake of the drug. In our patient, the hypoglycemia resolved after only one episode and discontinuation of Mercaptizol. Insulin antibodies were negative, and insulin levels (C-peptide) were relatively high. My conclusion is that physicians should be aware of Mercaptizol and PTU-induced hypoglycemia which can be life-threatening.

Topics: Adult; Atenolol; Autoantibodies; C-Peptide; Female; Humans; Hypoglycemia; Insulin Antibodies; Iodine; Sugars

A structured approach in the diagnostic process of hypoglycemia is important to find the right diagnosis. The first step is to recognize the symptoms of hypoglycemia, confirming the hypoglycemia during symptoms and dissolvement of complaints once the glucose level is restored to normal. This confirms the Whipple triad. The second step is to exclude common causes. The third, and most important, step is a diagnostic fasting test. Measurement of insulin and C-peptide during hypoglycemia will guide to exogenic or endogenic causes of hyperinsulinism. Targeted additional investigation is then required. Often the underlying cause is treatable. This justifies the need to measure a well-timed serum glucose when hypoglycemia is suspected to make a quick diagnosis.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Glucose; Humans; Hyperinsulinism; Hypoglycemia; Insulin

The progression to insulin deficiency in type 1 diabetes is heterogenous. This study aimed to identify early characteristics associated with rapid or slow decline of beta-cell function and how it affects the clinical course.. Stimulated C-peptide was assessed by mixed meal tolerance test in 50 children (<18 years) during 2004-2017, at regular intervals for 6 years from type 1 diabetes diagnosis. 40% of the children had a rapid decline of stimulated C-peptide defined as no measurable C-peptide (<0.03 nmol/L) 30 months after diagnosis.. At diagnosis, higher frequencies of detectable glutamic acid decarboxylase antibodies (GADA) and IA-2A (p=0.027) were associated with rapid loss of beta-cell function. C-peptide was predicted positively by age at 18 months (p=0.017) and 30 months duration (p=0.038). BMI SD scores (BMISDS) at diagnosis predicted higher C-peptide at diagnosis (p=0.006), 3 months (p=0.002), 9 months (p=0.005), 30 months (p=0.022), 3 years (p=0.009), 4 years (p=0.016) and 6 years (p=0.026), whereas high HbA1c and blood glucose at diagnosis predicted a lower C-peptide at diagnosis (p=<0.001) for both comparisons. Both GADA and IA-2A were negative predictors of C-peptide at 9 months (p=0.011), 18 months (p=0.008) and 30 months (p<0.001). Ten children had 22 events of severe hypoglycemia, and they had lower mean C-peptide at 18 months (p=0.025), 30 months (p=0.008) and 6 years (p=0.018) compared with others. Seven of them had a rapid decline of C-peptide (p=0.030), and the odds to experience a severe hypoglycemia were nearly fivefold increased (OR=4.846, p=0.04).. Low age and presence of multiple autoantibodies at diagnosis predicts a rapid loss of beta-cell function in children with type 1 diabetes. Low C-peptide is associated with an increased risk of severe hypoglycemia and higher Hemoglobin A1C. A high BMISDS at diagnosis is predictive of remaining beta-cell function during the 6 years of follow-up.

Topics: Adolescent; Autoantibodies; C-Peptide; Child; Diabetes Mellitus, Type 1; Humans; Hypoglycemia; Infant; Insulin

This study aimed to assess the association between fasting serum C-peptide levels and the presence of impaired awareness of hypoglycemia (IAH) in people with type 1 diabetes.. We performed a cross-sectional study among 509 individuals with type 1 diabetes (diabetes duration 5-65 years). Extensive clinical data and fasting serum C-peptide concentrations were collected and related to the presence or absence of IAH, which was evaluated using the validated Dutch version of the Clarke questionnaire. A multivariable logistic regression model was constructed to investigate the association of C-peptide and other clinical variables with IAH.. In 129 (25%) individuals, residual C-peptide secretion was detected, while 75 (15%) individuals reported IAH. The median (IQR) C-peptide concentration among all participants was 0.0 (0.0-3.9) pmol/L. The prevalence of severe hypoglycemia was lower in people with demonstrable C-peptide versus those with absent C-peptide (30% vs 41%, p=0.025). Individuals with IAH were older, had longer diabetes duration, more frequently had macrovascular and microvascular complications, and more often used antihypertensive drugs, antiplatelet agents and cholesterol-lowering medication. There was a strong association between IAH and having a severe hypoglycemia in the preceding year. In multivariable regression analysis, residual C-peptide, either continuously or dichotomous, was associated with lower prevalence of IAH (p=0.040-0.042), while age at diabetes onset (p=0.001), presence of microvascular complications (p=0.003) and body mass index (BMI) (p=0.003) were also independently associated with the presence of IAH.. Higher BMI, the presence of microvascular complications and higher age at diabetes onset were independent risk factors for IAH in people with type 1 diabetes, while residual C-peptide secretion was associated with lower risk of this complication.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Humans; Hypoglycemia; Surveys and Questionnaires

Low C-peptide levels, indicating beta-cell dysfunction, are associated with increased within-day glucose variation and hypoglycemia. In advanced type 2 diabetes, severe hypoglycemia and increased glucose variation predict cardiovascular (CVD) risk. The present study examined the association between C-peptide levels and CVD risk and whether it can be explained by visit-to-visit glucose variation and severe hypoglycemia.. Fasting C-peptide levels at baseline, composite CVD outcome, severe hypoglycemia, and visit-to-visit fasting glucose coefficient of variation (CV) and average real variability (ARV) were assessed in 1565 Veterans Affairs Diabetes Trial participants.. There was a U-shaped relationship between C-peptide and CVD risk with increased risk with declining levels in the low range (< 0.50 nmol/l, HR 1.30 [95%CI 1.05-1.60], p = 0.02) and with rising levels in the high range (> 1.23 nmol/l, 1.27 [1.00-1.63], p = 0.05). C-peptide levels were inversely associated with the risk of severe hypoglycemia (OR 0.68 [0.60-0.77]) and visit-to-visit glucose variation (CV, standardized beta-estimate - 0.12 [SE 0.01]; ARV, - 0.10 [0.01]) (p < 0.0001 all). The association of low C-peptide levels with CVD risk was independent of cardiometabolic risk factors (1.48 [1.17-1.87, p = 0.001) and remained associated with CVD when tested in the same model with severe hypoglycemia and glucose CV.. Low C-peptide levels were associated with increased CVD risk in advanced type 2 diabetes. The association was independent of increases in glucose variation or severe hypoglycemia. C-peptide levels may predict future glucose control patterns and CVD risk, and identify phenotypes influencing clinical decision making in advanced type 2 diabetes.

Topics: Aged; Biomarkers; Blood Glucose; C-Peptide; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fasting; Female; Glycemic Control; Heart Disease Risk Factors; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Time Factors; United States; United States Department of Veterans Affairs

We report on the transition in blood glucose levels before and after the onset of fulminant type 1 diabetes mellitus in a perinatal woman. In week 38 of pregnancy, before which the patient had normal glucose tolerance, idiopathic acute pancreatitis was diagnosed. Five days thereafter, she became hypoglycemic, so we closely monitored her blood glucose levels. A total of 13 days later, she was hyperglycemic with a blood glucose level >16.0 mmol/L and glycated hemoglobin of 6.4%. Her fasting serum C-peptide reactivity level was 3.6 ng/mL on the 5th day, and 0.2 ng/mL on the 18th day. Multiple insulin injection therapy was administered since the 18th day; after that, ketoacidosis did not occur. The patient was diagnosed with fulminant type 1 diabetes mellitus based on hyperglycemia without high glycated hemoglobin levels and sudden onset insulin-dependent diabetes. Monitoring glucose levels in the case of idiopathic acute pancreatitis during pregnancy and prompt initiation of insulin therapy are important.

Topics: Acute Disease; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes, Gestational; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Pancreatitis; Pregnancy; Pregnancy Complications

To identify the coefficient of variation (CV) threshold for unstable glucose variability (GV) and hypoglycemia, and to characterize a patient population with unstable GV and hypoglycemia.. This was an observational study that enrolled 284 Japanese outpatients with type 2 diabetes who underwent continuous glucose monitoring. The C-peptide index (CPI = [(fasting serum C-peptide) / (plasma glucose)] × 100) was used as a marker of endogenous insulin secretion. The CV threshold between stable and unstable GV was defined as the upper limit of the CV distribution in the subgroup of patients who did not receive insulin nor insulin secretagogues (relatively stable GV subgroup, n = 104). The optimal CV range corresponding to time below target range ≥4% was determined for all patients using receiver operating characteristic curve analysis. Various characteristics of patients with unstable GV and hypoglycemia were extracted using multivariate logistic regression analysis.. The upper limit of the CV in the relatively stable GV subgroup was 40. The optimal CV range corresponding to time below target range ≥4% was also defined as CV ≥40 (area under the curve 0.85) for all patients. The CPI was an independent risk for CV ≥40 (odds ratio 0.17, 95% confidence interval 0.04-0.50, P < 0.01). The optimal cut-off point for CPI to predict a CV cut-off value of 40 was equivalent to 0.81 (area under the curve 0.80).. A CV of 40 discriminates unstable GV and hypoglycemia from stable GV in Japanese outpatients with type 2 diabetes. Impaired insulin secretion might affect the stability of GV.

Topics: Aged; Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Secretion; Logistic Models; Male; Middle Aged; Reference Values; Risk Assessment; Risk Factors; ROC Curve; Time Factors

Following type 1 diabetes (T1D) diagnosis, declining C-peptide levels reflect deteriorating β cell function. However, the precise C-peptide levels that indicate protection from severe hypoglycemia remain unknown. In this issue of the JCI, Gubitosi-Klug et al. studied participants from the landmark and ongoing Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study that had long-standing (about 35 years) T1D. The authors correlated severe hypoglycemia and other disease outcomes with residual C-peptide levels. While C-peptide secretion failed to associate with hemoglobin A1c (HbA1c) or microvascular complications, C-peptide levels greater than 0.03 nmol/L were linked with fewer episodes of severe hypoglycemia. These findings suggest that efforts to preserve finite β cell function early in T1D can have meaningful, long-standing health benefits for patients.

Topics: C-Peptide; Diabetes Complications; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemia

Until now, diabetes during pregnancy has been associated with a high risk of maternal, fetal, and neonatal morbidities and mortalities. The main aim of this study was to evaluate the risk factors of hypoglycemia in infants of diabetic mothers (IDMs) and to study the relationship between umbilical cord (UC) C peptide levels and the risk of developing hypoglycemia.. UC blood C-peptide and serial serum blood glucose measurements were done for all included singleton newborns born to diabetic mothers during the study period. Maternal and neonatal data such as gestational age, maternal age, maternal weight, types of diabetics and its control, maternal glycated hemoglobin (HbA1C), birth weight, Apgar score, and neonatal complete blood picture were collected.. In total, 83 IDMs met the inclusion criteria. Fifty-four (65.06%) developed hypoglycemia and 29 (34.94%) remained normoglycemic. However, there were no significant differences between hypoglycemic and normoglycemic IDMs in terms of types of maternal diabetics (P value = 0.41), its duration (P value = 0.43). The hypoglycemia peak occurred within the first 3 h of life, with 33.11 ± 8.84 mg/dl for the hypoglycemia group and 54.10 ± 6.66 mg/dl for the normoglycemic group (P value < 0.0001). Most of the babies had no hypoglycemic manifestation (96.30%). Neonates with hypoglycemia their mothers had poor diabetes control in the last trimester (HbA1C 7.09 ± 0.96%) compared to normoglycemic babies (HbA1C 6.11 ± 0.38%), (P-value < 0.0001). The mean (SD) of UC C-peptide level in hypoglycemic neonates increased to 1.73 ± 1.07 ng/ml compared to normoglycemic ones with 1.08 ± 0.81 ng/ml (P value = 0.005).. Poor diabetes control, especially in the last trimester, is associated with neonatal hypoglycemia. Increased UC C-peptide levels could be used as an early indicator for the risk of developing neonatal hypoglycemia and a predictor for babies need neonatal admission.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes, Gestational; Female; Humans; Hypoglycemia; Infant; Infant, Newborn; Mothers; Pregnancy; Pregnancy in Diabetics; Umbilical Cord

Alpha-lipoic acid (ALA) is widely used as a dietary supplement and antiageing agent. Insulin autoimmune syndrome (IAS) is the most serious adverse reaction reported with the use of ALA. The purpose of this study was to explore the clinical characteristics of ALA-induced IAS and provide a scientific reference for clinical diagnosis, treatment and prevention.. We collected literature on IAS cases induced by ALA for retrospective analysis in Chinese and English.. The median age of 37 patients (28 females and 9 males) was 61 years (range 32-82). The symptoms occurred at night and in the early morning (60.7%), in the late postprandial period (50.0%) or after fasting (35.7%), within hours in some patients and up to 2 months in others after stopping ALA or during medication treatment. Autonomic nervous system symptoms (81.1%) and neurological hypoglycaemia (64.9%) are the main clinical manifestations of hypoglycaemia. The blood glucose concentration at the onset of hypoglycaemia was 2.19 mmol/L (median, range 1.09-3.52), the insulin concentration was ≥100 μIU/ml (94.6%), and the C-peptide concentration was ≤20 ng/ml (83.3%). Testing for IgG insulin autoantibodies (IAAs) was positive in 37 patients. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and abdominal sonography. Hypoglycaemia disappeared within 5 days to 8 months after withdrawing ALA alone or using corticosteroid treatment. IAA turned negative in 7 months (median; range 2-36). Follow-up showed no recurrent hypoglycaemic episodes at 7.25 months (median; range 1-36).. ALA-induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment or after drug withdrawal that should be treated promptly.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Autoimmune Diseases; Blood Glucose; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Retrospective Studies; Thioctic Acid

Several studies have associated the presence of residual insulin secretion capability (also referred to as being C-peptide positive) with lower risk of insulin-induced hypoglycemia in patients with type 1 diabetes (T1D), although the reason is unclear. We tested the hypothesis that C-peptide infusion would enhance glucagon secretion in response to hyperinsulinemia during euglycemic and hypoglycemic conditions in dogs (5 male/4 female). After a 2-hour basal period, an intravenous (IV) infusion of insulin was started, and dextrose was infused to maintain euglycemia for 2 hours. At the same time, an IV infusion of either saline (SAL) or C-peptide (CPEP) was started. After this euglycemic period, the insulin and SAL/CPEP infusions were continued for another 2 hours, but the glucose was allowed to fall to approximately 50 mg/dL. In response to euglycemic-hyperinsulinemia, glucagon secretion decreased in SAL but remained unchanged from the basal period in CPEP condition. During hypoglycemia, glucagon secretion in CPEP was 2 times higher than SAL, and this increased net hepatic glucose output and reduced the amount of exogenous glucose required to maintain glycemia. These data suggest that the presence of C-peptide during IV insulin infusion can preserve glucagon secretion during euglycemia and enhance it during hypoglycemia, which could explain why T1D patients with residual insulin secretion are less susceptible to hypoglycemia.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Dogs; Female; Glucagon; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Male

Determination of C-peptide is important in the investigation of unexplained hyperinsulinemic hypoglycemia because a high C-peptide concentration usually indicates endogenous insulin hypersecretion. Insulin autoimmune syndrome (IAS) denotes hyperinsulinemic hypoglycemia due to insulin-binding antibodies that prolong insulin half-life. C-peptide clearance is considered to be unaffected, and although a marked C-peptide immunoreactivity in hypoglycemic samples has been reported, it has been suspected to be artifactual. High-resolution mass spectrometry enables examination of the basis of C-peptide-immunoreactivity in IAS.. Precipitation of plasma with polyethylene glycol was followed by C-peptide immunoassay. Plasma peptides extracted by solvent precipitation were characterized by nano-LC-MS/MS and analyzed using an untargeted data-dependent method. Peptides related to proinsulin, in amino acid sequence, were identified using proprietary bioinformatics software and confirmed by repeat LC-MS/MS analysis. Gel filtration chromatography coupled to LC-MS/MS was used to identify proinsulin-related peptides present in IAS immunocomplexes. Results were compared with those from C-peptide immunoassay.. Polyethylene glycol precipitation of IAS plasma, but not control plasma, depleted C-peptide immunoreactivity consistent with immunoglobulin-bound C-peptide immunoreactivity. LC-MS/MS detected proinsulin and des 31,32 proinsulin at higher abundance in IAS plasma compared with control plasma. Analysis by gel filtration chromatography coupled to LC-MS/MS demonstrated proinsulin and des 31,32 proinsulin, but no C-peptide, in plasma immunocomplexes.. Antibody binding can enrich proinsulin and des 31,32 proinsulin in IAS immunocomplexes. Proinsulin cross-reactivity in some C-peptide immunoassays can lead to artifactually increased C-peptide results.

Topics: Autoimmune Diseases; C-Peptide; Chromatography, Liquid; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Antibodies; Molecular Weight; Peptides; Polyethylene Glycols; Proinsulin; Tandem Mass Spectrometry

Twelve years following gastric bypass surgery, a cachectic 69-year-old woman presented with both fasting and postprandial hypoglycaemia. Postprandial symptoms were relieved by dietary modification and acarbose, as is common in such cases. During a supervised fast, symptomatic hypoglycaemia occurred. Concurrent laboratory testing showed suppression of plasma insulin, c-peptide, proinsulin and insulin-like growth factor II. However, beta-hydroxybutyrate was also low, surprising given insulin deficiency. Elevated plasma free fatty acid (FFA) concentrations suggested that lipolysis was not impaired, making cachexia/malnutrition a less likely cause of hypoglycaemia. The apparent diagnosis was failure to counter-regulate-subsequent plasma carnitine measurements showed carnitine deficiency which presumably prevented FFA transport across mitochondrial membranes for ketogenesis. Repletion with high-dose oral carnitine supplements effected resolution of fasting hypoglycaemia.

Topics: Aged; C-Peptide; Carnitine; Fasting; Female; Gastric Bypass; Humans; Hypoglycemia; Insulin; Malnutrition

We present a case of a 73-year-old woman who developed recurrent hypoglycaemia during a prolonged hospital stay following a mechanical fall. She had a complex history of insulin-treated diabetes mellitus, hypothyroidism, diffuse systemic cutaneous sclerosis, Raynaud's disease, previous breast cancer, Barrett's oesophagus and previous partial gastrectomy for a benign mass. Hypoglycaemia persisted despite weaning of insulin. She had no clinical features of adrenal or pituitary insufficiency with an acceptable cortisol on stopping prednisolone and had an optimal thyroid replacement. A 72-hour fast elicited hypoglycaemia with corresponding low insulin level. Although the C-peptide was detectable, there were no clinical, biochemical or radiological features suggestive of insulinoma. Reactive hypoglycaemia post partial gastrectomy was ruled out based on limited relation of the hypoglycaemia to meals and the low insulin levels. Hydroxychloroquine (HCQ)-induced hypoglycaemia was considered based on previous case reports and the recent literature, with a successful resolution of hypoglycaemia on discontinuation of HCQ.

Topics: Aged; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemia; Insulin; Pancreatic Neoplasms

We present a case of hypoglycemia in a young patient without diabetes mellitus who presented initially with enlarging neck mass and weight loss, and was found to have aggressive melanoma with metastasis to multiple organs and diffuse lymphadenopathy. He had presented to the emergency room two times with neuroglycopenic symptoms that required admission and intravenous dextrose continuously. Evaluation of hypoglycemia included C-peptide, insulin levels, insulin-like growth factor (IGF) -I and -II, and ß- hydroxybutyrate. Insulin levels were suppressed appropriately during hypoglycemia, however, IGF-II:IGF-I ratio was high, suggesting non-islet tumour induced hypoglycemia. The presence of IGF-II produced by large tumors results in a low hepatic glucose output and increased uptake by skeletal muscle, resulting in hypoglycemia especially in a patient with extremely low appetite such as our patient. Treating the culprit malignancy leads to resolution of hypoglycemia, but corticosteroids have been used to suppress IGF-II levels and alleviate symptoms.

Topics: C-Peptide; Humans; Hypoglycemia; Insulin-Like Growth Factor II; Male; Melanoma

Post-prandial and oral glucose tolerance test-related hypoglycemia is common in cystic fibrosis (CF); however, the underlying mechanisms are unclear.. To understand the relationship of hypoglycemia with meal-related glucose excursion and insulin secretion, we analyzed plasma glucose, insulin, C-peptide, glucagon and incretins obtained during standardized mixed-meal tolerance tests (MMTT) in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF).. Hypoglycemia, defined as glucose <70 mg/dL, occurred in 9/34 subjects at 150 (range:120-210) minutes following initial meal ingestion. Hypoglycemia[+] and hypoglycemia[-] groups did not differ in gender, age, lung function, HbA1c, or BMI. While 11/14 hypoglycemia[-] individuals displayed normal glucose tolerance (NGT), only 2/9 hypoglycemia[+] had NGT. Peak glucose was higher in hypoglycemia[+] vs hypoglycemia[-]. Compared to hypoglycemia[-] NGT, hypoglycemia[+] exhibited lower early-phase insulin secretion (ISR-AUC. Hypoglycemia is common in PI-CF following MMTT and is associated with early glucose dysregulation (higher peak glucose), more impaired early-phase insulin secretion (lower ISR-AUC

Topics: Adolescent; Area Under Curve; Blood Glucose; C-Peptide; Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Female; Glucagon; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemia; Incretins; Insulin; Insulin Secretion; Male; Young Adult

To examine the relationship between baseline fasting C-peptide (FCP) and outcomes in insulin-naïve people with type 2 diabetes initiating basal insulin glargine 100 U/mL (Gla-100).. Post hoc pooled analysis of nine randomized, treat-to-target trials in patients with type 2 diabetes inadequately controlled on oral antihyperglycaemic drugs initiating once-daily Gla-100. Participants (n = 2165) were stratified at baseline according to FCP (≤0.40, >0.40-1.20, >1.20-2.00, >2.00 nmol/L). Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 24 weeks.. At baseline low FCP levels were associated with longer known diabetes duration, lower body mass index and higher fasting plasma glucose (FPG). Following Gla-100 introduction, the mean HbA1c reduction at week 24 was similar in all four FCP groups, albeit fewer people in the lowest FCP group achieved HbA1c <7.0% versus FCP groups >0.40 nmol/L. By contrast, FPG reduction and proportion reaching FPG ≤5.6 mmol/L were greatest in the lowest FCP group, diminishing at higher FCP levels. Gla-100 dose at week 24 was lowest in the ≤0.40 nmol/L FCP group and highest in the >1.20 nmol/L FCP group. Incidence and event rate of overall, nocturnal and severe hypoglycaemia were higher at week 24 in groups with lower FCP levels. In multivariable regression analysis baseline FCP, concomitant sulphonylurea use and endpoint HbA1c were strong predictors of hypoglycaemia.. FCP levels identified patients with type 2 diabetes experiencing different responses to basal insulin Gla-100. A low FCP identifies a markedly insulin-deficient, insulin-sensitive subgroup/phenotype with an enhanced risk of hypoglycaemia, which requires a low initial basal insulin dose, cautious titration and earlier addition of prandial glucose-lowering therapy.

Topics: Biomarkers; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fasting; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine

Hypoglycaemia has been reported as an unusual complication of tramadol use and in a few cases of tramadol poisoning, but the exact mechanism is not known.. An ambulance crew was dispatched to an unconscious 46-year old man. A glucometer point-of-care measurement revealed a profound hypoglycaemia (1.9 mmol/L). Treatment with intravenous glucose was started and the patient was transported to the hospital. The patient had several episodes of pulseless electrical activity requiring cardiopulmonary resuscitation in the ambulance and upon arrival in the hospital. Despite continuous glucose infusion the hypoglycaemia was difficult to correct during the next few hours and the patient developed hypokalaemia. Further investigation to identify the cause of hypoglycaemia revealed that insulin and C-peptide were inappropriately raised. A toxicological investigation revealed the presence of tramadol and its metabolites in lethal concentrations. Also acetaminophen, ibuprofen and lormetazepam were present. Ethanol screening was negative (< 0.1 g/L) and no sulfonylurea were detected. The patient developed multiple organ failure, but eventually recovered.. The hypoglycaemia was caused by inappropriate stimulation of insulin secretion in a patient intoxicated with tramadol. The sudden hypokalaemia was caused by a massive intracellular shift of potassium in response to the hyperinsulinemia, triggered by the intravenous administration of glucose.. To our knowledge, we are the first to document a significant rise in endogenous insulin production in a hypoglycaemic patient presenting with tramadol intoxication. Our observation suggests that hyperinsulinemia could be the cause of the hypoglycaemia associated with tramadol use.

Topics: Analgesics, Opioid; Blood Glucose; C-Peptide; Glucose; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Pain; Tramadol

The aim of the study was to characterize factors that may serve as clinical tools to identify neonates with transient neonatal hyperinsulinism hypoglycemia (HH) who may benefit from diazoxide treatment. This retrospective study included 141 neonates with transient HH (93 males) of whom 34 (24%) were treated with diazoxide. Diazoxide treatment was started at median age of 13 days (range 5-35) and discontinued at median age of 42 days (range 14-224). The maximal dose was 7.1 ± 2.3 mg/kg/day. Diazoxide-treated neonates required a higher glucose infusion rate (GIR) compared with non-treated neonates (16.6 ± 3.4 vs. 10.4 ± 4.0 mg/kg/min, respectively, P < .01), had a longer duration of intravenous fluids (15.9 ± 9.3 vs. 7.8 ± 6.5 days, P < .01), a longer hospitalization (32.8 ± 22.7 vs. 20.4 ± 13.4 days, P < .01), a longer duration of carbohydrate supplementation (38.9 ± 40.4 vs. 17.8 ± 21.4 days, P < .01), and higher mean C-peptide levels on "critical sample" (1.4 ± 0.9 vs. 0.8 ± 0.5 ng/ml, P < .01). Their insulin levels also tended to be higher (3.5 ± 2.9 vs. 2.2 ± 3.8 μU/ml, P = .07). A stepwise logistic regression model revealed that significant predictors of prolonged HH were maximal GIRs (odds ratio (OR) 1.56, 95%; confidence interval (CI) 1.3-1.88, P < .001) and C-peptide levels (OR 3.57, 95%; CI 1.3-12.1, P = .005).Conclusion: Higher C-peptide levels and higher GIR requirements may serve as clinical tools to identify neonates with transient HH who may benefit from diazoxide treatment.What is Known:• Neonates with transient hyperinsulinism usually do not require treatment beyond glucose supplementation due to its self-limited clinical course, but some may benefit from diazoxide treatment.What is New:• Higher C-peptide levels and higher GIR requirements may serve as clinical tools to identify neonates with transient HH who may benefit from diazoxide treatment.• The incidence of prolonged neonatal HH is higher than the currently accepted figures.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Diazoxide; Female; Gestational Age; Humans; Hyperinsulinism; Hypoglycemia; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Pregnancy; Retrospective Studies

The relationship between baseline fasting C-peptide (FCP) and glucose control was examined in insulin-naïve people with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs commencing basal insulin glargine 300 U/mL (Gla-300) or 100 U/mL (Gla-100) in the absence of sulfonylurea/glinides. Participants with FCP measurement from the EDITION 3 trial (n = 867) were stratified according to baseline FCP (≤0.40, >0.40-1.20, >1.20 nmol/L); 11.0%, 70.9% and 18.1% contributed to each group. Glycaemic control, body weight, insulin dose and hypoglycaemia were determined at 26 weeks. Glycaemic control (HbA1c, FPG) at 26 weeks was similar in each FCP group between insulins. However, end-of-study insulin dose was greater with higher FCP for both insulins. More people with lower baseline FCP experienced hypoglycaemia with both insulins, but with numerically lower incidence for Gla-300 versus Gla-100 across all FCP groups for all definitions (time periods and levels) of hypoglycaemia. This suggests that Gla-300 might be particularly advantageous for people who are at higher risk of hypoglycaemia.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fasting; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine

The domestic pig is commonly used as animal model in the pharmaceutical development of new therapeutics for treatment of diabetes. Since a formal definition of hypoglycaemia only exists in humans, the purpose of this study was to assess the counterregulatory response in the domestic pig at glucose levels known to induce symptoms of hypoglycaemia in humans. Six pigs were included in hyperinsulinaemic glucose clamps with plasma glucose targets of 2, 3 and 5 mmol/L in a cross-over design, and the associated glucose counterregulatory response was assessed by measuring glucose kinetics and levels of glucagon, c-peptide, catecholamines, cortisol and growth hormone. Results showed that the 2 and 3 vs 5 mmol/L clamps significantly decreased and increased the secretion of c-peptide and glucagon, respectively (P < .05). This finding was associated with increased rate of glucose appearance (R

Topics: Animals; Blood Glucose; C-Peptide; Catecholamines; Epinephrine; Female; Glucagon; Glucose; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin; Models, Animal; Norepinephrine; Swine

Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome that secretes incompletely processed high molecular weight insulin growth factor 2 (big-IGF2), which results in stimulation of the insulin receptor and subsequently induces hypoglycemia. Gastrointestinal stromal tumor (GIST) is a common intestinal mesenchymal neoplasm of the gastrointestinal tract. The most frequent site of GIST is the stomach; NICTH induced by IGF2-producing stomach GISTs is rare.. An 84-year-old man was admitted to the hospital due to impaired consciousness (JCS II-10) in the morning. At the time of admission, his serum glucose was 44 mg/dL; his consciousness was restored with 20 ml of 50% glucose. To avoid hypoglycemia, a continuous intravenous infusion of glucose as well as dietary intervention was required. At the time of hypoglycemia, the levels of insulin and C-peptide were suppressed. Additionally, IGF1 levels were below the normal range. Abdominal computed tomography revealed that he had a large lobulated mass (116 × 70 × 72 mm) around the gastric corpus. Pathological analysis of biopsy specimens identified disarray of spindle cells and positivity for c-kit as well as strong positivity for DOG-1. Further analysis revealed high levels of Ki-67 (Mib-1 index: 15.5%) and mitotic index (7/50HPF); the tumor was diagnosed as high-risk GIST, and complete surgical resection was performed. Hypoglycemia resolved immediately after tumor resection. The resected tumor specimen was positive for IGF2 staining, and big-IGF2 (11-18 kDa) was detected in preoperative serum and tumor samples; the patient was diagnosed with NICTH due to an IGF2-producing tumor.. NICTH is rare in GIST of the stomach; however, the large GIST could produce big-IGF2 and subsequently cause severe hypoglycemia, requiring prompt evaluation and complete tumor resection.

Topics: Aged, 80 and over; C-Peptide; Gastrointestinal Stromal Tumors; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Paraneoplastic Syndromes; Stomach Neoplasms; Tomography, X-Ray Computed

Oral glucose tolerance test (OGTT)-related hypoglycemia is common in pancreatic-insufficient cystic fibrosis (PI-CF), but its mechanistic underpinnings are yet to be established.. To delineate the mechanism(s) underlying OGTT-related hypoglycemia.. We performed 180-minute OGTTs with frequent blood sampling in adolescents and young adults with PI-CF and compared results with those from a historical healthy control group. Hypoglycemia (Hypo[+]) was defined as plasma glucose <65 mg/dL. We hypothesized that CF-Hypo[+] would demonstrate impaired early phase insulin secretion and persistent late insulin effect compared with control-Hypo[+], and explored the contextual counterregulatory response.. OGTT 1-hour and nadir glucose, insulin, C-peptide, and insulin secretory rate (ISR) incremental areas under the curve (AUC) between 0 and 30 minutes (early) and between 120 and 180 minutes (late), and Δglucagon120-180min and Δfree fatty acids (FFAs)120-180min were compared between individuals with CF and control participants with Hypo[+].. Hypoglycemia occurred in 15/23 (65%) patients with CF (43% female, aged 24.8 [14.6-30.6] years) and 8/15 (55%) control participants (33% female, aged 26 [21-38] years). The CF-Hypo[+] group versus the control-Hypo[+] group had higher 1-hour glucose (197 ± 49 vs 139 ± 53 mg/dL; P = 0.05) and lower nadir glucose levels (48 ± 7 vs 59 ± 4 mg/dL; P < 0.01), while insulin, C-peptide, and ISR-AUC0-30 min results were lower and insulin and C-peptide, and AUC120-180min results were higher (P < 0.05). Individuals with CF-Hypo[+] had lower Δglucagon120-180min and ΔFFA120-180min compared with the control-Hypo[+] group (P < 0.01).. OGTT-related hypoglycemia in PI-CF is associated with elevated 1-hour glucose, impaired early phase insulin secretion, higher late insulin exposure, and less increase in glucagon and FFAs. These data suggest that hypoglycemia in CF is a manifestation of islet dysfunction including an impaired counterregulatory response.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Case-Control Studies; Child; Cystic Fibrosis; Female; Glucagon; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Male; Time Factors; Young Adult

BACKGROUND The main purpose of diagnostic imaging after pancreas transplantation is to exclude potential complications. As long as standard anatomical imaging such as sonography, contrast-enhanced computed tomography, and magnetic resonance imaging (MRI) are sufficient to display macroscopic vasculature, early changes within the graft caused by insufficient microperfusion will not be displayed for evaluation. MATERIAL AND METHODS Patients with pancreas allograft function in good condition were included in the study. No specific preparation was demanded before the MRI examination. The results of MRI were correlated with Igls criteria. It was a preliminary study to examine diffusion tensor imaging (DTI) value and safety in pancreas transplantation. RESULTS Our results indicated that higher fractional anisotropy (FA) values of the graft's head were associated with delayed graft function and insulin intake. We also compared grafts' images in early and late periods and found differences in T1 signal intensity values. DTI is a reliable noninvasive tool, requiring no contrast agent, to assess graft microstructure in correlation with its function, with FA values showing the most consistent results. By Igls criteria, no graft failure, 76% had optimal function, 10% had good function, and 14% had marginal function. CONCLUSIONS Our results suggest that DTI can be safely used in patients after pancreas transplantation and is advantageous in detecting early as well as late postoperative complications such as intra-abdominal fluid collection, malperfusion, and ischemia of the graft. Our findings correspond with clinical condition and Igls criteria. DTI is free of ionizing agents and is safe for kidney grafts.

Topics: Adult; Allografts; Anisotropy; C-Peptide; Contrast Media; Delayed Graft Function; Diffusion Tensor Imaging; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Insulin-Secreting Cells; Ischemia; Male; Pancreas Transplantation; Postoperative Complications; Prospective Studies; Transplantation, Homologous; Treatment Outcome

The aim of the study was to evaluate the association between C-peptide levels, glycaemic variability and hypoglycaemia in patients with insulin-treated type 2 diabetes (T2D).. A total of 98 patients with T2D treated with basal-bolus insulin were enrolled in a cross-sectional study. Glycaemic variability and hypoglycaemia were assessed from continuous glucose monitoring (CGM) data recorded over 6 days: Glycemic variability was assessed by calculating the mean coefficient of variation (CV), while hypoglycemia was defined as sensor glucose levels ≤ 3.9 mmol/L or < 3.0 mmol/L. Fasting C-peptide and fasting glucose were measured on day 1.. In patients with insulin-treated T2D, low levels of C-peptide are associated with greater glycaemic variability and higher risk of hypoglycaemia, suggesting that C-peptide levels should be taken into consideration when optimizing insulin treatment and assessing hypoglycaemia risk.

Topics: Aged; Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged

Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA. We conducted a cross-sectional case-control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C-peptide after a mixed-meal tolerance test. We compared self-reported hypoglycaemia (n = 160), HbA. Adults with Type 1 diabetes and preserved endogenous insulin production receiving usual care in the UK have lower daily insulin doses and fewer self-reported hypoglycaemic episodes, but no difference in HbA

Topics: Adolescent; Adult; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Practice Patterns, Physicians'; United Kingdom; Young Adult

Insulin autoimmune syndrome (IAS) is a relatively rare cause of hypoglycemia characterized by endogenous hyperinsulinism and autoantibodies against endogenous insulin despite no prior exposure to exogenous insulin. We present a series of IAS cases and describe the clinical characteristics of these cases.. The medical records of inpatients with the final diagnosis of IAS were collected from August 2007 to August 2017 in Peking Union Medical College Hospital. Clinical characteristics and laboratory test results were summarized. The results of serum glucose, insulin, true insulin, and C-peptide testing during 5-h oral glucose tolerance tests were also summarized. Circulating immune complexes were assessed qualitatively by precipitation with polyethylene glycol (PEG) in some patients.. Sixteen patients were included in this study. Insulin autoimmune antibody test results were found positive in 12 patients and weakly positive in 1 patient. Nine patients had an insulin to C-peptide molar ratio >1, whereas 6 patients had an insulin to C-peptide molar ratio <1. Circulating immune complexes were verified in all 4 patients who had been assessed with PEG. During 5-h oral glucose tolerance tests, the C-peptide level responded earlier to the glucose tolerance and had a shorter peak value period compared with insulin, although C-peptide's fluctuation still lagged behind the glucose fluctuation. Three patients presented with self-limited disease courses or limited disease course after discontinuing use of the sulfhydryl group drugs. Some patients' symptoms were relieved after small frequent meals, and some were relieved after taking acarbose. Only 3 patients took glucocorticoids as the anti-immune therapy.. The insulin to C-peptide molar ratios were not consistently >1 in patients with confirmed diagnoses of IAS in our study, which suggested the low sensitivity of insulin to C-peptide molar ratio to detect IAS. The therapy in our study also revealed the self-limited disease course of IAS, and despite the effectiveness of anti-immunity therapy, convenient therapy, such as frequent small meals and adding acarbose, performed well in many patients.

Topics: Acarbose; Adult; Aged; Aged, 80 and over; Autoantibodies; Autoimmune Diseases; C-Peptide; Child; Female; Glucocorticoids; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Male; Middle Aged; Syndrome; Young Adult

The aim of this study was to determine whether random non-fasting C-peptide (rCP) measurement can be used to assess hypoglycaemia risk in insulin-treated type 2 diabetes.. We compared continuous glucose monitoring-assessed SD of blood glucose and hypoglycaemia duration in 17 patients with insulin-treated type 2 diabetes and severe insulin deficiency (rCP < 200 pmol/l) and 17 matched insulin-treated control patients with type 2 diabetes but who had preserved endogenous insulin (rCP > 600 pmol/l). We then assessed the relationship between rCP and questionnaire-based measures of hypoglycaemia in 256 patients with insulin-treated type 2 diabetes and a comparison group of 209 individuals with type 1 diabetes.. Continuous glucose monitoring (CGM)-assessed glucose variability and hypoglycaemia was greater in individuals with rCP < 200 pmol/l despite similar mean glucose. In those with low vs high C-peptide, SD of glucose was 4.2 (95% CI 3.7, 4.6) vs 3.0 (2.6, 3.4) mmol/l (p < 0.001). In the low-C-peptide vs high-C-peptide group, the proportion of individuals experiencing sustained hypoglycaemia ≤ 4 mmol/l was 94% vs 41% (p < 0.001), the mean rate of hypoglycaemia was 5.5 (4.4, 6.7) vs 2.1 (1.4, 2.9) episodes per person per week (p = 0.004) and the mean duration was 630 (619, 643) vs 223 (216, 230) min per person per week (p = 0.01). Hypoglycaemia ≤ 3 mmol/l was infrequent in individuals with preserved C-peptide (1.8 [1.2, 2.6] episodes per person per week vs 0.4 [0.1, 0.8] episodes per person per week for low vs high C-peptide, p = 0.04) and only occurred at night. In a population-based cohort with insulin-treated type 2 diabetes, self-reported hypoglycaemia was twice as frequent in those with rCP < 200 pmol/l (OR 2.0, p < 0.001) and the rate of episodes resulting in loss of consciousness or seizure was five times higher (OR 5.0, p = 0.001). The relationship between self-reported hypoglycaemia and C-peptide was similar in individuals with type 1 and type 2 diabetes.. Low rCP is associated with increased glucose variability and hypoglycaemia in patients with insulin-treated type 2 diabetes and represents a practical, stable and inexpensive biomarker for assessment of hypoglycaemia risk.

Topics: Aged; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male

Insulinoma is the commonest functioning pancreatic neuroendocrine tumor causing hyperinsulinemic hypoglycemia.. This study is aimed to evaluate the clinical features, preoperative laboratory and imaging diagnosis and pathologic findings of insulinoma.. Data of the patients from 2001 to 2016 diagnosed as insulinoma in Tongji Hospital, China were retrospectively extracted and analyzed.. A total of 40 patients were diagnosed as insulinoma with a male/female ratio of 0.68:1. The median onset age was 46.5 years. Nearly all the included patients presented neurological symptoms and 60% presented autonomic symptoms. More than 95% of the patients met the functional European Neuroendocrine Tumor Society criteria including glucose, insulin and C-peptide levels. The preoperative detection rates of ultrasonography, enhanced computed tomography, magnetic resonance imaging, and endoscopic ultrasonography were 60.50%, 84.95%, 80% and 83.3% respectively. The joint imaging examinations can markedly increase the detection rate. The mean tumor size was 1.89 ± 0.72 cm. Ki-67 index by histopathological diagnosis were all less than 20%. The positive rates of insulin, synaptophysin and chromogranin A were close to 100%.. Laboratory tests of glucose, insulin and C-peptide are reliable for preoperative diagnosis. Combination of the imaging examinations can improve the diagnosis.

Topics: Adult; Aged; Blood Glucose; C-Peptide; China; Endosonography; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Magnetic Resonance Imaging; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Tomography, X-Ray Computed; Ultrasonography; Young Adult

Complete loss of β-cell function in patients with type 1 diabetes mellitus (T1DM) may lead to an increased risk of severe hypoglycemia.. We aimed to determine the impact of C-peptide status on glucagon response and endogenous glucose production (EGP) during hypoglycemia in patients with T1DM.. We conducted an open, comparative trial.. Ten C-peptide positive (C-pos) and 11 matched C-peptide negative (C-neg) patients with T1DM were enrolled.. Plasma glucose was normalized over the night fast, and after a steady-state (baseline) plateau all patients underwent a hyperinsulinemic, stepwise hypoglycemic clamp with glucose plateaus of 5.5, 3.5, and 2.5 mmol/L and a recovery phase of 4.0 mmol/L. Blood glucagon was measured with a specific and highly sensitive glucagon assay. EGP was determined with a stable isotope tracer technique.. Impact of C-peptide status on glucagon response and EGP during hypoglycemia.. Glucagon concentrations were significantly lower in C-pos and C-neg patients than previously reported. At baseline, C-pos patients had higher glucagon concentrations than C-neg patients (8.39 ± 4.6 vs 4.19 ± 2.4 pmol/L, P = 0.016, mean ± standard deviation) but comparable EGP rates (2.13 ± 0.2 vs 2.04 ± 0.3 mg/kg/min, P < 0.391). In both groups, insulin suppressed glucagon levels, but hypoglycemia revealed significantly higher glucagon concentrations in C-pos than in C-neg patients. EGP was significantly higher in C-pos patients at hypoglycemia (2.5 mmol/L) compared with C-neg patients.. Glucagon concentrations and EGP during hypoglycemia were more pronounced in C-pos than in C-neg patients, which indicates that preserved β-cell function may contribute to counterregulation during hypoglycemia in patients with T1DM.

Topics: Adult; Awareness; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Drug Administration Schedule; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Norepinephrine; Young Adult

Insulinoma is a rare pancreatic tumor and, usually, a benign disease but can be a malignant one and, sometimes, a highly aggressive disease. The aim of this study was to determine differences between benign and malignant tumors.. Retrospective study of 103 patients with insulinoma treated in a tertiary center. It was analyzed demographic, clinical, laboratory, localization and histologic analysis of tumor and follow up data of subjects in order to identify differences between individuals benign and malignant disease.. Almost all patients (87%) had a benign tumor and survival rates of 100% following pancreatic tumor surgery. Those with malignant tumors (13%) have a poor prognosis, 77% insulinoma-related deaths over a period of 1-300 months after the diagnosis with a survival rate of 24% in five years. The following factors are associated with an increased risk of malignant disease: duration of symptoms < 24 months, fasting time for the occurrence of hypoglycemia < 8 h, blood plasma insulin concentration ≥ 28 μU/mL and C-peptide ≥ 4.0 ng/mL at the glycemic nadir and tumor size ≥ 2.5 cm.. Our data help to base the literature about these tumors, reinforcing that although insulinoma is usually a single benign and surgically treated neoplasia, the malignant one is difficult to treat. We highlight the data that help predict a malignancy behavior of tumor and suggest a long follow up after diagnosis in these cases.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cohort Studies; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Retrospective Studies; Risk Factors; Survival Analysis; Young Adult

Defined outcomes for beta cell replacement therapy in the treatment of diabetes are critically needed. Progress towards the clinical acceptance of pancreas and islet transplantation has been hampered by the lack of clear definitions of functional and efficacy outcomes, as well as a lack of consistently applied glycaemic control metrics, together with poor alignment with the field of artificial insulin delivery/artificial pancreas development. To address this problem, the International Pancreas & Islet Transplant Association (IPITA) collaborated with the European Pancreas and Islet Transplant Association (EPITA) to develop a consensus for a joint statement on the definition of function and failure of beta cell replacement therapies, which is summarised in this commentary.

Topics: Blood Glucose; C-Peptide; Europe; Glycated Hemoglobin; Guidelines as Topic; Humans; Hypoglycemia; International Cooperation; Islets of Langerhans Transplantation; Pancreas Transplantation; Patient Satisfaction; Societies, Medical; Treatment Outcome

Exposure to high altitude has been shown to enhance both glucose and lipid utilization depending on experimental protocol. In addition, high and low blood glucose levels have been reported at high altitude. We hypothesized that gradual ascent to high altitude results in changes in glucose levels in healthy young adults.. Twenty-five adult volunteers, split into two teams, took part in the British Services Dhaulagiri Medical Research Expedition completing 14 d of trekking around the Dhaulagiri circuit in Nepal reaching a peak altitude of 5300 m on day 11 of the trek. Participants wore blinded continuous glucose monitors (CGM) throughout. Blood samples for C-peptide, proinsulin, and triacylglycerides were taken at sea level (United Kingdom) and in acclimatization camps at 3600, 4650, and 5120 m. Energy intake was determined from food diaries.. There was no difference in time spent in hypoglycemia stratified by altitude. Nocturnal CGM readings (2200-0600 h) were chosen to reduce the short-term effect of physical activity and food intake and showed a significant (P < 0.0001) increase at 3600 m (5.53 ± 0.22 mmol·L), 4650 m (4.77 ± 0.30 mmol·L), and 5120 m (4.78 ± 0.24 mmol·L) compared with baseline altitude 1100 m (vs 4.61 ± 0.25 mmol·L). Energy intake did not differ by altitude. Insulin resistance and beta-cell function, calculated by homeostatic model assessment, were reduced at 3600 m compared with sea level.. We observed a significant increase in nocturnal CGM glucose at 3600 m and greater despite gradual ascent from 1100 m. Taken with the changes in insulin resistance and beta-cell function, it is possible that the stress response to high altitude dominates exercise-enhanced insulin sensitivity, resulting in relative hyperglycemia.

Topics: Acclimatization; Adolescent; Adult; Altitude; Altitude Sickness; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Energy Intake; Female; Homeostasis; Humans; Hypoglycemia; Insulin Resistance; Insulin-Secreting Cells; Male; Proinsulin; Triglycerides; Young Adult

Patient characteristics associated with hypoglycaemia frequency during insulin glargine 100 U/mL (Gla-100) titration and clinical outcomes at Week 24 were examined using participant-level data from 16 treat-to-target trials involving individuals with type 2 diabetes mellitus who were inadequately controlled with oral antidiabetes drugs and were initiating Gla-100 (n = 3549). Hypoglycaemia (plasma glucose <3.9 mmol/L or severe) during the first 8 weeks of titration was stratified by number of events (0, 1-3 and ≥4), resulting in 72.5%, 20.6% and 6.9% of participants in each group, respectively. Changes in glycaemia, body weight and insulin dose from baseline to Weeks 12 and 24 were analysed. Hypoglycaemia was more common in participants with lower BMI and fasting C-peptide, and in those undergoing sulfonylurea treatment. Glycaemic outcomes at Week 24 were similar in each hypoglycaemia group, despite the fact that the Week 24 mean daily dose and dose increase for Gla-100 were highest in participants without hypoglycaemia and were lowest in those experiencing ≥4 events. The risk of hypoglycaemia during Gla-100 titration depends mainly on patient characteristics and on sulfonylurea use and may delay dose titration, which apparently has little effect on short-term glycaemic control in a clinical trial setting.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fasting; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Male; Middle Aged; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Time Factors; Treatment Outcome

Fetal hyperinsulinemia in gestational diabetes mellitus (GDM) not only is important during intrauterine life, a time when it can result in macrosomia, but also at delivery, since it can result in neonatal hypoglycemia and hyperbilirubinemia. The question is, how long before delivery does maternal glycemic control contribute to newborn insulinemia in GDM?. In 72 women with GDM, we calculated Spearman's rank (r. At an early visit (32.95 ± 1.8 weeks), r. To further reduce the risk of hypoglycemia and hyperbilirubinemia in infants born to women with GDM, besides applying a strict in-patient glucose control protocol at delivery, it is necessary to improve even more the quality of maternal glucose control during the last 2 weeks prior to delivery.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes, Gestational; Female; Fetal Blood; Fetal Diseases; Glycated Hemoglobin; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Longitudinal Studies; Pregnancy; Prospective Studies

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy that leads to unfavourable neurological outcome if not treated adequately. In patients with severe diffuse CHI it remains under discussion whether pancreatic surgery should be performed or intensive medical treatment with the acceptance of recurrent episodes of mild hypoglycaemia is justified. Near-total pancreatectomy is associated with high rates of insulin-dependent diabetes mellitus and exocrine pancreatic insufficiency. Little is known about the management and long-term glycaemic control of CHI patients with diabetes after pancreatic surgery. We searched the German/Austrian DPV database and compared the course of 42 CHI patients with diabetes to that of patients with type 1 diabetes mellitus (T1DM). Study groups were compared at diabetes onset and after a follow-up period of 6.1 [3.3-9.7] (median [interquartile range]) years.. The majority of CHI patients with diabetes were treated with insulin (85.2% [70.9-99.5] at diabetes onset, and 90.5% [81.2-99.7] at follow-up). However, compared to patients with T1DM, significantly more patients in the CHI group with diabetes were treated with conventional insulin therapy (47.8% vs. 24.4%, p = 0.03 at diabetes onset, and 21.1% vs. 6.4% at follow-up, p = 0.003), and only a small number of CHI patients were treated with insulin pumps. Daily insulin dose was significantly lower in CHI patients with diabetes than in patients with T1DM, both at diabetes onset (0.3 [0.2-0.5] vs. 0.6 IE/kg/d [0.4-0.8], p = 0.003) and follow-up (0.8 [0.4-1.0] vs. 0.9 [0.7-1.0] IE/kg/d, p = 0.02), while daily carbohydrate intake was comparable in both groups. Within the first treatment year, HbA1c levels were significantly lower in CHI patients with diabetes (6.2% [5.5-7.9] vs. 7.2% [6.5-8.2], p = 0.003), but increased to a level comparable to that of T1DM patients at follow-up. Interestingly, in CHI patients, the risk of severe hypoglycaemia tends to be higher only at diabetes onset (14.8% vs. 5.8%, p = 0.1).. In surgically treated CHI patients insulin treatment needs to be intensified in order to achieve good glycaemic control. Our data furthermore emphasize the need for improved medical treatment options for patients with diazoxide- and/or octreotide-unresponsive CHI.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Child, Preschool; Congenital Hyperinsulinism; Diabetes Mellitus, Type 1; Diazoxide; Female; Humans; Hypoglycemia; Insulin; Male; Octreotide; Pancreas; Pancreatectomy

The hemoglobin glycation index (HGI) is an index of differences in the glycation of hemoglobin according to blood glucose level. The glycation gap (G-gap) is an empiric measure of the extent of disagreement between hemoglobin A1C (HbA1C) and glycated albumin (GA). The aim of this study was to investigate the extent of agreement between the HGI and G-gap with respect to GA level, and to elucidate factors related to a high HGI.. Data were obtained from 105 patients with type 2 diabetes, and fasting blood glucose (FBG), HbA1c, and GA values were measured simultaneously. The G-gap was calculated as the difference between the measured and GA-based predicted HbA1c levels. HGI was calculated as the difference between measured and FBG-based predicted HbA1c levels.. The HGI and G-gap were highly correlated according GA (r=0.722, P<0.001). In general, the two indices were similar in terms of both direction and magnitude. The classification of patients as high, moderate, or low glycators based on HGI versus G-gap was consistent for the majority of the population and only 5% of patients were reclassified from high to low or low to high. Fasting C-peptide levels decreased linearly, and the percentage of patients using insulin increased linearly, between the lowest and highest HGI tertile (both P<0.05).. There was 95% agreement between the HGI and G-gap using GA among type 2 diabetes patients. Furthermore, a high HGI was associated with a higher prevalence of insulin use among type 2 diabetes patients.

Topics: Algorithms; Blood Glucose; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Models, Biological; Reproducibility of Results; Republic of Korea; Retrospective Studies; Serum Albumin; Severity of Illness Index; Up-Regulation

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a hereditary metabolic disease arising from biallelic mutations of SLC25A13. This study aimed to explore the characteristics of fasting blood glucose (FBG), fasting insulin (FINS) and C-peptide (C-P) levels in NICCD infants, analyze their SLC25A13 genetic mutations and further discuss the correlation between SLC25A13 genetic mutations and biochemical changes. Seventy-two cases of infants with cholestasis disease were gathered. Among them, 36 cases with NICCD diagnosis were case group. Meanwhile, 36 cases with unknown etiology but excluded NICCD were control group. FBG, FINS, C-P, ALT, AST, GGT, ALP, TG, HDL-C, LDL-C and Non-HDL-C were collected from all subjects, and DNA was extracted from venous blood for SLC25A13 mutations detection. The incidence of hypoglycemia was 3% in NICCD group. There were no significant statistical difference of FBG, FINS and C-P between NICCD and INC groups ( P > 0.05). ALT, LDL-C and Non-HDL-C levels in NICCD group were lower than the INC group, while SLC25A13 mutations were associated with the level of GGT ( P < 0.05). Ten different SLC25A13 genetic mutations were detected, among which, 851del4, IVS16ins3kb, IVS6+5 G > A and 1638ins23 mutations made up 82% of all mutations. The incidence of hypoglycemia may be higher in small gestational age infants with NICCD. Low LDL-C may be one of the characteristics of dyslipidemia in NICCD infants. There was a correlation between SLC25A13 gene mutations distribution and the GGT level, but the meaning of this finding remains to be further in-depth study. Impact statement This study aims to compare FBG, FINS, C-P, other biochemical and clinical manifestations between NICCD and non-NICCD infants, and discuss differential diagnosis of NICCD and INC beyond the genetic analysis. And investigate the correlation between SLC25A13 genetic mutations and biochemical changes. This work presented that incidence of hypoglycemia may be higher in small gestational age infants with NICCD. Low LDL-C may be one of the characteristics of dyslipidemia in NICCD infants. There was a correlation between SLC25A13 gene mutations distribution and the GGT level.

Topics: Blood Glucose; C-Peptide; Cholestasis; Citrullinemia; Diagnosis, Differential; Female; Humans; Hypoglycemia; Incidence; Infant; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Male; Mitochondrial Membrane Transport Proteins; Mutation

The 72-hour fast is used to document Whipple's triad and understand the mechanism of hypoglycemia. Although hypoglycemia develops within 24 hours in the majority of fasts, identifying possible determinants of fast duration may help to predict the need for admission. Therefore, we determined the relation between anthropometric features on fast duration and assessed end of fast parameters on maximal tumor size, extent of disease, or tumor recurrence.. A retrospective analysis of patients with insulinoma in the past 25 years who underwent a 72-hour fast was conducted. Electronic medical records were reviewed to obtain anthropometric patient data and tumor characteristics.. A total of 233 patients underwent the 72-hour fast. The mean age at diagnosis was 50 ± 16 years, with a body mass index (BMI) of 29 ± 7 kg/m. Duration of fast was not significantly related age, gender, weight, or BMI, although end-of-fast C-peptide and proinsulin may provide some information regarding tumor characteristics. Consequently, the duration of fast cannot be predicted a priori and should be allowed to run for the planned length unless hypoglycemia develops. Abbreviation: BMI = body mass index.

Topics: Adult; Aged; Anthropometry; Blood Glucose; Body Mass Index; C-Peptide; Fasting; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin; Retrospective Studies; Time Factors; Tumor Burden

Pancreas transplantation (PTx) represents the method of choice in type 1 diabetic patients with conservatively intractable hypoglycemia unawareness syndrome. In 2005, the Institute for Clinical and Experimental Medicine (IKEM) launched a program to investigate the safety potential of islet transplantation (ITx) in comparison to PTx.. This study aims to compare the results of PTx and ITx regarding severe hypoglycemia elimination, metabolic control, and complication rate.. We analyzed the results of 30 patients undergoing ITx and 49 patients treated with PTx. All patients were C-peptide-negative and suffered from hypoglycemia unawareness syndrome. Patients in the ITx group received a mean number of 12,349 (6,387-15,331) IEQ/kg/person administered percutaneously into the portal vein under local anesthesia and radiological control. The islet number was reached by 1-3 applications, as needed. In both groups, we evaluated glycated hemoglobin, insulin dose, fasting and stimulated C-peptide, frequency of severe hypoglycemia, and complications. We used the Mann Whitney test, Wilcoxon signed-rank test, and paired t-test for analysis. We also individually assessed the ITx outcomes for each patient according to recently suggested criteria established at the EPITA meeting in Igls.. Most of the recipients showed a significant improvement in metabolic control one and two years after ITx, with a significant decrease in HbA1c, significant elevation of fasting and stimulated C-peptide, and a markedly significant reduction in insulin dose and the frequency of severe hypoglycemia. Seventeen percent of ITx recipients were temporarily insulin-independent. The results in the PTx group were comparable to those in the ITx group, with 73% graft survival and insulin independence in year 1, 68% 2 years and 55% 5 years after transplantation. There was a higher rate of complications related to the procedure in the PTx group. Severe hypoglycemia was eliminated in the majority of both ITx and PTx recipients.. This report proves the successful initiation of pancreatic islet transplantation in a center with a well-established PTx program. ITx has been shown to be the method of choice for hypoglycemia unawareness syndrome, and may be considered for application in clinical practice if conservative options are exhausted.

Topics: Adult; Blood Glucose; C-Peptide; Choice Behavior; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Graft Survival; Humans; Hypoglycemia; Islets of Langerhans Transplantation; Male; Middle Aged; Pancreas Transplantation; Retrospective Studies; Risk Assessment; Syndrome; Young Adult

Antibodies against exogenous insulin are common in type 1 diabetes mellitus patients. They can cause hypoglycemia, albeit uncommonly.. A 14-year-old girl with type 1 diabetes mellitus presented with recurrent hypoglycemia.. High insulin, low C-peptide and raised insulin antibody levels documented during hypoglycemia. Plasmapheresis led to remission of hypoglycemia.. Antibodies to exogenous insulin should be considered as a cause of recurrent refractory hypoglycemia in type 1 diabetes mellitus patients.

Topics: Adolescent; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Insulin; Insulin Antibodies

Diabetes frequently develops in patients with chronic pancreatitis. We examined the alterations in the glucagon response to hypoglycemia and to oral glucose administration in patients with diabetes due to chronic pancreatitis.. Ten patients with diabetes secondary to chronic pancreatitis were compared with 13 patients with type 2 diabetes and 10 healthy control subjects. A stepwise hypoglycemic clamp and an oral glucose tolerance test (OGTT) were performed.. Glucose levels during the OGTT were higher in patients with diabetes and chronic pancreatitis and lower in control subjects (. α-Cell responses to oral glucose ingestion and to hypoglycemia are disturbed in patients with diabetes and chronic pancreatitis and in patients with type 2 diabetes. The similarities between these defects suggest a common etiology.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose Tolerance Test; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Pancreatitis, Chronic

The aim of the study was to address the origin and natural history of malignant insulinoma.. Retrospective review of medical records of patients diagnosed with insulinoma at Cedars-Sinai Medical Center between 2000 and 2015 was conducted. Hormonal expression in tumor specimens was examined by immunostaining.. All the 9 patients with malignant insulinoma (35% of 26 patients with insulinoma) already had liver metastasis at hypoglycemia presentation with bulky cumulative tumor burden. Six patients had de novo diagnosis, 2 had known metastatic nonfunctioning pancreatic neuroendocrine tumor, and 1 had a known pancreatic mass. Tumor grade at presentation was G1 in 4 patients, G2 in 4, and unknown in 1. Four patients died 2 to 32 months after presentation, all with extensive liver tumor involvement. Tumor expression of proinsulin and insulin was heterogeneous and overall infrequent. The proinsulin levels and proinsulin/insulin molar ratio in patients with malignant versus benign insulinoma were 334 versus 44 pmol/L and 2.1 versus 0.9, respectively.. Malignant insulinoma seems to arise from and behave like nonfunctioning pancreatic neuroendocrine tumor oncologically but with metachronous hyperinsulinemic hypoglycemia. High proinsulin levels and proinsulin/insulin molar ratio may suggest malignant insulinoma.

Topics: Adult; Aged; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Proinsulin; Retrospective Studies

In patients with Type 2 diabetes, intensive glycaemic control is associated with hypoglycaemia and possibly increased mortality. However, no blood biomarkers exist to predict these outcomes. Using participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesized that insulin deficiency and islet autoantibodies in patients with clinically diagnosed Type 2 diabetes would be associated with severe hypoglycaemia and death.. A nested case-control study design was used. A case (n = 86) was a participant who died with at least one episode of severe hypoglycaemia, defined as hypoglycaemia requiring assistance, at any point during ACCORD follow-up. A control (n = 344) was a participant who did not die and did not have severe hypoglycaemia during follow-up. Each case was matched to four controls (glycaemic intervention arm, race, age and BMI). Baseline insulin deficiency (fasting C-peptide ≤ 0.15 nmol/l) and islet autoantibodies [glutamic acid decarboxylase (GAD), tyrosine phosphatase-related islet antigen 2 (IA2), insulin (IAA) and zinc transporter (ZnT8)] were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used.. Death during ACCORD in those who experienced at least one episode of severe hypoglycaemia was associated with insulin deficiency [OR 4.8 (2.1, 11.1): P < 0.0001], GAD antibodies [OR 2.3 (1.1, 5.1): P = 0.04], the presence of IAA or baseline insulin use [OR 6.1 (3.5,10.7): P < 0.0001], which remained significant after adjusting for age, BMI, and diabetes duration. There was no significant association with IA2 or ZnT8 antibodies.. In patients with Type 2 diabetes, C-peptide or GAD antibodies may serve as blood biomarkers predicting higher odds of subsequent severe hypoglycaemia and death. (Clinical Trial Registry No: NCT00000620, www.clinicaltrials.gov for original ACCORD study).

Topics: Aged; Autoantibodies; Biomarkers; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glutamate Decarboxylase; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Logistic Models; Male; Middle Aged; Mortality; Receptor-Like Protein Tyrosine Phosphatases, Class 8; Severity of Illness Index; Zinc Transporter 8

We report the long-term follow-up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C-peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin-independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A1c was 6.3% (45 mmol/mol). All subjects experienced progressive decline in the C-peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glycated Hemoglobin; Graft Survival; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans Transplantation; Male; Middle Aged; Prognosis; Risk Factors

Severe hypoglycemia is common in older adults with long-standing type 1 diabetes, but little is known about factors associated with its occurrence.. A case-control study was conducted at 18 diabetes centers in the T1D Exchange Clinic Network. Participants were ≥60 years old with type 1 diabetes for ≥20 years. Case subjects (n = 101) had at least one severe hypoglycemic event in the prior 12 months. Control subjects (n = 100), frequency-matched to case subjects by age, had no severe hypoglycemia in the prior 3 years. Data were analyzed for cognitive and functional abilities, social support, depression, hypoglycemia unawareness, various aspects of diabetes management, C-peptide level, glycated hemoglobin level, and blinded continuous glucose monitoring (CGM) metrics.. Glycated hemoglobin (mean 7.8% vs. 7.7%) and CGM-measured mean glucose (175 vs. 175 mg/dL) were similar between case and control subjects. More case than control subjects had hypoglycemia unawareness: only 11% of case subjects compared with 43% of control subjects reported always having symptoms associated with low blood glucose levels (P < 0.001). Case subjects had greater glucose variability than control subjects (P = 0.008) and experienced CGM glucose levels <60 mg/dL for ≥20 min on 46% of days compared with 33% of days in control subjects (P = 0.10). On certain cognitive tests, case subjects scored worse than control subjects.. In older adults with long-standing type 1 diabetes, greater hypoglycemia unawareness and glucose variability are associated with an increased risk of severe hypoglycemia. A study to assess interventions to prevent severe hypoglycemia in high-risk individuals is needed.

Topics: Aged; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Risk Factors

The most common cause of organic fasting hypoglycemia in adults is the presence of an insulin-producing pancreatic adenoma, but when high insulin levels are not found, the differential diagnosis is challenging. Misdiagnosis can lead to an unnecessary pancreatectomy. Insulin concentrations may be low in some cases despite a clinical history suggestive of insulinoma. In these cases, a proinsulinoma should be suspected, although the rarity of this condition requires an extensive workup before reaching a final diagnosis. We describe an unusual case of a 38-year-old man with a severe hypoglycemic syndrome due to a proinsulin-secreting pancreatic adenoma. Insulin was measured by the specific assay and suppressed under the lower detection limit during fasting hypoglycemia. Serum proinsulin and C-peptide levels were abnormally elevated, and further tests revealed an islet cell tumor. The tumor was surgically removed, relieving the fasting hypoglycemia. Histopathological study showed a conventional well-differentiated neuroendocrine tumor with high immunoreactivity against proinsulin and with lesser intensity against insulin. Interestingly, GS-9A8 antibody clone used for immunostaining proinsulin did not cross-react with human insulin or C-peptide, providing an unbiased picture of proinsulin secretion. The resolution of symptoms, the fall of proinsulin concentrations after tumor removal and the histopathology study confirmed the diagnosis of proinsulinoma.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Pancreatic Neoplasms; Proinsulin; Syndrome

Most cases of insulinomas are benign. We report a case of a malignant form of insulinoma. A 46-year-old man presented with behavioural changes associated with hypoglycaemia. Diagnostic work up revealed high serum insulin, high C-peptide and low glucose levels, compatible with endogenous hyperinsulinaemic hypoglycaemia. CT imaging of the abdomen revealed a pancreatic head mass and multiple liver masses. Biopsy of the pancreatic mass revealed a grade three pancreatic neuroendocrine carcinoma. Histological analysis of a liver mass showed that it was identical to the pancreatic mass, confirming its metastatic nature. The patient underwent distal pancreatectomy with en bloc splenectomy. There was persistence of hypoglycaemic symptoms after removal of the pancreatic mass, suggesting that the liver metastases were also functioning. Symptoms were controlled by diazoxide and octreotide long-acting release. The patient is already 1 year postsurgery with no recurrence of severe hypoglycaemia, and he has good functional capacity and has returned to his office job.

Topics: Biopsy; Blood Glucose; C-Peptide; Carcinoma, Neuroendocrine; Diazoxide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Liver Neoplasms; Male; Middle Aged; Octreotide; Pancreas; Pancreatectomy; Pancreatic Neoplasms

What is the prevalence of reactive hypoglycemia (RH) in polycystic ovary syndrome (PCOS) versus age- and body mass index (BMI)-matched healthy controls.. The prevalence of RH was increased in PCOS versus controls.. Previous studies suggested an increased prevalence of RH in PCOS.. Cross-sectional study of 88 women with PCOS and 34 healthy age- and BMI-matched controls.. Eighty-eight women with PCOS and 34 age- and BMI-matched controls were included. The study was conducted at Odense University Hospital, Denmark. Participants underwent 5 h oral glucose tolerance test (5 h OGTT). Indices of insulin resistance, β-cell function, and area under the curve (AUC) for glucose, insulin and C-peptide were calculated. Insulin clearance was estimated as 5 h AUC C-peptide/insulin. RH was defined as blood glucose ≤3.3 mmol/l during 5 h OGTT.. RH occurred in 15/88 (17%) women with PCOS versus 0/34 controls ( ITALIC! P = 0.01). Nine out of 15 women with RH were obese and 6 were lean ( ITALIC! P = 0.42). Obese patients with RH had significantly higher 5 h AUCs insulin and C-peptide compared with lean patients with RH ( ITALIC! P = 0.02 and 0.04, respectively). Obese patients with RH had significantly lower 5 h AUC C-peptide/insulin versus obese patients without RH ( ITALIC! P = 0.02). In lean patients with RH, 5 h AUCs insulin and C-peptide were similar to lean controls.. The 5 h OGTT was used to diagnose RH and may be a limitation of the study. Although the 5 h OGTT is the most widely accepted method, no gold standard exists in terms of diagnosing RH. The 5 h OGTT was suggested to over-estimate the incidence of RH compared with meal test.. The study supports previous suggestions of increased prevalence of RH in women with PCOS compared with controls.. This study was funded by Jacob Madsen's and Olga Madsen's Foundation, Institute of Clinical Research, Odense University Hospital, Kolding Hospital, AP Møller's Foundation, Bernhard and Marie Kleins Foundation, The Novo Nordisk Foundation, and The Danish Medical Association. The authors declare no conflict of interest.. The trial was registered at www.clinicaltrials.gov (registration numbers NCT00451568 (patients) and NCT01995773 (controls)).

Topics: Adolescent; Adult; Area Under Curve; Blood Glucose; Body Mass Index; C-Peptide; Cross-Sectional Studies; Denmark; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Resistance; Obesity; Polycystic Ovary Syndrome; Prevalence

History and admission findings | A 41year old woman presented at our internistic clinic after treatment by an emergency doctor because of confusion and amnesia accompanied by a hypoglycaemic episode while driving her car. Only by giving continuous glucose intravenously a stable clinical state could be achieved. In her medical history she took Lamotrigin for 12 years since she had seizures of unknown aetiology. 16 years ago she had similar sudden attacks with confusion and hypoglycaemia. At that time thorough diagnostics at the clinic for internal medicine did not reveal any evidence for hyperinsulinaemia. While taking Lamotrigin the patient had no seizures or similar symptoms for 12 years. Treatment and course | In the present case we detected a tumor in the pancreas and a two-fold increased insulin secretion. Histopathological work-up of the removed tissue confirmed the suspected diagnosis of insulinoma. Postoperatively, Lamotrigin treatment was terminated. Since then the patient remained asymptomatic.

Topics: Adult; Amnesia; Anticonvulsants; C-Peptide; Confusion; Endosonography; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Lamotrigine; Pancreatic Neoplasms; Recurrence; Seizures; Tomography, X-Ray Computed; Triazines

A 61-year-old woman with multiple metastatic and unresectable gastrointestinal stromal tumors (GISTs) was referred for investigation of refractory hypoglycemia that developed four months before this hospitalization. On admission, her fasting plasma glucose was 38 mg/dL despite 10% glucose infusion. Investigations revealed that her serum C-peptide, insulin and growth hormone levels were suppressed, and big insulin-like growth factor II was observed. She was diagnosed with non-islet cell tumor hypoglycemia, which resolved after glucocorticoid treatment. Clinicians should thus be vigilant to identify hypoglycemia in patients with large metastatic GISTs because glucocorticoid therapy is useful even if the GIST is inoperable.

Topics: Blood Glucose; C-Peptide; Female; Gastrointestinal Stromal Tumors; Glucocorticoids; Human Growth Hormone; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor II; Middle Aged

HNF4A is an established cause of maturity onset diabetes of the young (MODY). Congenital hyperinsulinism can also be associated with mutations in the HNF4A gene. A dual phenotype is observed in HNF4A-MODY with hyperinsulinaemic hypoglycaemia in the neonatal period progressing to diabetes in adulthood. The nature and timing of the transition remain poorly defined. We performed an observational study to establish changes in glycaemia and insulin secretion over a 6-year period. We investigated glycaemic variability and hypoglycaemia in HNF4A-MODY using a continuous glucose monitoring system (CGMS).. An OGTT with measurement of glucose, insulin and C-peptide was performed in HNF4A participants with diabetes mellitus (DM) (n = 14), HNF4A-IGT (n = 7) and age- and BMI-matched MODY negative family members (n = 10). Serial assessment was performed in the HNF4A-IGT cohort. In a subset of HNF4A-MODY mutation carriers (n = 10), CGMS was applied over a 72-h period.. There was no deterioration in glycaemic control in the HNF4A-IGT cohort. The fasting glucose-to-insulin ratio was significantly lower in the HNF4A-IGT cohort when compared to the normal control group (0.13 vs. 0.24, p = 0.03). CGMS profiling demonstrated prolonged periods of hypoglycaemia in the HNF4A-IGT group when compared to the HNF4A-DM group (432 vs. 138 min p = 0.04).. In a young adult HNF4A-IGT cohort, we demonstrate preserved glucose, insulin and C-peptide secretory responses to oral glucose. Utilising CGMS, prolonged periods of hypoglycaemia are evident despite a median age of 21 years. We propose a prolonged hyperinsulinaemic phase into adulthood is responsible for the notable hypoglycaemic episodes.

Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 2; Disease Progression; Female; Glucose Tolerance Test; Hepatocyte Nuclear Factor 4; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Mutation

Prediction of risk of severe hypoglycemia (SH) in patients with type 1 diabetes is important to prevent future episodes, but it is unknown if it is possible to predict the long-term risk of SH. The aim of the study is to assess if long-term prediction of SH is possible in type 1 diabetes.. A follow-up study was performed with 98 patients with type 1 diabetes. At baseline and at follow-up, the patients filled in a questionnaire about diabetes history and complications, number of SH in the preceding year and state of awareness, and HbA1c and C-peptide levels were measured.. During the 12 years of follow-up, there was a decrease in HbA1c, C-peptide levels, and incidence of SH (1.1 to 0.4 episodes per patient-year; P < .001). At baseline, the relative rate of SH was 3.6 (P = .001) and 10.9 (P < .0001) in patients with impaired awareness and unawareness of hypoglycemia, respectively, as compared to patients with normal awareness. At follow-up, patients with unawareness at baseline tended to have maintained an increased rate of SH (RR = 3.1; P = .07). Impaired awareness, HbA1c and C-peptide determined at baseline did not correspond with an increased rate of SH at follow-up.. Long-term prediction of severe hypoglycemia in type 1 diabetes was not possible, although baseline hypoglycemia unawareness tended to remain a predictor for risk of SH at follow-up. Therefore, it is important repeatedly to assess the different risk factors of SH to determine the actual risk.

Topics: Adult; Aged; C-Peptide; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glycated Hemoglobin; History, 17th Century; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Insulin; Male; Middle Aged; Risk Factors

Topics: Adult; Antidepressive Agents, Second-Generation; Blood Glucose; C-Peptide; Cyclohexanols; Drug Overdose; Female; Glucose; Humans; Hypoglycemia; Insulin; Venlafaxine Hydrochloride

Maintenance of endogenous pancreatic β-cell function could be an important goal in the management of type 1 diabetes. However, the impact of stimulated C-peptide level on overall glycemic control is unknown. The relationship between C-peptide and parameters of glucose control was therefore characterized in a cohort with rapidly changing β-cell function following islet transplantation.. Standardized mixed-meal tolerance test was undertaken in 12 consecutive islet recipients at 1-6-month intervals, with graft function determined by 90-min stimulated C-peptide. Continuous glucose monitoring was undertaken in the week preceding each assessment and the relationship between C-peptide and glucose control evaluated by mixed Poisson regression.. Recipients completed 5 (1-14) [median (range)] clinical assessments over 18 (1-51) months posttransplant encompassing a wide range of stimulated C-peptide levels (7-2,622 pmol/L). Increasing β-cell function across predefined C-peptide groups was associated with reduced insulin dose, HbA1c, mean glucose (low [<200 pmol/L] 10.7 vs. excellent [>1,000 pmol/L] 7.5 mmol/L), and glucose SD (low, 4.4 vs. excellent, 1.4 mmol/L). Highly statistically significant continuous associations between stimulated C-peptide and mean interstitial glucose (lower by 2.5% [95% CI 1.5-3.5%] per 100 pmol/L higher C-peptide), glucose SD, time outside glucose target range, and measures of hyper-/hypoglycemia risk were confirmed.. Repeated assessment of islet transplant recipients has enabled modeling of the relationship between endogenous β-cell function and measures of glycemic control providing quantitative estimates of likely impact of an acute change in β-cell function in individuals with type 1 diabetes.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Islets of Langerhans Transplantation; Male; Middle Aged; Prospective Studies

Small studies using ultrasensitive C-peptide assays suggest endogenous insulin secretion is frequently detectable in patients with long-standing type 1 diabetes (T1D), but these studies do not use representative samples. We aimed to use the stimulated urine C-peptide-to-creatinine ratio (UCPCR) to assess C-peptide levels in a large cross-sectional, population-based study of patients with T1D.. We recruited 924 patients from primary and secondary care in two U.K. centers who had a clinical diagnosis of T1D, were under 30 years of age when they received a diagnosis, and had a diabetes duration of >5 years. The median age at diagnosis was 11 years (interquartile range 6-17 years), and the duration of diabetes was 19 years (11-27 years). All provided a home postmeal UCPCR, which was measured using a Roche electrochemiluminescence assay.. Eighty percent of patients (740 of 924 patients) had detectable endogenous C-peptide levels (UCPCR >0.001 nmol/mmol). Most patients (52%, 483 of 924 patients) had historically very low undetectable levels (UCPCR 0.0013-0.03 nmol/mmol); 8% of patients (70 of 924 patients) had a UCPCR ≥0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycemia. Absolute UCPCR levels fell with duration of disease. Age at diagnosis and duration of disease were independent predictors of C-peptide level in multivariate modeling.. This population-based study shows that the majority of long-duration T1D patients have detectable urine C-peptide levels. While the majority of patients are insulin microsecretors, some maintain clinically relevant endogenous insulin secretion for many years after the diagnosis of diabetes. Understanding this may lead to a better understanding of pathogenesis in T1D and open new possibilities for treatment.

Topics: Adult; C-Peptide; Child; Creatinine; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Insulin; Insulin Secretion; Male; Postprandial Period; Time Factors; Young Adult

A 63-year-old man was diagnosed with diabetes mellitus at 42 years of age. He subsequently exhibited poor blood glucose control for a prolonged period, and his renal failure worsened. He therefore underwent hemodialysis and abdominal magnetic resonance imaging, which revealed a mass in the pancreatic tail. The immunoreactive insulin and C-peptide immunoreactivity levels were significantly elevated, and the results of a fasting test led to a diagnosis of insulinoma. The patient received treatment with oral diazoxide and continuous glucose monitoring (CGM), which resulted in the resolution of the hypoglycemia. This is a rare case of renal failure in which the CGM findings showed improvements in the blood glucose level after diazoxide administration.

Topics: Antihypertensive Agents; Biomarkers, Tumor; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diazoxide; Humans; Hypoglycemia; Insulin; Insulinoma; Kidney Failure, Chronic; Male; Middle Aged; Pancreatic Neoplasms; Renal Dialysis; Treatment Outcome; Vasodilator Agents

Insulinomas are rare neuroendocrine tumours (NETs) of the pancreas, characterized clinically by neuroglycopenic symptoms during periods of substrate deficiency. The gold standard test for diagnosing an insulinoma is a 72-h fast. However, the prognostic value of parameters in the standardized 72-h fast on histopathological tumour criteria and clinical presentation has not been examined.. In thirty-three patients diagnosed with an insulinoma records, and data were investigated retrospectively. Histopathological tumour characteristics, including staging, grading and size, were reviewed. Grading was performed using Ki-67 index. Cut-off values for classical grading (G(clas)) were set at G1(clas) ≤ 2%, G2(clas) 3-20% & G3(clas) >20% and for modified grading (G(mod)) at G1(mod) <5%, G2(mod) 5-20% & G3(mod) >20%.. When G(mod) criteria were applied, the initial blood glucose was lower in GII/III(mod) patients compared to GI(mod) (2.8 ± 0.8 vs 3.8 ± 1.3 mmol/l; P = 0.046). Basal and end of fast levels of insulin (basal insulin 71 ± 61 vs 20 ± 16 mU/l; P < 0.001; end of fast insulin 77 ± 51 vs 21 ± 20 mU/l; P < 0.001) and c-peptide (basal c-peptide 5.4 ± 2.4 vs 2.7 ± 1.6 μg/l; P = 0.004; end of fast c-peptide 5.3 ± 2.4 vs 2.5 ± 1.4 μg/l; P = 0.001) were significantly higher in GII/III(mod) than in GI(mod). No differences between the groups were observed when G(clas) criteria were applied. Additionally, close correlations were observed between insulin concentration, Ki-67 index and tumour size.. This study shows an impact of histopathological tumour characteristics in patients suffering from an insulinoma on clinical presentation during a standardized 72-h fast. Lower initial blood glucose levels and higher concentrations of insulin and c-peptide are associated with worse tumour grading and larger tumour size.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cohort Studies; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Pancreatic Neoplasms; Retrospective Studies; Tumor Burden

To investigate the characteristics of immunological hypoglycemia associated with insulin antibodies (IAbs) induced by exogenous insulin in Chinese patients with diabetes.. The clinical data of patients with immunological hypoglycemia due to IAbs were retrospectively analyzed by screening patients with diabetes discharged from West China Hospital from 2007 to 2013.. A total of 11 patients (eight men and three women) were identified. Insulin-C-peptide separation was found in all patients via insulin and C-peptide release test. Previous insulin use was ceased after admission and was switched to oral hypoglycemic agents (OHAs) (8/11), lifestyle modification only (2/11), or regular human insulin (1/11). Hypoglycemia was ameliorated after a median of 20 days (interquartile range [IQR], 11-40), while IAbs turned negative after a median of 17 months (IQR, 4-19), and serum immunoreactive insulin (IRI) levels dropped substantially after a median of 22 months (IQR, 9-32) in these cases.. In insulin-treated patients with unexpected and refractory hypoglycemia even after insulin therapy was gradually reduced or even withdrawn, IAbs induced by exogenous insulin should be considered, and insulin withdrawal might be promptly needed. The course of immunological hypoglycemia was benign and self-limited.

Topics: Aged; Blood Glucose; C-Peptide; China; Diabetes Mellitus; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Antibodies; Male; Middle Aged; Retrospective Studies

Blood insulin and C-peptide are key investigations in the differential diagnosis of hypoglycaemia. Analogues of insulin have modified primary-sequences compared to native human insulin, as such may not cross react with insulin assays. This has important implications in detecting surreptitious or malicious insulin administration. The aim of this study is to assess the cross-reactivity of all insulins currently listed in the British National Formulary (BNF65, 2013) in clinical insulin assays currently used in UK clinical laboratories.. Sample sets were prepared for all 15 exogenous insulin classes listed in the BNF, at concentrations of 1000 pmol/L and 300 pmol/L, using pooled human serum. Samples were sent blinded to 5 participating analytical laboratories to cover analysis on the 10 major clinical insulin assays used in the UK.. The ability of insulin assays to detect exogenous insulin preparations was highly variable and ranged from 0% to >140% for a single exogenous insulin. Four assays were highly specific for the human insulin sequence and had no cross-reactivity with any synthetic analogue insulin. Two detected all insulin types (human sequence, animal and synthetic analogue), with the remaining having variable cross-reactivity.. The cross-reactivity of the 15 exogenous insulin preparations is highly variable in the assays used in clinical laboratories around the UK. It is important that laboratories and clinicians are aware of the limitations of their local assays to avoid missing the important diagnosis of hypoglycaemia secondary to excessive exogenous insulin. Where necessary, samples should be referred to specialist centres for insulin analysis and ideally by a validated and fully-quantitative mass spectrometry-based method.

Topics: Antibodies, Monoclonal; Biomarkers; C-Peptide; Cross Reactions; Humans; Hypoglycemia; Immunoassay; Insulin; Prescription Drugs; Sensitivity and Specificity

To test potential efficacy of liraglutide, a GLP-1 receptor agonist, in subjects with type 1 diabetes (T1DM).. We have recruited nine T1DM patients (age 40.1 ± 6.4 years, duration of diabetes 19.2 ± 8.8 years, BMI 24.3 ± 3.5 kg/m(2), HbA1c 8.2 ± 1.0 %-66 ± 11 mmol/mol, daily insulin dose: 0.6 ± 0.1 IU/kg) on continuous subcutaneous insulin therapy with undetectable C-peptide. In addition to existing treatment was administered in single-blind (a) therapy subcutaneously with 0.1 ml of saline solution for 3 days and (b) 0.1 ml of liraglutide (0.6 mg/day) for a further 3 days with daily glucose excursions recorded by continuous glucose monitoring.. Adding liraglutide resulted in a significant reduction in mean blood glucose (138 ± 29 vs. 163 ± 29 mg/dl, p < 0.0001) and standard deviation (42 ± 9 vs. 60 ± 15 mg/dl, p < 0.0001). The area under the curve (AUC) for blood glucose >140 mg/dl was also significantly reduced (22.2 ± 16.4 vs. 41.1 ± 19.7 mg/dl h, p < 0.05) with no difference in AUC for blood glucose <70 mg/dl (liraglutide 0.7 ± 0.9 mg/dl h; placebo: 0.8 ± 1.4 mg/dl h, p = NS). Finally, adding liraglutide reduced daily insulin requirement (37.5 ± 17.2 vs. 42.9 ± 22.4 UI/day, p < 0.01).. Short-term treatment with liraglutide, in T1DM, reduces average blood glucose, blood glucose variability and daily insulin requirement without increasing risk of hypoglycemia.

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Middle Aged

We report the successful treatment of autoimmune hypoglycemia in an 82-year-old non-diabetic Caucasian male with hydrothermally modified slow release corn starch, a product which is used in other conditions associated with hypoglycemia, most typically glycogen storage disease type I. An 82-year-old-Caucasian male presented with recurrent spontaneous hypoglycemia as low as 30 mg/dl following in-patient treatment for community acquired pneumonia. During a fasting-test, symptomatic hypoglycemia occurred. Plasma concentrations of c-peptide and insulin were considerably elevated. Autoimmune hypoglycemia was confirmed by the presence of insulin autoantibodies. While dietary restriction alone did not result in sufficient glucose control in this patient with autoimmune hypoglycemia, treatment with hydrothermally modified slow release corn starch led to stable euglycemia. This easy, well tolerated and non-invasive treatment may constitute a new therapeutic option for hypoglycemia in patients with autoimmune hypoglycemia who do not achieve sufficient control of hypoglycemia by dietary restriction alone.

Topics: Aged, 80 and over; C-Peptide; Delayed-Action Preparations; Glycogen Storage Disease Type I; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Male; Starch; Zea mays

Hypoglycemia in apparently healthy adults is a rare finding in clinical practice requiring a thorough investigation of the cause. During the investigation, identification of hypoglycemia associated with inappropriately high levels of insulin and C-peptide should prompt the exclusion of rare causes of hypoglycemia, including pancreatic islet-cells disease and autoimmune hypoglycemia. In this paper, we describe two cases of hypoglycemia associated with endogenous hyperinsulinism, whose causes are uncommon in clinical practice, and review important aspects of the diagnosis and treatment of hyperinsulinemic hypoglycemia.

Topics: C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Multiple Myeloma; Pancreas; Pancreatic Neoplasms; Proinsulin; Ultrasonography

Anti-CD3 antibody has been employed for various immune-mediated disorders. However, whether anti-CD3 administration leads to rapid metabolic alternation has not been well investigated. In the current study, we studied how anti-CD3 treatment affected blood glucose levels in mice. We found that anti-CD3 treatment induced immediate reduction of blood glucose after administration. Furthermore, a single dose of anti-CD3 treatment corrected hyperglycemia in all nonobese diabetic mice with recently diagnosed diabetes. This glucose-lowering effect was not attributable to major T cell produced cytokines. Of interest, when tested in a normal strain of mice (C57BL/6), the serum levels of C-peptide in anti-CD3 treated animals were significantly lower than control mice. Paradoxically, anti-CD3 treated animals were highly tolerant to exogenous glucose challenge. Additionally, we found that anti-CD3 treatment significantly induced activation of T and B cells in vitro and in vivo. Further studies demonstrated that anti-CD3 treatment lowered the glucose levels in T cell culture media and increased the intracellular transportation of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2 deoxyglucose (2-NBDG) particularly in activated T and B cells. In addition, injection of anti-CD3 antibodies induced enhanced levels of Glut1 expression in spleen cells. This study suggests that anti-CD3 therapy-induced hypoglycemia likely results from increased glucose transportation and consumption by the activated lymphocytes.

Topics: Animals; Antibodies, Monoclonal; Biological Transport; Blood Glucose; C-Peptide; CD3 Complex; Cytokines; Diabetes Mellitus, Experimental; Glucose; Glucose Tolerance Test; Hypoglycemia; Inflammation Mediators; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred NOD; Mice, Knockout

Roux-and-Y gastric bypass (RYGB) rapidly reduces insulin requirements in patients with insulin-dependent type 2 diabetes mellitus (T₂DMi). A too modest reduction in insulin dose may lead to hypoglycaemia in the early postoperative period.. To evaluate a regimen designed to maintain blood glucose levels between 5-15 mmol/l and to prevent hypoglycaemic events (blood glucose <3.5 mmol/l) after RYGB surgery.. The effect of a 75% reduction in insulin dose was studied in 85 T₂DMi patients during the first ten days after RYGB. Patients with severe b-cell failure (fasting C-peptide <0.3 nmol/l) were excluded.. percentage of patients exceeding the upper or lower blood glucose limits, and the number of hypoglycaemic events.. The mean blood glucose level was 12.4±0.3 mmol/l (mean ± SE) on the day of surgery (day 0), 10.7±0.3 mmol/l on day 1, 10.0±0.5 mmol/l on day 2, and 8.3±0.3 on day 10. Of all measurements performed during this ten-day period, 12.4% were above the target range, and 2.6% were <5 mmol/l. There were no hypoglycaemic events during the stay in hospital. During the first week at home 2% of the measurements were <3.5 mmol/l.. A 75% reduction in insulin dose is safe in T₂DMi patients without severe b-cell failure, and prevents hypoglycaemia in the early postoperative period of RYGB in most cases.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Gastric Bypass; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity, Morbid; Perioperative Period; Time Factors

Defective glucagon secretion during hypoglycemia after islet transplantation has been reported in animals and humans with type 1 diabetes. To ascertain whether this is true of islets from nondiabetic humans, subjects with autoislet transplantation in the intrahepatic site only (TP/IAT-H) or in intrahepatic plus nonhepatic (TP/IAT-H+NH) sites were studied. Glucagon responses were examined during stepped hypoglycemic clamps. Glucagon and symptom responses during hypoglycemia were virtually absent in subjects who received islets in the hepatic site only (glucagon increment over baseline = 1 ± 6, pg/mL, mean ± SE, n = 9, p = ns; symptom score = 1 ± 1, p = ns). When islets were transplanted in both intrahepatic + nonhepatic sites, glucagon and symptom responses were not significantly different than Control Subjects (TP/IAT-H + NH: glucagon increment = 54 ± 14, n = 5; symptom score = 7 ± 3; control glucagon increment = 67 ± 15, n = 5; symptom score = 8 ± 1). In contrast, glucagon responses to intravenous arginine were present in TP/IAT-H recipients (TP/IAT: glucagon response = 37 ± 8, n = 7). Transplantation of a portion of the islets into a nonhepatic site should be seriously considered in TP/IAT to avoid posttransplant abnormalities in glucagon and symptom responses to hypoglycemia.

Topics: Adult; Arginine; Autografts; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Liver; Male; Pancreatectomy; Pancreatic Diseases; Pancreatic Ducts; Pancreatitis; Treatment Outcome

Insulin autoimmune syndrome (IAS) is a condition characterized by hypoglycemia associated with the presence of autoantibodies to insulin in patients who have not been injected with insulin.. A female patient (aged 16 years and 3 months) presented with the complaint of being overweight. Physical examination revealed a body weight of 78.2 kg (+2.6 SD) and a height of 167 cm (+0.73 SD). While the patient's fasting blood glucose level was found to be 40 mg/dl, blood ketone was negative and the serum insulin level was determined as 379 mIU/ml. The patient was diagnosed with hyperinsulinemic hypoglycemia. Abdominal ultrasound, pancreas MRI and endoscopic ultrasound were normal. The daily blood glucose profile revealed postprandial hyperglycemia and reactive hypoglycemia in addition to fasting hypoglycemia. The results of anti-insulin antibody measurements were as high as 41.8% (normal range 0-7%). A 1,600-calorie diet containing 40% carbohydrate and divided into 6 meals a day was given to the patient. Simple sugars were excluded from the diet. Hypoglycemic episodes were not observed, but during 2 years of observation, serum levels of insulin and anti-insulin antibodies remained elevated.. In all hyperinsulinemic hypoglycemia cases, IAS should be considered in the differential diagnosis and insulin antibody measurements should be carried out.

Topics: Adolescent; Autoantibodies; Autoimmune Diseases; Blood Glucose; C-Peptide; Diet, Carbohydrate-Restricted; Diet, Diabetic; Female; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Syndrome

Insulin autoimmune syndrome (IAS) is an extremely rare cause of hypoglycemia, particularly in non-Asian populations.. In this report, we describe a white male patient with elevated total insulin (>100.0 μIU/mL), C-peptide, and proinsulin levels who was diagnosed with IAS due to anti-insulin antibodies. He also had a small IgG κ M-protein.. We show that anti-insulin antibodies and/or the monoclonal protein can significantly interfere with insulin and C-peptide immunoassays and propose polyethylene glycol precipitation to quantitate free C-peptide levels as a useful assay in differentiating IAS due to anti-insulin antibodies from insulinoma.. In patients presenting with hypoglycemia with excessively high insulin levels, consideration needs to be given to autoimmune hypoglycemia due to anti-insulin antibodies as a cause. Additionally, if total C-peptide levels are increased, free C-peptide needs to be quantitated following polyethylene glycol precipitation.

Topics: Autoantibodies; Autoimmune Diseases; C-Peptide; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Male; Middle Aged

A 68-year-old man presented to the accident and emergency department with a history of central chest pain associated with exertion. He was admitted for assessment and when an acute coronary syndrome was excluded, he underwent exercise stress testing. His exercise stress testing was discontinued due to lightheadedness. His capillary glucose was checked and it showed hypoglycaemia (2.2 mmol/l). In light of this, a 72 h supervised fast was performed and it became positive within 24 h with low plasma glucose, inappropriately high insulin and C peptide levels. Sulfonylurea screen was negative. CT, MRI and endoscopic ultrasound revealed a 2 cm pancreatic tail insulinoma. He underwent successful surgical enucleation of this lesion.

Topics: Aged; Blood Glucose; C-Peptide; Exercise Test; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Pancreatic Neoplasms

The objective of the present study was to determine whether a plasma β-hydroxybutyrate (BOHB) level >2700 μmol/l during the 72-h fasting test is sufficient to rule out the diagnosis of endogenous hyperinsulinaemic hypoglycaemia (EHH).. We retrospectively studied BOHB levels in 39 patients with EHH who had undergone a 72-H fasting test to make the diagnosis of EHH, and we compared EHH patients with BOHB levels 2700 MOL/L (group 1), EHH PATIENTS with BOHB levels 2700 MOL/L (group 2) and 59 controls (median glycaemia: 3.2  mmol/l and median BOHB: 6095 μmol/l).. During a 72-h fasting test, nine patients (group 1) had BOHB levels >2700  μmol/l (median 6140 and range 2957-7824) and 30 patients (group 2) had BOHB levels <2700 μmol/l (median 542 and range 0-2607). In group 1, four patients had undergone partial pancreatectomy previously and were evaluated for the recurrence of hypoglycaemia, whereas none of the group 2 patients had been operated. The duration of the fasting test was longer in group 1 than in group 2 (P<0.0001), and at the end of the fasting test, plasma glucose concentrations were not significantly different (P=0.0617), but insulin (P=0.004), C-peptide (P=0.0015) and proinsulin (P=0.0038) levels were significantly lower in group 1 patients than in group 2 patients, suggesting lower insulin secretion and/or impaired glycaemic counter-regulation.. During a fasting test, a BOHB level >2700 μmol/l is observed in some EHH patients, suggesting that BOHB levels cannot rule out the recurrence of EHH, in particular, after partial pancreatectomy.

Topics: 3-Hydroxybutyric Acid; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; C-Peptide; Diagnosis, Differential; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatectomy; Pancreatic Neoplasms; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Time Factors; Treatment Outcome

Nesidioblastosis is a rare cause of non insulinoma pancreatogenous hypoglycemic syndrome seen in adults. It is characterized by postprandial hypoglycemia with high insulin and C-peptide levels without any detectable pancreatic lesion. The definitive diagnosis can be made only on histopathological examination of the resected specimen.. We report a case of a 50-year-old lady presenting with hypoglycemic attacks being misdiagnosed preoperatively as insulinoma and treated with enucleation leading to recurrence of symptoms after 6 months. Later medical therapy was tried which failed and patient needed subtotal pancreatectomy for resolution of symptoms.. Nesidioblastosis should be suspected in patients with endogenous hyperinsulinemic hypoglycemia without any detectable pancreatic tumor on preoperative imaging.

Topics: C-Peptide; Diagnosis, Differential; Diagnostic Errors; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Islets of Langerhans; Middle Aged; Nesidioblastosis; Pancreatectomy; Pancreatic Neoplasms

To determine the prevalence of residual β-cell function (RBF) in children after 3-6 years of type 1 diabetes, and to examine the association between RBF and incidence of severe hypoglycemia, glycemic control, and insulin requirements.. A total of 342 children (173 boys) 4.8-18.9 years of age with type 1 diabetes for 3-6 years were included. RBF was assessed by testing meal-stimulated C-peptide concentrations. Information regarding severe hypoglycemia within the past year, current HbA1c, and daily insulin requirements was retrieved from the medical records and through patient interviews.. Ninety-two children (27%) had RBF >0.04 nmol/L. Patients with RBF <0.04 nmol/L were significantly more likely to have severe hypoglycemia than patients with RBF >0.04 nmol/L (odds ratio, 2.59; 95% CI, 1.10-7.08; P < 0.03). HbA1c was significantly higher in patients with RBF <0.04 nmol/L compared with patients with RBF >0.04 nmol/L (mean, 8.49 ± 0.08% [69.3 ± 0.9 mmol/mol] vs. 7.92 ± 0.13% [63.1 ± 1.4 mmol/mol]; P < 0.01), and insulin requirements were significantly lower in patients with RBF >0.2 nmol/L (mean ± SE: 1.07 ± 0.02 vs. 0.93 ± 0.07 units/kg/day; P < 0.04).. We demonstrated considerable phenotypic diversity in RBF among children after 3-6 years of type 1 diabetes. Children with RBF are at lower risk for severe hypoglycemia, have better diabetes regulation, and have lower insulin requirements compared with children without RBF. There appears to be a lower limit for stimulated RBF of ∼0.04 nmol/L that confers a beneficial effect on hypoglycemia and metabolic control.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Meals; Registries

The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UK's nationally funded integrated islet transplant program. Twenty islet recipients with C-peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at [median (interquartile range)] 24 (13.5-36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7-50) episodes/patient-year pretransplant to 0.3 (0-1.6) episodes/patient-year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed [pretransplant: Gold score 6 (5-7); 24 (13.5-36) months: 3 (1.5-4.5); p < 0.03]. Target HbA1c of <7.0% was attained/maintained in 70% of recipients [pretransplant: 8.0 (7.0-9.6)%; 24 (13.5-36) months: 6.2 (5.7-8.4)%; p < 0.001], with 60% reduction in insulin dose [pretransplant: 0.51 (0.41-0.62) units/kg; 24 (13.5-36) months: 0.20 (0-0.37) units/kg; p < 0.001]. Metabolic outcomes were comparable 12 months posttransplant in those receiving transported versus only locally isolated islets [12 month stimulated C-peptide: transported 788 (114-1764) pmol/L (n = 9); locally isolated 407 (126-830) pmol/L (n = 11); p = 0.32]. Metabolic goals have been attained within the equitably available, fully integrated UK islet transplant program with both transported and locally isolated preparations.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Graft Survival; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome; United Kingdom

The aim of this study was to clarify the association between C-peptide immunoreactivity (CPR), a marker of beta cell function, and future glycemic control in patients with type 2 diabetes. We conducted a retrospective analysis of 513 consecutive patients with type 2 diabetes who were admitted to our hospital between 2000 and 2007 and followed up for 2 years. Serum and urinary CPR levels were measured during admission, and CPR index was calculated as the ratio of CPR to plasma glucose. The associations between these markers at baseline and glycemic control after 2 years were assessed by means of logistic regression models. After 2 years, 167 patients (32.6%) showed good glycemic control (HbA1c <6.9%). Baseline serum and urinary CPR indices were significantly associated with good glycemic control after 2 years, and the postprandial CPR to plasma glucose ratio (postprandial CPR index) showed the strongest association (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.12-1.50, P = 0.001) among CPR indices. Multivariate analyses showed consistent results (OR 1.23, 95%CI 1.03-1.48, P = 0.021). In conclusion, preserved beta cell function at baseline was associated with better glycemic control thereafter in patients with type 2 diabetes.

Topics: Aged; Algorithms; Biomarkers; Blood Glucose; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Insulin-Secreting Cells; Logistic Models; Male; Medical Records; Middle Aged; Postprandial Period; Retrospective Studies

Topics: Aged, 80 and over; Blood Glucose; C-Peptide; Confusion; Diazoxide; Epilepsy, Tonic-Clonic; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Vasodilator Agents; Weight Gain

One endpoint of clinical islet cell transplantation for type 1 diabetic patients is the elimination or reduction of hypoglycemia. We previously developed a simple tool to evaluate islet graft function: the secretory unit of islet transplant objects (SUITO) index. The aim of this study is to clarify the association between the SUITO index and hypoglycemic episodes. Data from 310 clinical evaluations of 11 islet recipients were included in this study. Fasting plasma C-peptide and glucose levels were measured at every evaluation. The SUITO index was calculated according to the following formula: 1500 × C-peptide level (ng/ml)/[blood glucose level (mg/dl) - 63]. The number of hypoglycemic events (<3.8 mmol/L) and severe hypoglycemic events (<2.2 mmol/L or hypoglycemic unawareness) was assessed on the basis of interviews and self-monitoring of blood glucose (SMBG). Receiver operating characteristic (ROC) analysis was performed to determine the cut-off values of the SUITO index for hypoglycemic events. Based on the ROC study, follow-up data after transplantations were divided into the following three groups: low-SUITO (SUITO index <10, n = 91), middle-SUITO (10 ≤SUITO index <26, n = 83), high-SUITO (SUITO index ≤26, n = 125). The frequency of total hypoglycemia in the high-SUITO group was significantly decreased when compared to the other groups (value with Kruskal-Wallis test p < 0.001). The frequency of total severe hypoglycemia was significantly decreased in the low-SUITO group compared to pretransplant status and further decreased in the middle- and high-SUITO group. Spearman correlation coefficients were -0.663 (p < 0.001) between the number of total hypoglycemic events per one month and the SUITO index and -0.521 (p < 0.001) between that of severe events and the SUITO index. The SUITO index could predict the severity of hypoglycemic episodes in type 1 diabetic patients who received islet cell transplantations.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Middle Aged; ROC Curve; Treatment Outcome

Topics: Blood Glucose; C-Peptide; Choristoma; Confusion; Diagnosis, Differential; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Middle Aged; Nesidioblastosis; Pancreatectomy; Pancreatic Diseases; Postprandial Period; Spleen; Syncope

To correctly evaluate the glucose control system, it is crucial to account for both insulin sensitivity and secretion. The disposition index (DI) is the most widely accepted method to do so. The original paradigm (hyperbolic law) consists of the multiplicative product of indices related to insulin sensitivity and secretion, but more recently, an alternative formula has been proposed with the exponent α (power function law). Traditionally, curve-fitting approaches have been used to evaluate the DI in a population: the algorithmic implementations often introduce some critical issues, such as the assumption that one of the two indices is error free or the effects of the log transformation on the measurement errors. In this work, we review the commonly used approaches and show that they provide biased estimates. Then we propose a novel nonlinear total least square (NLTLS) approach, which does not need to use the approximations built in the previously proposed alternatives, and show its superiority. All of the traditional fit procedures, including NLTLS, account only for uncertainty affecting insulin sensitivity and secretion indices when they are estimated from noisy data. Thus, they fail when part of the observed variability is due to inherent differences in DI values between individuals. To handle this inevitable source of variability, we propose a nonlinear mixed-effects approach that describes the DI using population hyperparameters such as the population typical values and covariance matrix. On simulated data, this novel technique is much more reliable than the curve-fitting approaches, and it proves robust even when no or small population variability is present in the DI values. Applying this new approach to the analysis of real IVGTT data suggests a value of α significantly smaller than 1, supporting the importance of testing the power function law as an alternative to the simpler hyperbolic law.

Topics: Adult; Aged; Aging; Algorithms; Blood Glucose; C-Peptide; Computer Simulation; Glucose Tolerance Test; Homeostasis; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Least-Squares Analysis; Middle Aged; Models, Biological; Nonlinear Dynamics; Young Adult

Our group has reported a high incidence of reactive hypoglycemia following Roux-en-Y gastric bypass (RYGB) with specific interest in postprandial insulin and the ratio of 1- to 2-h serum glucose levels. The purpose of this study is to compare the 6-month response to oral glucose challenge in patients undergoing RYGB, duodenal switch (DS), and vertical sleeve gastrectomy (VSG).. Thirty-eight patients meeting the NIH criteria for bariatric surgery who have reached the 6-month postoperative mark are the basis of this report. Preoperatively and at 6 months follow-up, patients underwent blood draw to determine levels of fasting glucose, fasting insulin, HbA1c, C peptide, and 2 h oral liquid glucose challenge test (OGTT). HOMA-IR and 1 to 2 h ratios of glucose and fasting to 1 h ratio of insulin were calculated.. All patients underwent a successful laparoscopic bariatric procedure (VSG =13, DS =13, and RYGB = 12). All operations reduced BMI, HgbA1c, fasting glucose, and fasting insulin. HOMA IR and glucose tolerance improved with all procedures. In response to OGTT at 6 months, there was a 20-fold increase in insulin at 1 h in RYGB, which was not seen in DS. At 6 months, 1-h insulin was markedly lower in DS (p < .05), yet HbA1C was also lower in DS (p < .05). This resulted in 1- to 2-h glucose ratio of 1.9 for RYGB, 1.8 for VSG, and 1.3 for DS (p < .05).. All operations improve insulin sensitivity and decrease HgbA1c. Six-month weight loss was substantial in all groups between 22-29% excess body weight. RYGB results in marked rise in glucose following challenge with corresponding rise in 1-h insulin. VSG has a similar response to RYGB. In comparison, at 6 months following surgery, DS causes a much lower rise in 1-h insulin, with this difference being statistically significant at p < .05. As a result, DS results in a less abrupt reduction in blood glucose. Although 1-h insulin is lower, DS patients had the lowest HbA1C at 6 months (p < .05). We believe that these findings have important implications for the choice of bariatric procedure for both diabetic and non-diabetic patients.

Topics: Adult; Blood Glucose; Body Mass Index; C-Peptide; Duodenum; Female; Follow-Up Studies; Gastric Bypass; Gastroplasty; Glucose Tolerance Test; Glycated Hemoglobin; Homeostasis; Humans; Hypoglycemia; Insulin Resistance; Male; Obesity, Morbid; Prospective Studies; Treatment Outcome; Weight Loss

Topics: Adult; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Factitious Disorders; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kidney Transplantation; Pancreas Transplantation; Predictive Value of Tests; Recurrence; Self Medication; Treatment Outcome

We report an exceptional case of non-islet cell tumor-induced hypoglycemia (NICTH) secondary to "Big"-IGF-2 oversecretion due to a giant phyllode tumor of the breast.. A 49-year-old woman was admitted in emergency for brutal neurologic defect revealing severe hypoglycemia. Several similar episodes were observed throughout hospitalization, requiring continue perfusion of hypertonic glucose solution. Beside these metabolic disorders, we observed a giant and hard tumor of the left breast (about 30cm in diameter).. Supplementary blood analysis revealed serum levels of C-peptide and insulin suppressed during hypoglycemia, excluding the possibility of either endogenous or exogenous hyperinsulinism. Low plasma levels of GH and IGF-1 were found, suggesting a negative feedback loop on somatotroph axis function. Therefore, the hypothesis of an insulinomimetic compound released by tumor cells was evoked because of abnormal presence of high-weight and immature form of IGF-2 (called "Big"-IGF-2) in the serum identified by western immunoblot analysis. A left mastectomy was performed and completely restored glucose homeostasis and confirmed the paraneoplastic origin of hypoglycemia because of markedly elevated expression of IGF-2 mRNA (qPCR) within the tumor cells. Finally, the anatomopathology analysis diagnosed a mesenchymatous tumor, namely a high-grade phyllode sarcoma of the breast.. Although NICTH due to "Big"-IGF-2 overproduction is a rare phenomenon, mainly observed in case of mesenchymatous tumor, it should be considered in presence of severe hypoglycemia with voluminous tumor and without hyperinsulinism.

Topics: Breast Neoplasms; C-Peptide; Fatal Outcome; Female; Human Growth Hormone; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Mastectomy; Middle Aged; Phyllodes Tumor; Protein Precursors

Topics: Aged; Autoantibodies; Autoimmune Diseases; Autoimmunity; C-Peptide; China; Diagnosis, Differential; Humans; Hypoglycemia; Immune System; Immunoglobulins; Insulin; Insulin Antibodies; Male; Syndrome

Topics: Area Under Curve; Blood Glucose; C-Peptide; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Hypoglycemia; Immune Tolerance; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Middle Aged; Tacrolimus

Here we present a case of refractory hypoglycaemia associated with use of the antibiotic trimethoprim-sulfamethoxazole (TMP-SMX). This was used to treat Pneumocystis jirovecii pneumonia (PCP) infection. The patient had significant pre-existing renal impairment with a kidney transplant in situ. Refractory hypoglycaemia occurred 5 days after starting the antibiotic and persisted for 36 h after its cessation. SMX contains the same sulphanilamide structural group as the oral hypoglycaemic agents called sulphonureas. SMX could therefore act as an insulin secretagogue. The inappropriately raised insulin and c-peptide levels seen in our patient support this theory. The 5-day asymptomatic period would allow sufficient time for the drug to accumulate and the extended period seen after its cessation would be seen in a dose-dependent side effect. Following 3 days of observation and continuous glycaemic support on the High Dependency Unit she was discharged back to the ward, with no further occurrence of hypoglycaemia.

Topics: Anti-Bacterial Agents; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Kidney Transplantation; Middle Aged; Pneumonia, Pneumocystis; Renal Insufficiency; Trimethoprim, Sulfamethoxazole Drug Combination; White People

Recent biochemical diagnostic guidelines for insulinomas require demonstration of hypoglycemia with inappropriately elevated (nonsuppressed) insulin, C-peptide, or proinsulin, but these criteria may overlap with those in patients without insulinomas. Use of an "amended" insulin-glucose ratio that accounts for the normal variation in insulin secretion according to prevailing glycemia may improve diagnostic accuracy.. To compare the diagnostic accuracy of current diagnostic guideline criteria with the amended insulin-glucose ratio in patients with a suspected insulinoma.. Retrospective cohort study.. 2 specialized university departments in Germany.. 114 patients with suspected hypoglycemia over 10 years having diagnostic prolonged fasts.. Glucose, insulin, C-peptide, and the amended insulin-glucose ratio were measured during and at discontinuation of prolonged fasts.. Of 114 patients who were evaluated, 49 had surgical resection of histologically confirmed insulinomas. Insulinoma was excluded in 65 patients; follow-up for a mean of 10 years (range, 0 to 16 years) showed no progressively severe hypoglycemic events or diagnoses of insulinoma. Patients with insulinoma had lower glucose levels and higher insulin and C-peptide levels overall than did control patients at the end of prolonged fasts, but there was considerable overlap. The amended insulin-glucose ratio correctly identified 48 of 49 patients with insulinoma and excluded the diagnosis in 64 of 65 control patients, resulting in positive and negative predictive values of 0.98 (95% CI, 0.89 to 1.00) and 0.99 (CI, 0.92 to 1.00), respectively, compared with 0.75 (CI, 0.63 to 0.85) and 0.98 (CI, 0.89 to 1.00), respectively, for glucose, insulin, and C-peptide concentration criteria.. The study had a retrospective design, no proinsulin concentrations were available, and a nonspecific insulin immunoassay (crossreactive with proinsulin) was used.. The amended insulin-glucose ratio showed improved diagnostic accuracy over established criteria that use glucose, insulin, and C-peptide concentrations.. None.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Fasting; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Practice Guidelines as Topic; Predictive Value of Tests; Radioimmunoassay; Retrospective Studies

Uremic type 2 diabetic patients on hemodialysis need various types of antidiabetic therapies. The aim of the present study was to identify differences between patients on oral antidiabetic drug therapy or insulin substitution or diet therapy alone during their first year of hemodialysis.. Sixty-four type 2 diabetic patients who had started hemodialysis (HD) at our dialysis center between 2003 and 2007 were included in the study. Kidney-transplanted patients (n = 1) and those with chronic infectious or malignant diseases (n = 4) were excluded. Patients were divided into three groups according to their antidiabetic therapy: group 1 consisted of patients on oral antidiabetic drug therapy (n = 12), group 2 of those on insulin therapy (n = 42), and group 3 of those being treated with diet alone (n = 10). At the start of HD and 12 months later, we measured fasting plasma glucose (FPG), HbA1c, the incidence of hypoglycemia (n/patient/month), cholesterol, triglycerides, body weight, and insulin requirements in the insulin-treated group. C-peptide was only measured at the start of dialysis. We evaluated changes in antidiabetic therapy during the first year on dialysis, and the prevalence of vascular disease in each group at the start of HD.. FPG and HbA1c values were similar in all groups at the start of HD and after 1 year. Hypoglycemia occurred more frequently in insulin-treated patients; however, the difference was not significant. Cholesterol levels were similar in all groups, whereas triglycerides were significantly lower in insulin-treated patients (138 ± 28 vs. 176 ± 46 mg/dl; P < 0.05). Body weight was similar in all groups. No significant change in body weight was observed in any group after 12 months on dialysis. At the start of HD, C-peptide levels were lower in insulin-treated patients than in the other groups (1.8 ± 0.9 ng/ml vs. 2.2 ± 1.1 and 2.4 ± 1.1 ng/ml; P < 0.05). During the first 12 months on HD, two patients from group 1 were shifted to group 3 (diet alone), while four patients could reduce their drug dosage (33%). However, two subjects became insulin-dependent. In group 2, insulin therapy could be terminated in two cases, while the insulin dose could be reduced in 20 patients (48%). In group 3, one patient was switched to oral antidiabetic therapy. The prevalence of vascular disease was slightly higher in group 3 (NS).. Within 1 year after the start of HD, the dose of sulfonylurea as well as insulin could be reduced in a large majority of patients. Metabolic control was similar in all groups. Only triglycerides were significantly lower in group 2. The frequency of hypoglycemia and the prevalence of vascular disease were just slightly higher in the group on insulin therapy.

Topics: Aged; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Sulfonylurea Compounds; Triglycerides; Vascular Diseases

Tight glucose control (TGC) using a sliding scale based on intermittent blood glucose measurements occasionally can have a fatal outcome as a result of insulin-induced hypoglycemia. The present study was undertaken to examine whether the use of an artificial pancreas to achieve TGC would be possible in postoperative patients with sepsis. The retrospective study was carried out as an exploratory study, focusing on the possibility of precise evaluation of the significance of TGC as a beneficial intervention by serological monitoring of various mediators. TGC was accomplished using an artificial pancreas (STG-22; (Nikkiso, Tokyo, Japan). The patients were divided into two groups: the TGC group (6 patients with sepsis in whom the target blood glucose level set at <150 mg/dl was attempted using the artificial pancreas), and the glucose control (GC) group (6 patients with sepsis in whom glucose control was attempted using a sliding scale; target blood glucose level was set at 200 mg/dl or lower). The mean blood glucose level was 129.7 ± 9.7 mg/dl in the TGC group and 200.9 ± 14.7 mg/dl in the GC group (P < 0.01, ANOVA). No hypoglycemia associated with the artificial pancreas was seen in any of the patients. The serum levels of S100A12 and HMGB-1 tended to decrease, and those of sRAGE tended to increase, in the TGC group. Further data collection from a larger number of cases would be expected to allow a precise assessment of TGC as a potentially beneficial intervention in sepsis patients.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Blood Glucose; C-Peptide; C-Reactive Protein; Cohort Studies; Cytokines; Energy Intake; Female; Glycation End Products, Advanced; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Pancreas, Artificial; Postoperative Complications; Respiration, Artificial; Retrospective Studies; Sepsis

We present the case of a 55 yr female who had recurrent severe hypoglycemic attacks with neuroglycopenic symptoms and altered sensorium including coma. The hypoglycemic episodes were not related to fasting. The hypoglycemia was hyperinsulinemic but all imaging modalities for insulinoma were negative. Selective arterial calcium stimulation test localized the lesion to splenic artery territory and distal pancreatectomy left to the splenic vein was done. The histopathology was consistent with nesidioblastosis and gradient guided pancreatectomy relieved the hypoglycemic episodes.

Topics: Blood Glucose; C-Peptide; Calcium; Female; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Immunohistochemistry; Injections, Intra-Arterial; Insulin; Insulinoma; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Syndrome; Treatment Outcome

Continuous glucose monitoring devices measure interstitial glucose and are commonly used to investigate hypoglycemia. The relationship between interstitial glucose and blood glucose is not completely understood, particularly at low blood glucose concentrations. Interstitial glucose during hypoglycemia is generally lower than blood glucose in young subjects without diabetes and those with type 1 diabetes, but the effect of insulin resistance and obesity in type 2 diabetes on this relationship has not been examined previously. We studied the relationship between blood and interstitial glucose during experimental hypoglycemia in subjects with type 2 diabetes treated with insulin or sulfonylureas and matched controls without diabetes.. Twenty subjects with type 2 diabetes (10 sulfonylurea-treated and 10 insulin-treated) and 10 controls without diabetes of similar age and weight underwent stepped hyperinsulinemic hypoglycemic clamps. We compared blood and interstitial glucose at different levels of hypoglycemia using random effects modeling.. Interstitial glucose was significantly higher than blood glucose at all levels of hypoglycemia (P<0.001), and this difference increased as glucose fell. For every 1 mmol/L drop in blood glucose, the difference increased by 0.32 mmol/L (P<0.001). This difference was not affected by presence of type 2 diabetes or by modality of treatment (P=0.10).. In older subjects with or without type 2 diabetes, interstitial glucose is significantly higher than blood glucose, and this difference increases with increasing severity of hypoglycemia. Continuous glucose monitors may underestimate hypoglycemia in this group, and this should be taken into account when interpreting results obtained using this technology.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Extracellular Fluid; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Middle Aged; Severity of Illness Index; Sulfonylurea Compounds

Topics: C-Peptide; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Sulfonylurea Compounds

When patients do not become insulin independent after islet cell transplantation (ICT), another aim is to eliminate severe hypoglycemia. Previously we reported that a secretory unit of islet transplant objects (SUITO) index score >10 was associated with a reduction of severe hypoglycemia. In this study, we assessed patients' satisfaction with their insulin therapy based on the SUITO index.. The study involved 11 islet recipients with type 1 diabetes who underwent ICT but still used insulin. From those patients, 41 Insulin Therapy Satisfaction Questionnaires (ITSQ) were collected. The SUITO index (fasting C-peptide [ng/mL] × 1500/blood glucose [mg/dL] - 63) was calculated at the same outpatient visits that the survey was administered. ITSQ scores were summarized using subscales and compared among 3 groups: the pre-ICT group, the low-SUITO group (SUITO index score <10 post-ICT), and the high-SUITO group (SUITO index score ≥10). Higher survey scores indicated better satisfaction.. Significant trend relationships across the 3 groups were observed in the ITSQ total score (P = .02 with Jonckheere-Terpstra test) and subscale scores of glycemic control (P < .001), hypoglycemic control (P = .01), and inconvenience of regimen (P = .004). The pairwise comparisons between the 3 groups found significant differences: high SUITO versus both pre-ICT and low SUITO for the total ITSQ score (P = .03 and .005, respectively) and glycemic control score (P = .008 and .001, respectively), and high SUITO versus low SUITO for hypoglycemic control score (P = .04) and inconvenience of regimen score (P = .008).. Islet recipients with a SUITO index ≥10 experienced higher satisfaction with insulin injection therapy compared with the pre-ICT group, even though they were insulin dependent. A SUITO index ≥10 is a reasonable benchmark for successful ICT.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Graft Survival; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Middle Aged; Outpatients; Patient Satisfaction; Surveys and Questionnaires; Treatment Outcome

The glucose-lowering effect of fat and protein is attenuated or absent in diabetic patients, which suggests that the same may occur in insulin-resistant subjects without diabetes.. The objective was to determine whether the postprandial metabolic responses elicited by fat and protein were influenced by the insulin sensitivity of the subjects and whether fat and protein modulate glucose responses through different mechanisms.. Healthy nondiabetic subjects aged 18-45 y took 50 g oral glucose with 0-30-g doses of canola oil and whey protein on 11 separate mornings after fasting overnight. The subjects were classified into 3 fasting serum insulin (FSI) groups: FSI < 40 pmol/L (n = 9), 40 < or = FSI < 70 pmol/L (n = 8), and FSI > or = 70 pmol/L (n = 8). The relative glycemic response was expressed as the incremental area under the curve (AUC) after each test meal divided by the mean AUC of the glucose control in each subject.. Protein significantly decreased glucose (P < 0.0001) and hepatic insulin extraction (P <0.0001) and increased insulin (P < 0.0001) and glucagon-like peptide 1 (P = 0.004); however, protein had no significant effect on C-peptide (P = 0.69) or on the insulin secretion rate (P = 0.13). No significant FSI x fat (P = 0.19) or FSI x protein (P = 0.08) interaction effects on glucose AUC were observed. In addition, the changes in relative glycemic response per gram of fat (r = -0.05, P = 0.82) or protein (r = -0.08, P = 0.70) were not related to FSI.. The hypoglycemic effect of fat and protein was not blunted by insulin resistance. Protein increased insulin but had no effect on C-peptide or the insulin secretion rate, which suggests decreased hepatic insulin extraction or increased C-peptide clearance.

Topics: Adult; Blood Glucose; Blood Pressure; Body Height; Body Mass Index; Body Weight; C-Peptide; Dietary Fats; Dietary Proteins; Ethnicity; Fasting; Fatty Acids, Monounsaturated; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Liver; Male; Middle Aged; Milk Proteins; Racial Groups; Rapeseed Oil; Reference Values; Waist Circumference; Whey Proteins; Young Adult

An 8-week-old infant presented to the emergency department with lethargy, tachycardia, and a blood glucose concentration of 1.8 mmol/L. After admission, hypoglycemia recurred on 3 additional occasions. Initial urinalysis results were negative for ketones, and the results of additional laboratory tests did not support the diagnosis of cortisol or growth hormone deficiency, oral hypoglycemic ingestion, or an inborn error of metabolism. Difficulty restoring and maintaining glucose concentrations along with a transient response to glucagon during 1 hypoglycemic episode suggested hyperinsulinism. In 1 hypoglycemic episode, elevated insulin and low C-peptide concentrations suggested exogenous insulin administration, but 2 subsequent blood samples obtained during hypoglycemia contained appropriately decreased concentrations of insulin. The insulin immunoassay initially used in this case (Roche ElecSys/cobas [Roche Diagnostics, Indianapolis, IN]) was insensitive to insulin analogs. Two additional immunoassays, 1 with intermediate (Immulite [Siemens, Deerfield, IL]) and 1 with broad (radioimmunoassay [Millipore, Inc, Billerica, MA]) reactivity to insulin analogs were used to characterize insulin in each of the critical blood samples. Samples obtained during hypoglycemia displayed a graded reactivity similar to that observed in type 1 diabetic patients prescribed insulin analogs, whereas a sample obtained from the patient and a control subject during euglycemia showed equal reactivity among the 3 assays. These data suggested administration of insulin analog to the child, and further characterization of insulin by using tandem mass spectrometry confirmed the presence of Humalog. The child was subsequently placed in foster care with no further recurrence of hypoglycemia.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diagnosis, Differential; Emergency Service, Hospital; Female; Glucagon; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Infant; Insulin; Insulin Aspart; Male; Munchausen Syndrome by Proxy; Pregnancy; Pregnancy in Diabetics; Recurrence

Topics: Awareness; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Middle Aged; Monitoring, Physiologic; Transplantation, Homologous; Treatment Outcome

A man, aged 65 years, presented with frequent episodes of hypoglycemia and unconsciousness. Hypoglycemia was accompanied by undetectable serum insulin and C-peptide levels and a high serum insulin-like growth factor (IGF)-II level. He was found to have a retroperitoneal solitary fibrous tumor. He underwent successful resection of the tumor and had no hypoglycemic episodes after the operation. Immunohistochemical analysis revealed positive immunostaining for IGF-II in tumor cells. The presence of the high-molecular-weight form of IGF-II in the patient's serum was confirmed by immunoblotting, which suggests that his hypoglycemia was due to an increase in the plasma level of IGF-II secreted by the tumor.

Topics: Aged; C-Peptide; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor II; Male; Neoplasm Proteins; Radiography; Retroperitoneal Neoplasms; Unconsciousness

The objective of this study was to measure the serum insulin and C-peptide concentrations among diabetic patients known to be taking sulfonylurea agents who presented to the emergency department with hypoglycemia thought to be due to therapeutic usage as opposed to overdose. A recently published systematic review of 22 articles involving 76 patients with sulfonylurea-induced hypoglycemia (glucose <49 mg/dL) resulting from accidental ingestion or intentional overdose found that patients had an average serum insulin concentration of 3.9 μIU/mL or higher and an average serum C-peptide concentration of 1.4 ng/mL or higher.. This is a prospective cross-sectional descriptive case series.. Thirteen of 14 study subjects had initial insulin and C-peptide levels consistent with the diagnosis of sulfonylurea-induced hypoglycemia as previously defined among patients presenting after overdose.. Patients presenting with hypoglycemia resulting from therapeutic sulfonylurea use demonstrate similar insulin and C-peptide levels as has previously been published among patients who presented with presumed overdose.

Topics: Aged; Aged, 80 and over; C-Peptide; Cross-Sectional Studies; Drug Overdose; Female; Glipizide; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Prospective Studies; Sulfonylurea Compounds

We report the case of an obese 79-year-old woman who experienced postprandial hypoglycemia in the morning. The serum immunoreactive insulin (IRI) and C-peptide levels responded in parallel with her serum glucose level during a 75-g oral glucose tolerance test. A prolonged fast test lowered her serum glucose level to 30 mg/dL, but serum IRI was not fully suppressed. Abdominal computed tomography revealed a tumor in the uncinate process of the pancreas. The tumor was histologically diagnosed as benign insulinoma after surgery. Therefore, glucose-responsive insulinoma as well as reactive hypoglycemia should be considered in patients who exhibit postprandial hypoglycemia.

Topics: Aged; Blood Glucose; C-Peptide; Circadian Rhythm; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Postprandial Period; Tomography, X-Ray Computed

Topics: Autoimmune Diseases; C-Peptide; Diabetes Mellitus, Type 1; Factitious Disorders; Humans; Hypoglycemia; Insulin Antibodies; Insulin Resistance; Insulin-Secreting Cells

The goal was to describe the temporal pattern of neonatal plasma glucose levels and associations with maternal glucose levels, cord serum C-peptide levels, and neonatal size and adiposity.. A total of 17,094 mothers and infants were included in the Hyperglycemia and Adverse Pregnancy Outcome Study (15 centers in 9 countries). Mothers underwent a 75-g, 2-hour, oral glucose tolerance test (OGTT) at 24 to 32 weeks of gestation. Cord blood and neonatal blood samples were collected. Biochemical neonatal hypoglycemia was defined as glucose levels of <10th percentile (2.2 mmol/L). Clinically identified hypoglycemia was ascertained through medical record review and associations were assessed.. Plasma glucose concentrations were stable during the first 5 hours after birth. Maternal glucose levels were weakly positively associated with biochemical neonatal hypoglycemia (odds ratios: 1.07-1.14 for 1-SD higher OGTT glucose levels). Frequency of neonatal hypoglycemia was higher with higher cord C-peptide levels (odds ratio: 11.6 for highest versus lowest C-peptide category). Larger and/or fatter infants were more likely to have hypoglycemia (P < .001), and infants with hypoglycemia tended to have a higher frequency of cord C-peptide levels of >90th percentile.. Mean neonatal plasma glucose concentrations varied little in the first 5 hours after birth, which suggests normal postnatal adjustment. Biochemical and clinical hypoglycemia were weakly related to maternal OGTT glucose measurements but were strongly associated with elevated cord serum C-peptide levels. Larger and/or fatter infants were more likely to develop hypoglycemia and hyperinsulinemia. These relationships suggest physiologic relationships between maternal glycemia and fetal insulin production.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk Factors

Topics: Adult; Blood Glucose; C-Peptide; Diagnostic Errors; Dietary Carbohydrates; Female; Glucose; Humans; Hypoglycemia; Infusions, Intravenous; Insulin; Insulinoma; Pancreatic Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Treatment Outcome

Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes to avoid severe hypoglycaemic events. Erythropoietin has neuroprotective potential. However, the role of erythropoietin during hypoglycaemia is unclear. The aim of the study was to explore plasma erythropoietin response to hypoglycaemia and the relationship to basal renin-angiotensin system (RAS) activity and cognitive function.. We performed a single-blinded, controlled, cross-over study with induced hypoglycaemia or maintained glycaemic level. Nine patients with type 1 diabetes with high and nine with low activity in RAS were studied. Hypoglycaemia was induced using a standardized insulin-infusion.. Overall, erythropoietin concentrations increased during hypoglycaemia. In the high RAS group erythropoietin rose 29% (p=0.032) whereas no significant response was observed in the low RAS group (7% increment; p=0.43). Independently, both hypoglycaemia and high RAS activity were associated with higher levels of erythropoietin (p=0.02 and 0.04, respectively). Low plasma erythropoietin at baseline was associated with poorer cognitive performance during hypoglycaemia.. Hypoglycaemia triggers a rise in plasma erythropoietin in patients with type 1 diabetes. The response is influenced by basal RAS activity. Erythropoietin may carry a neuroprotective potential during hypoglycaemia.

Topics: Adult; Blood Glucose; C-Peptide; Cognition; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 1; Erythropoietin; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Renin-Angiotensin System; Single-Blind Method

Islet transplantation can restore normoglycemia to patients with unstable type 1 diabetes mellitus, but long-term insulin independence is usually not sustained. Identification of predictor(s) of islet allograft dysfunction (IGD) might allow for early intervention(s) to preserve functional islet mass.. Fourteen islet transplantation recipients with long-term history of type 1 diabetes mellitus underwent metabolic testing by mixed meal tolerance test, intravenous glucose tolerance test, and arginine stimulation test every 3 months postislet transplant completion. Metabolic responses were compared between subjects who maintained insulin independence at 18 months (group 1; n=5) and those who restarted insulin within 18 months (group 2; n=9). Data were analyzed before development of islet graft dysfunction and while insulin independent.. The 90-min glucose, time-to-peak C-peptide, and area under the curve for glucose were consistently higher in group 2 and increased as a function of time. At 12 months, acute insulin release to glucose in group 2 was markedly reduced as compared with baseline (5.62+/-1.21 microIU/mL, n=4 vs. 16.14+/-3.69 microIU/mL, n=8), whereas it remained stable in group 1 (22.36+/-4.98 microIU/mL, n=5 vs. 27.70+/-2.83 microIU/mL, n=5). Acute insulin release to glucose, acute C-peptide release to glucose (ACpRg), and mixed meal stimulation index were significantly decreased and time-to-peak C-peptide, 90-min glucose, and area under the curve for glucose were significantly increased when measured at time points preceding intervals where IGD occurred compared with intervals where there was no IGD.. The intravenous glucose tolerance test and mixed meal tolerance test may be useful in the prediction of IGD and should be essential components of the metabolic testing of islet transplant recipients.

Topics: Arginine; Awareness; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Drug Administration Schedule; Fasting; Follow-Up Studies; Glucose Tolerance Test; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans Transplantation; Postoperative Complications; Transplantation, Homologous

A 45-year-old woman was referred to us for hypoglycemia. The patient had been operated on for a duodenal ulcer by bilateral troncular vagotomy and pyloroplasty 20 years ago and, since then, she showed a dumping syndrome. Two months before consultation she developed repetitive episodes of symptomatic hypoglycemia. An oral glucose tolerance test showed hypoglycemia with endogenous hyperinsulinism. The continuous glucose monitoring system sensor demonstrated fasting hypoglycemia. The endoscopic ultrasound of the pancreas showed a pancreatic tumor that was confirmed in the pathologic study after surgery. Moreover, nesidiodysplasia image was found surrounding pancreatic parenchyma. We report, for the first time, both histologic lesions associated in a patient with a history of vagotomy and pyloroplasty for a duodenal ulcer and we discuss the possible pathogenic mechanisms.

Topics: C-Peptide; Duodenal Ulcer; Female; Glucose; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Islets of Langerhans; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Time Factors; Vagotomy

Diabetes management in older adults is challenging. Poor glycemic control and high risk of hypoglycemia are common in older patients on a complicated insulin regimen. Newer oral hypoglycemic agents have provided an opportunity to simplify regimens in patients with type-2 diabetes on insulin. Serum c-peptide is a test to assess endogenous production of insulin. We analyze the use of serum c-peptide level in simplifying diabetes regimen by decreasing or stopping insulin injection and adding oral hypoglycemic agents in older adults.. One hundred patients aged over 65 years with either poor glycemic control or difficulty coping with insulin regimen seen at a geriatric diabetes clinic were analyzed for this study. The data on serum c-peptide levels and A1c, along with demographic information, were obtained from medical charts.. Sixty-five of 100 patients (aged 79+/-14 years, duration of diabetes 21+/-13 years) had detectable serum c-peptide levels. Forty-six of 65 patients were available for simplification of regimen. Eleven of 46 patients had other co-morbidities preventing use of oral hypoglycemic agents. In 35/65 patients, simplification was completed successfully. Nineteen of 35 patients were converted to all-oral regimens (off insulin), while 16/35 had simplification of regimen by addition of oral hypoglycemic agents and lowering the number of insulin injections from an average of 2.7 to 1.5 injections/day (P=.001). Glycemic control improved significantly in patients with a simplified regimen (8.0%+/-1.5% vs 7.4%+/-1.5%; P<.002), and patients reported fewer hypoglycemia episodes.. Serum c-peptide level can be used to simplify insulin regimen in older adults with diabetes.

Topics: Administration, Oral; Aged; Aged, 80 and over; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Male; Retrospective Studies

Topics: Aged; C-Peptide; Fatal Outcome; Female; Humans; Hypoglycemia; Insulin; Ovarian Neoplasms; Palliative Care; Unconsciousness

Repeated hypoglycemia is associated with hypoglycemia-associated autonomic failure (HAAF), a syndrome of defective counterregulation.. HAAF increases the risk of severe hypoglycemia in diabetes, although its mechanism remains unresolved. Because beta-endorphin influences the autonomic response to hypoglycemia via opioid receptor activation, we hypothesized that it is also involved in the pathogenesis of HAAF.. We asked whether opioid receptor blockade during antecedent hypoglycemia (60 mg/dl) on d 1 would prevent development of HAAF on d 2 in eight nondiabetic subjects (five males, 3 females; age, 28 +/- 3.5 yr; body mass index, 24.2 +/- 2.1 kg/m(2)). On four occasions, d 1 was: 1) two 90-min hypoglycemic clamps (N-); 2) two 90-min hypoglycemic clamps plus naloxone (N+); 3) two euglycemic 90-min clamps (C); or 4) two euglycemic 90-min clamps plus naloxone (C+).. Day 1 hypoglycemia caused marked deterioration of d 2 hormonal responses to hypoglycemia, consistent with HAAF-i.e. decreased plasma epinephrine, norepinephrine, and glucagon compared to control (C) (374 +/- 71 vs. 810 +/- 94, 307 +/- 65 vs. 686 +/- 98, and 71 +/- 9 vs. 93 +/- 4 pg/ml, respectively, P < 0.01), as well as in endogenous glucose production (24 vs. 163%; P < 0.01). In contrast, naloxone on d 1 completely prevented the defective counterregulatory responses; epinephrine, norepinephrine, and glucagon (852 +/- 82, 769 +/- 77, and 98 +/- 7 pg/ml) and endogenous glucose production recovery (167%) were identical to those after d 1 euglycemia (P < NS for all). Infusion of naloxone alone during euglycemia on d 1 (C+) had no effect on d 2 responses.. These data suggest that the opioid signaling system is a promising target for further studies to prevent HAAF.

Topics: Adult; Autonomic Nervous System Diseases; beta-Endorphin; Blood Glucose; C-Peptide; Epinephrine; Female; Glucagon; Gluconeogenesis; Humans; Hypoglycemia; Insulin; Male; Naloxone; Narcotic Antagonists; Norepinephrine; Receptors, Opioid; Syndrome

Patients with diabetes rely on symptoms to identify hypoglycaemia. Previous data suggest patients with Type 2 diabetes develop greater symptomatic and hormonal responses to hypoglycaemia at higher glucose concentrations than non-diabetic controls and these responses are lowered by insulin treatment. It is unclear if this is as a result of insulin therapy itself or improved glucose control. We compared physiological responses to hypoglycaemia in patients with Type 2 diabetes patients treated with sulphonylureas (SUs) or insulin (INS) with non-diabetic controls (CON).. Stepped hyperinsulinaemic hypoglycaemic clamps were performed on 20 subjects with Type 2 diabetes, 10 SU-treated and 10 treated with twice-daily premixed insulin, and 10 age- and weight-matched non-diabetic controls. Diabetic subjects were matched for diabetes duration, glycated haemoglobin (HbA(1c)) and hypoglycaemia experience. We measured symptoms, counterregulatory hormones and cognitive function at glucose plateaux of 5, 4, 3.5, 3 and 2.5 mmol/l.. Symptomatic responses to hypoglycaemia occurred at higher blood glucose concentrations in SU-treated than INS-treated patients [3.5 (0.4) vs. 2.6 (0.5) mmol/l SU vs. INS; P = 0.001] or controls [SU vs. CON 3.5 (0.4) vs. 3.0 (0.6) mmol/l; P = 0.05]. They also had a greater increase in symptom scores at hypoglycaemia [13.6 (11.3) vs. 3.6 (6.1) vs. 5.1 (4.3) SU vs. INS vs. CON; P = 0.017]. There were no significant differences in counterregulatory hormone responses or impairment of cognitive function among groups.. Sulphonylurea-treated subjects are more symptomatic of hypoglycaemia at a higher glucose level than insulin-treated subjects. This may protect them from severe hypoglycaemia but hinder attainment of glycaemic goals.

Topics: Aged; Blood Glucose; C-Peptide; Case-Control Studies; Cognition; Diabetes Mellitus, Type 2; Epinephrine; Fasting; Glucagon; Glucose Clamp Technique; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Middle Aged; Norepinephrine; Sulfonylurea Compounds; Tremor

As of October 1, 2007, 25 North American medical institutions and one European islet transplant center reported detailed information to the Registry on 315 allograft recipients, of which 285 were islet alone (IA) and 30 were islet after kidney (IAK). Of the 114 IA recipients expected at 4 years after their last infusion, 12% were insulin independent, 16% were insulin dependent with detectable C-peptide, 40% had no detectable C-peptide, and 32% had missing C-peptide data or were lost to follow-up. Of the IA recipients, 72% achieved insulin independence at least once over 3 years and multiple infusions. Factors associated with achievement of insulin independence included islet size >1.0 expressed as IEQs per islet number [hazard ratio (HR) = 1.5, p = 0.06], additional infusions given (HR = 1.5, p = 0.01), lower pretransplant HbA(1c) (HR = 1.2 each %-age unit, p = 0.02), donor given insulin (HR = 2, p = 0.003), daclizumab given at any infusion (HR = 1.9, p = 0.06), and shorter cold storage time (HR = 1.04, p = 0.03), mutually adjusted in a multivariate model. Severe hypoglycemia prevalence was reduced from 78-83% preinfusion to less than 5% throughout the first year post-last infusion, and to 18% adjusted for missing data at 3 years post-last infusion. In Year 1 post-first infusion for IA recipients, 53% experienced a Grade 3-5 or serious adverse event (AE) and 35% experienced a severe AE related to either an infusion procedure or immunosuppression. In Year 1 post-first infusion, 33% of IA subjects and 35% of IAK subjects had an AE related to the infusion procedure, while 35% of IA subjects and only 27% of IAK subjects had an AE related to the immunosuppression therapy. Five deaths were reported, of which two were classified as probably related to the infusion procedure or immunosuppression, and 10 cases of neoplasm, of which two were classified as probably related to the procedure or immunosuppression. Islet transplantation continues to show short-term benefits of insulin independence, normal or near normal HbA(1C) levels, and sustained marked decrease in hypoglycemic episodes.

Topics: Adolescent; Adult; Aged; C-Peptide; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Europe; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Immunosuppression Therapy; Insulin; Islets of Langerhans Transplantation; Kidney Transplantation; Male; Middle Aged; North America; Organ Preservation; Registries; Time Factors; Transplantation, Homologous; Treatment Outcome; Young Adult

Type 2 diabetes is a heterogeneous disease with multiple causes revolving around beta cell dysfunction, insulin resistance and enhanced hepatic glucose output. Clinical judgement based on obesity status, age of onset and the clinical perception of residual beta cell insulin secretory function (hence insulin-requiring or not), has been used to determine therapeutic choices for each patient. Further laboratory testing of the clinically defined type 2 diabetes unmasks the various aetiologic types within the single clinical group.. To determine the aetiological types of the clinically defined type 2 diabetic patients, their chosen therapies at recruitment and the quality of glycaemic control achieved.. Descriptive cross-sectional study.. Diabetes out-patient clinic of Kenyatta National Hospital, Nairobi, Kenya.. A total of 124 patients with clinical type 2 diabetes were included, 49.2% were males. The mean duration of diabetes in males was 26.09 (20.95) months and that of females was 28.68 (20.54) months. The aetiological grouping revealed the following proportions: Type 1A-3.2%, Type 1B-12.1%, LADA-5.7%, and "true" type 2 diabetes 79.0%. All the patients with Type 1A were apparently, and rightly so, on "insulin-only" treatment even though they did not achieve optimal glycaemic control with HbA1c % = 9.06. However the study patients who were type 1B and LADA were distributed all over the treatment groups where most of them did not achieve optimal glycaemic control, range of HbA1c of 8.46 -10.6%. The patients with "true" type 2 were also distributed all over the treatment groups where only subjects on 'diet only' treatment had good HbA1c of 6.72% but those in other treatment groups did not achieve optimal glycaemic control of HbA1c, 8.07 - 9.32%.. Type 2 diabetes is a heterogeneous disease where clinical judgement alone does not adequately tell the various aetiological types apart without additional laboratory testing of C-peptide levels and GAD antibody status. This may partly explain the inappropriate treatment choices for the various aetiological types with consequent sub-optimal glycaemic control of those patients.

Topics: Adult; Ambulatory Care; Blood Glucose; Body Mass Index; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Kenya; Male; Middle Aged; Quality of Health Care; Risk Factors

Hypoglycemia, the limiting factor in the glycemic management of diabetes, is the result of the interplay of therapeutic insulin excess and compromised glycemic defenses. The key feature of the latter is an attenuated sympathoadrenal response to hypoglycemia that typically follows an episode of recent antecedent iatrogenic hypoglycemia, a phenomenon termed hypoglycemia-associated autonomic failure (HAAF) in diabetes. We investigated the role of cerebral mechanisms in HAAF by measuring regional brain activation during recurrent hypoglycemia with attenuated counterregulatory responses and comparing it with initial hypoglycemia in healthy individuals.. We used [(15)O]water and positron emission tomography to measure regional cerebral blood flow as a marker of brain synaptic activity during hyperinsulinemic hypoglycemic clamps (55 mg/dl [3.0 mmol/l]) in the naïve condition (day 1) and after approximately 24 h of interval interprandial hypoglycemia (day 2) in nine healthy adults.. Interval hypoglycemia produced attenuated sympathoadrenal, symptomatic, and other counterregulatory responses to hypoglycemia on day 2, a model of HAAF. Synaptic activity in the dorsal midline thalamus during hypoglycemia was significantly greater on day 2 than day 1 (P = 0.004).. Greater synaptic activity associated with attenuated counterregulatory responses indicates that the dorsal midline thalamus plays an active inhibitory role in reducing sympathoadrenal and symptomatic responses to hypoglycemia when previous hypoglycemia has occurred, the key feature of HAAF in diabetes.

Topics: Adult; Blood Glucose; C-Peptide; Cerebrovascular Circulation; Female; Glucose; Homeostasis; Humans; Hypoglycemia; Hypothalamus; Infusions, Intravenous; Insulin; Magnetic Resonance Imaging; Male; Oxygen Radioisotopes; Positron-Emission Tomography; Recurrence; Reference Values

Insulin glargine is a long-acting insulin analogue increasingly used instead of neutral protamine Hagedorn (NPH) insulin in young subjects with type 1 diabetes.. We evaluated the clinical course of diabetes in children and adolescents who were switched from NPH to insulin glargine.. Between August 2003 and November 2004, a total of 76 subjects were switched to glargine in our clinic, treating 340 children with type 1 diabetes. All the subjects had been receiving insulin NPH, and their serum C-peptide levels had been non-detectable for at least 1 yr. Data were collected retrospectively, and 12-18 months after the change, experiences with glargine were inquired using a questionnaire. Seven subjects (9.2%) discontinued glargine before 12 months, and seven refused to participate.. Data for 62 subjects were analyzed. At the switch (0 months), their mean age was 12.7 yr (range 5.1-17.5), mean duration of diabetes was 6.7 yr (range 1.8-14.3), and mean hemoglobin A1c was (HbA1c) 9.2%. Twelve months later (+12 months), the mean HbA1c remained similar (9.2%), the proportion of long-acting insulin was smaller (47.7 vs. 58.1%; p < 0.001), and the daily insulin dose was lower (0.97 vs. 1.05 IU/kg; p < 0.001). The number of injections was lower at +12 months (17.7% with more than five injections vs. 64.5%; p < 0.001). No differences were seen in weight for height or the number of severe hypoglycemias. Most subjects who continued with glargine for > or =12 months considered glargine better than NPH.. A switch to insulin glargine retains a similar glycemic control and does not change the number of severe hypoglycemias.

Topics: Adolescent; Age of Onset; Biomarkers; Blood Glucose; Body Height; Body Weight; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Isophane; Insulin, Long-Acting; Male; Reference Values; Retrospective Studies

A 67 year old female patient was admitted to our clinic with recurrent hypoglycemia in December 2006. Laboratory findings revealed an elevated insulin, and C-peptide. Imaging techniques revealed a tumor of the pancreas involving the spleen with metastases of the liver, expressing somatostatin receptors. Ultrasound-guided biopsy was performed and confirmed the suspected insulinoma. Since the hypoglycemias could not sufficiently be controlled by subcutaneous administration of octreotide and by oral glucose intake, surgical debulking was performed in a palliative intention. After resection the patient was free of hypoglycemia. In case of diagnosed insulinoma, underlying MEN (multiple endocrine neoplasia) should be considered. Excision of the tumor is recommended in patients with benign solitary insulinomas. If complete excision is impossible, there are several therapeutic options that aim at preventing hypoglycemia. Thus, in contrast to other extended tumors, surgery is reasonable in malignant insulinoma even in case of metastatic disease.

Topics: Aged; Blood Glucose; C-Peptide; Chromogranin A; Diagnosis, Differential; Disease Progression; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Liver Neoplasms; Magnetic Resonance Imaging; Palliative Care; Pancreatic Neoplasms; Recurrence; Ultrasonography

During the recent years, multiple studies demonstrated that C-peptide is not an inert peptide, but exerts important physiological effects. C-peptide binds to cell membranes, stimulates the Na,K-ATPase and the endothelial nitric oxide (NO) synthase. Moreover, there is evidence that C-peptide decreases glomerular hyperfiltration and increases glucose utilisation. Nevertheless, there is still limited knowledge concerning mechanisms leading to an increased glucose utilisation either in rats or in humans. The aim of this paper is to give an overview over the published studies regarding C-peptide and glucose metabolism from in vitro studies to longer lasting studies in humans.

Topics: Animals; Biological Transport; Blood Glucose; C-Peptide; Glucose; Glucose Clamp Technique; Humans; Hypoglycemia; Insulin; Models, Animal; Muscle, Skeletal; Randomized Controlled Trials as Topic

Amino acids stimulate glucagon responses to hypoglycemia and may be utilized by the brain. The aim of this study was to assess the responses to hypoglycemia in nondiabetic and type 1 diabetic subjects after ingestion of an amino acid mixture.. Ten nondiabetic and 10 diabetic type 1 subjects were studied on three different occasions during intravenous insulin (2 mU . kg(-1) . min(-1)) plus variable glucose for 160 min. In two studies, clamped hypoglycemia (47 mg/dl plasma glucose for 40 min) was induced and either oral placebo or an amino acid mixture (42 g) was given at 30 min. In the third study, amino acids were given, but euglycemia was maintained.. Plasma glucose and insulin were no different in the hypoglycemia studies with both placebo and amino acids (P > 0.2). After the amino acid mixture, plasma amino acid concentrations increased to levels observed after a mixed meal (2.4 +/- 0.13 vs. placebo study 1.7 +/- 0.1 mmol/l, P = 0.02). During clamped euglycemia, ingestion of amino acids resulted in transient increases in glucagon concentrations, which returned to basal by the end of the study. During clamped hypoglycemia, glucagon response was sustained and increased more in amino acid studies versus placebo in nondiabetic and diabetic subjects (P < 0.05), but other counter-regulatory hormones and total symptom score were not different. Beta-OH-butyrate was less suppressed after amino acids (200 +/- 15 vs. 93 +/- 9 micromol/l, P = 0.01). Among the cognitive tests administered, the following indicated less deterioration after amino acids than placebo: Trail-Making part B, PASAT (Paced Auditory Serial Addition Test) (2 s), digit span forward, Stroop colored words, and verbal memory tests for nondiabetic subjects; and Trail-Making part B, digit span backward, and Stroop color tests for diabetic subjects.. Oral amino acids improve cognitive function in response to hypoglycemia and enhance the response of glucagon in nondiabetic and diabetic subjects.

Topics: Administration, Oral; Adult; Amino Acids; Area Under Curve; Blood Glucose; C-Peptide; Cognition; Diabetes Mellitus, Type 1; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Norepinephrine; Pancreatic Polypeptide; Reference Values; Surveys and Questionnaires; Trail Making Test

It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes.. A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia.. For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker.. Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels.

Topics: Adult; Blood Glucose; C-Peptide; Cesarean Section; Female; Fetal Blood; Fetal Macrosomia; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Infant, Newborn; Odds Ratio; Pregnancy; Pregnancy Complications; Pregnancy Outcome

The aim of our study was to establish whether the well-known defective or absent secretion of glucagon in type 1 diabetes in response to hypoglycaemia is selective or includes lack of responses to other stimuli, such as amino acids.. Responses of glucagon to hypoglycaemia were measured in eight patients with type 1 diabetes and six non-diabetic subjects during hyperinsulinaemic (insulin infusion 0.5 mU kg(-1) min(-1)) and eu-, hypo- and hyperglycaemic clamp studies (sequential steps of plasma glucose 5.0, 2.9, 5.0, 10 mmol/l). Subjects were studied on three randomised occasions with infusion of low- or high-dose alanine, or saline.. With saline, glucagon increased in hypoglycaemia in non-diabetic subjects but not in diabetic subjects. Glucagon increased further with low-dose (181 +/- 16 ng l(-1) min(-1)) and high-dose alanine (238 +/- 20 ng l(-1) min(-1)) in non-diabetic subjects, but only with high-dose alanine in diabetic subjects (area under curve 112 +/- 5 ng l(-1) min(-1)). The alanine-induced glucagon increase in diabetic subjects paralleled the spontaneous glucagon response to hypoglycaemia in non-diabetic subjects not receiving alanine. The greater responses of glucagon to hypoglycaemia with alanine infusion were offset by recovery of eu- or hyperglycaemia.. In type 1 diabetes, the usually deficient responses of glucagon to hypoglycaemia may improve after increasing the concentration of plasma amino acids. Amino acid-enhanced secretion of glucagon in response to hypoglycaemia remains under physiological control since it is regulated primarily by the ambient plasma glucose concentration. These findings might be relevant to improving counter-regulatory defences against insulin-induced hypoglycaemia in type 1 diabetes.

Topics: Adolescent; Adult; Alanine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Homeostasis; Humans; Hyperglycemia; Hypoglycemia; Male; Middle Aged; Norepinephrine; Reference Values

The intra-islet insulin hypothesis proposes that the decrement in beta-cell insulin secretion during hypoglycemia provides an activation signal for alpha-cells to release glucagon. A more recent hypothesis proposes that zinc atoms suppress glucagon secretion via their ability to open alpha-cell ATP-sensitive K(+) channels. Since insulin binds zinc, and zinc is co-secreted with insulin, we tested whether decreased zinc delivery to the alpha-cell activates glucagon secretion. In streptozotocin-induced diabetic Wistar rats, we observed that switching off intrapancreatic artery insulin infusions in vivo during hypoglycemia greatly improved glucagon secretion (area under the curve [AUC]: control group 240 +/- 261 and experimental group 4,346 +/- 1,259 pg x ml(-1) x 90 min(-1); n = 5, P < 0.02). Switching off pancreatic artery infusions of zinc chloride during hypoglycemia also improved the glucagon response (AUC: control group 817 +/- 107 and experimental group 3,445 +/- 573 pg x ml(-1) x 90 min(-1); n = 6, P < 0.01). However, switching off zinc-free insulin infusions had no effect. Studies of glucose uptake in muscle and liver cell lines verified that the zinc-free insulin was biologically active. We conclude that zinc atoms, not the insulin molecule itself, provide the switch-off signal from the beta-cell to the alpha-cell to initiate glucagon secretion during hypoglycemia.

Topics: Animals; Blood Glucose; C-Peptide; Glucagon; Glucagon-Secreting Cells; Hyperglycemia; Hypoglycemia; Insulin; Male; Rats; Rats, Wistar; Streptozocin; Zinc

The intraislet insulin hypothesis has been proposed to explain absent glucagon responses to hypoglycemia. Recently we directly confirmed this hypothesis by restoring glucagon secretion via provision of a pancreatic artery insulin infusion, which was switched off at the time of hypoglycemia in Wistar rats made diabetic by streptozotocin. The current study examined this hypothesis in a model of spontaneous, autoimmune diabetes, the insulin-dependent diabetic BB rat. The insulin switch-off signal restored the defective glucagon responses to hypoglycemia. However, the magnitude of the restored response was markedly less than that observed in control nondiabetic BB rats (4- to 5-month-old diabetic BB rats = 147 +/- 27; 2-month-old nondiabetic BB rats = 1038 +/- 112 pg/ml, peak delta; P < 0.0001). Because time was required for the BB rat to spontaneously develop diabetes, we asked whether the incomplete restoration of the glucagon response might be related to the animals' growth and development. This led us to compare the glucagon response to hypoglycemia in nondiabetic BB and Wistar rats at 2 and 4-5 months of age. We observed age-related deterioration of not only glucose tolerance and insulin sensitivity but also glucagon responses to hypoglycemia in both strains. There was no significant difference between the glucagon responses to hypoglycemia in age-matched nondiabetic BB rats and diabetic BB rats provided with the insulin switch-off signal. We conclude that defective glucagon responses to hypoglycemia in BB rats can be corrected by restoring regulation of alpha-cell function by insulin.

Topics: Animals; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Glucagon; Hypoglycemia; Insulin; Male; Rats; Rats, Inbred BB; Rats, Wistar

Insulin resistance and obesity play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). It is known that experimentally induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion. It is not yet known whether the long-term insulin resistance as found in PCOS patients alters the leptin response to hypo- and hyperglycaemia.. We induced hyper- and hypoglycaemia by glucose clamp technique in 7 patients with PCOS and 20 healthy controls. After a plasma glucose level of 8.8 mmol/l was reached, the plasma glucose level was reduced stepwise to 6.8, 4.8 and 2.8 mmol/l.. The PCOS patients required lower glucose infusion rates to reach the glycaemic targets (P < 0.05). Serum insulin and C-peptide concentrations increased significantly during the clamp compared with the baseline in both groups (P < 0.001 for insulin, and P < 0.001, P < 0.005 for C-peptide control and PCOS, respectively) and increased significantly more in PCOS patients compared with the control group (both P < 0.05). Basal leptin levels were significantly higher in the PCOS group than in the control group (P = 0.005). In the controls, the leptin concentration increased significantly during the clamp (P < 0.001 for each glycaemic target), whereas in the PCOS group, leptin secretion increased only during hypoglycaemia (P = 0.04).. Compared with the healthy controls, the response of leptin secretion to hyper- and hypoglycaemia was diminished in PCOS patients. Changes in leptin secretion seem not to be caused by hyper- and hypoglycaemia, but rather by hyperinsulinaemia. Reduced insulin sensitivity seems to be responsible for the diminished leptin response, which might contribute to the obesity found in PCOS patients.

Topics: Adult; Blood Glucose; C-Peptide; Female; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Resistance; Leptin; Polycystic Ovary Syndrome

Hyperinsulinemic hypoglycemia is newly recognized as a rare but important complication after Roux-en-Y gastric bypass (GB). The etiology of the syndrome and metabolic characteristics remain incompletely understood. Recent studies suggest that levels of incretin hormones are increased after GB and may promote excessive beta-cell function and/or growth.. We performed a cross-sectional analysis of metabolic variables, in both the fasting state and after a liquid mixed-meal challenge, in four subject groups: 1) with clinically significant hypoglycemia [neuroglycopenia (NG)] after GB surgery, 2) with no symptoms of hypoglycemia at similar duration after GB surgery, 3) without GB similar to preoperative body mass index of the surgical cohorts, and 4) without GB similar to current body mass index of the surgical cohorts.. Insulin and C-peptide after the liquid mixed meal were both higher relative to the glucose level achieved in persons after GB with NG compared with asymptomatic individuals. Glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide levels were higher in both post-GB surgical groups compared with both overweight and morbidly obese persons, and glucagon-like peptide 1 was markedly higher in the group with NG. Insulin resistance, assessed by homeostasis model assessment of insulin resistance, the composite insulin sensitivity index, or adiponectin, was similar in both post-GB groups. Dumping score was also higher in both GB groups but did not discriminate between asymptomatic and symptomatic patients. Notably, the frequency of asymptomatic hypoglycemia after a liquid mixed meal was high in post-GB patients.. A robust insulin secretory response was associated with postprandial hypoglycemia in patients after GB presenting with NG. Increased incretin levels may contribute to the increased insulin secretory response.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Eating; Female; Food; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Postoperative Complications

Topics: C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin-Secreting Cells; Insulin, Long-Acting; Metformin; Peptides; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Venoms; Weight Gain; Weight Loss

Glucagon-like peptide 1 (GLP-1) lowers glycemia by modulating gastric emptying and endocrine pancreatic secretion. Rapidly after its secretion, GLP-1-(7-36) amide is degraded to the metabolite GLP-1-(9-36) amide. The effects of GLP-1-(9-36) amide in humans are less well characterized. Fourteen healthy volunteers were studied with intravenous infusion of GLP-1-(7-36) amide, GLP-1-(9-36) amide, or placebo over 390 min. After 30 min, a solid test meal was served, and gastric emptying was assessed. Blood was drawn for GLP-1 (total and intact), glucose, insulin, C-peptide, and glucagon measurements. Administration of GLP-1-(7-36) amide and GLP-1-(9-36) amide significantly raised total GLP-1 plasma levels. Plasma concentrations of intact GLP-1 increased to 21 +/- 5 pmol/l during the infusion of GLP-1-(7-36) amide but remained unchanged during GLP-1-(9-36) amide infusion [5 +/- 3 pmol/l; P < 0.001 vs. GLP-1-(7-36) amide administration]. GLP-1-(7-36) amide reduced fasting and postprandial glucose concentrations (P < 0.001) and delayed gastric emptying (P < 0.001). The GLP-1 metabolite had no influence on insulin or C-peptide concentrations. Glucagon levels were lowered by GLP-1-(7-36) amide but not by GLP-1-(9-36) amide. However, the postprandial rise in glycemia was reduced significantly (by approximately 6 mg/dl) by GLP-1-(9-36) amide (P < 0.05). In contrast, gastric emptying was completely unaffected by the GLP-1 metabolite. The GLP-1 metabolite lowers postprandial glycemia independently of changes in insulin and glucagon secretion or in the rate of gastric emptying. Most likely, this is because of direct effects on glucose disposal. However, the glucose-lowering potential of GLP-1-(9-36) amide appears to be small compared with that of intact GLP-1-(7-36) amide.

Topics: Adult; Blood Glucose; C-Peptide; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Insulin; Lipid Metabolism; Male; Peptides; Time Factors

The reported risk of severe hypoglycaemia in insulin-treated Type 2 diabetes is highly variable and few studies have evaluated the influence of risk factors. We assessed the incidence and the influence of potential risk factors for severe hypoglycaemia in a questionnaire survey in subjects with insulin-treated Type 2 diabetes receiving currently recommended multifactorial intervention.. Consecutive patients with insulin-treated Type 2 diabetes (n = 401) completed a questionnaire about occurrence of hypoglycaemia in the past, hypoglycaemia awareness and socio-demographic factors. A zero-inflated negative binomial model was used to assess the influence of potential risk factors on the rate of severe hypoglycaemia.. The overall incidence of severe hypoglycaemia in the preceding year was 0.44 episodes/person year. Sixty-six (16.5%) patients had experienced at least one event. The risk of any episode of severe hypoglycaemia positively correlated with impaired hypoglycaemia awareness, being married and long duration of diabetes. The risk of repeated episodes of severe hypoglycaemia positively correlated with the presence of peripheral neuropathy, while long duration of diabetes prior to insulin treatment and treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists (ARBs) were associated with reduced risk. C-peptide concentration and HbA1c were not associated with the risk of severe hypoglycaemia.. In this cohort of insulin-treated Type 2 diabetic patients, the incidence of severe hypoglycaemia is higher than reported in most studies, corresponding to about one-third of that in Type 1 diabetes. Impaired hypoglycaemia awareness is the most important risk factor for severe hypoglycaemia.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Attitude to Health; C-Peptide; Cross-Sectional Studies; Denmark; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Insulin; Male; Middle Aged; Receptors, Angiotensin; Risk Factors

Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), characterized by postprandial neuroglycopaenia, negative prolonged fasts and negative perioperative localization studies for insulinoma, but positive selective arterial calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas, is a rare hypoglycaemic disorder of undetermined aetiology. We analysed the clinical, morphological and immunohistological features to further clarify the aetiology and pathogenesis of this rare disease.. Ten consecutive patients with NIPHS (nine men and one woman, aged 29-78 years) were included in the study. Six of the 10 received a gradient-guided subtotal (70%) or distal (50%) pancreatectomy. In the remaining four patients, diazoxide treatment was initiated and the precise mechanism of its action was assessed by meal tests.. All of the patients showed a combination of postprandial neuroglycopaenia, negative prolonged fasts (except one patient) and negative localization studies for insulinoma, but positive calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas. Immunohistological studies of the resected pancreatic tissues revealed neither an increased rate of proliferation of beta-cells nor an abnormal synthesis and/or processing of either proinsulin or amylin. Evidence of overexpression of the two pancreatic differentiation factors, PDX-1 and Nkx-6.1, as well as the calcium sensing receptor (CaSR) was absent. Nevertheless, abnormal expression of islet neogenesis-associated protein (INGAP), a human cytokine expressed only in the presence of islet neogenesis, in ducts and/or islets, was identified in three of the five patients studied. All of the six patients who received a surgical operation were relieved of further neuroglycopaenic attacks, but one patient who received a subtotal pancreatectomy developed diabetes. In the remaining four patients who received diazoxide treatment, hypoglycaemic episodes were satisfactorily controlled with an attenuated response of beta-cell peptides to meal stimulation.. Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from beta-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying beta-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6.1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted.

Topics: Adult; Aged; Amyloid; Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; C-Peptide; Cell Proliferation; Diazoxide; Fasting; Female; Homeodomain Proteins; Humans; Hyperinsulinism; Hypoglycemia; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Lectins, C-Type; Male; Middle Aged; Nesidioblastosis; Pancreatectomy; Pancreatitis-Associated Proteins; Postprandial Period; Proinsulin; Receptors, Calcium-Sensing; Syndrome; Trans-Activators

A 60-year-old woman presented to her primary care physician with fatigue and anemia. Laboratory evaluation revealed a hemoglobin level of 9.8 g/dL and an erythrocyte sedimentation rate (ESR) of 64 mm/hour. She subsequently developed nocturnal episodes of diaphoresis, confusion, and hypothermia. Capillary glucose measurements during the spells revealed hypoglycemia. During two supervised fasts, the patient's plasma glucose levels fell to 35 mg/dL and 32 mg/dL, respectively. Plasma insulin and C-peptide levels were appropriately suppressed, but a low concentration of beta-hydroxy-butyrate and normal increase of plasma glucose concentration after a glucagon injection suggested the presence of an insulin-like substance. Computed tomographic (CT) scan of the abdomen and subsequent positron emission tomographic (PET) scan revealed extensive lymphadenopathy. Biopsy of periaortic lymph nodes revealed Hodgkin's disease of the mixed cellularity type. Following chemotherapy, a complete remission ensued, the spells abated, and hypoglycemia was not induced by a 23-hour fast. We believe that the patient's Hodgkin's disease was producing an insulin-like substance. The observations of others suggest that this substance may be an autoantibody to the insulin receptor.

Topics: Antineoplastic Combined Chemotherapy Protocols; Autoantibodies; Bleomycin; C-Peptide; Dacarbazine; Doxorubicin; Female; Hodgkin Disease; Humans; Hypoglycemia; Hypothermia; Insulin; Middle Aged; Receptor, Insulin; Remission Induction; Vinblastine

Coronary artery disease (CAD) is the most common cause of death in patients with type 1 diabetes. Asymptomatic CAD is common in uremic diabetic patients, but its prevalence in nonuremic type 1 diabetic patients is unknown. The prevalence of CAD was determined by coronary angiography and the performance of noninvasive cardiac investigation evaluated in type 1 diabetic islet transplant (ITX) candidates with preserved renal function.. A total of 60 consecutive type 1 diabetic ITX candidates (average age 46 years [mean 24-64], 23 men, and 47% ever smokers) underwent coronary angiography, electrocardiographic stress testing (EST), and myocardial perfusion imaging (MPI) in a prospective cohort study. CAD was indicated on angiography by the presence of stenoses >50%. Models to predict CAD were examined by logistic regression.. Most subjects (53 of 60) had no history or symptoms of CAD; 23 (43%) of these asymptomatic subjects had stenoses >50%. CAD was associated with age, duration of diabetes, hypertension, and smoking. Although specific, EST and MPI were not sensitive as predictors of CAD on angiography (specificity 0.97 and 0.93, sensitivity 0.17 and 0.04, respectively) but helped identify two of three subjects requiring revascularization. EST and MPI did not enhance logistic regression models. A clinical algorithm to identify low-risk subjects who may not require angiography was highly sensitive but was applicable only to a minority (n = 8, sensitivity 1.0, specificity 0.27, negative predictive value 1.0).. Nonuremic type 1 diabetic patients with hypoglycemic unawareness and/or metabolic lability referred for ITX are at high risk for asymptomatic CAD despite negative noninvasive investigations. Aggressive management of cardiovascular risk factors and further investigation into optimal cardiac risk stratification in type 1 diabetes are warranted.

Topics: Adult; Aged; Awareness; Blood Pressure; C-Peptide; Coronary Angiography; Coronary Disease; Coronary Stenosis; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Female; Humans; Hypoglycemia; Islets of Langerhans Transplantation; Male; Middle Aged; Postoperative Complications; Predictive Value of Tests; Risk Factors; Sensitivity and Specificity; Smoking

To determine whether systematic evaluation of cognitive function by the Mini-Mental State Examination (MMSE) allows the objective detection and documentation of cognitive deterioration in patients referred for evaluation of suspected hypoglycaemic disorders by the 72-h fast.. Prospective case series.. In 50 patients referred for evaluation of suspected hypoglycaemic disorders, the MMSE score (maximum 30 points) was assessed at the start and at the end of the fast.. The fast was terminated before 72 h in 14 patients because they developed neuroglycopenic symptoms due to hypoglycaemic disorders. Their MMSE score fell from a median of 29 points (range 20-30) at the beginning to 17 points (range 0-24) at the termination of the fast. The score dropped by > or =6 points in all patients with hypoglycaemic disorders. Median (range) plasma glucose concentration at the end of the fast was 2.1 (1.1-2.5) mmol/l. Thirty-six individuals developed no neuroglycopenic symptoms throughout the 72-h fast, their MMSE score remained between 27 and 30 throughout the fast and their median plasma glucose concentration dropped to 2.9 (2-3.6) mmol/l.. Systematic evaluation of cognitive function by the MMSE at the beginning and at the termination of the fast allows objective determination and documentation of the deterioration of the cognitive state in patients with hypoglycaemic disorders. A decline in the cognitive performance by > or =6 points in the MMSE score rather than a distinct plasma glucose concentration should be used as the criterion to terminate the prolonged fast before 72 h.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Cognition; Cognition Disorders; Fasting; Female; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Prospective Studies; Time Factors

Diabetic patients with end-stage renal disease have a high mortality rate. A combined kidney-pancreas transplant is associated with greater life expectancy. Pancreas islet transplantation is an alternative involving a lower degree of morbidity. We present two patients, of 41 and 37 years of age, with a long history of diabetes mellitus (C-peptide negative), both with a previous kidney transplant, who had been treated with 22 and 28 U of insulin/d, respectively. Both patients had frequent episodes of unawareness hypoglycemia. Pancreatic islets were infused to a total of 7809 and 19,180 IE/kg, respectively. Basal posttransplant C peptide levels were 2.9 and 1.3 ng/mL. After the implant, one patient required occasional doses of insulin, and the other patient more than 50% reduced dose. After the first implant neither patient had any episodes of unawareness hypoglycemia. HbA1c at 4 months were 6.2% and 6.9%. There were no transplant-related complications.

Topics: Adult; Awareness; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Complications; Postoperative Period

Tyrosinaemia type I (TT I) (McKusick 276700) is a heterogeneous disorder with a broad spectrum of clinical phenotypes. Although histological abnormalities of the pancreas are well recognized, there are only incidental reports of pancreatic dysfunction manifested as insulin-dependent diabetes mellitus. We report three subjects with TT I and acute liver dysfunction who had hyperinsulinism in early infancy. Hypoglycaemia persisted despite dietary treatment and one patient had inadequate lipolysis at the time of hypoglycaemia. All three patients were successfully treated with diazoxide (10 mg/kg per day) and chlorthiazide (35 mg/kg per day) and treatment was gradually withdrawn after 9, 13 and 34 months, respectively. The mechanism of pancreatic dysfunction in TT I is unknown but may be related to the toxic metabolites that accumulate in this condition. We conclude that hyperinsulinism is not a rare complication in TT I. In patients with persistent hypoglycaemia, C-peptide should always be measured. Treatment with diazoxide and chlorthiazide is highly effective, appears to be safe, and does not need to be continued lifelong.

Topics: Blood Glucose; C-Peptide; Chlorothiazide; Diazoxide; Diuretics; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Liver Diseases; Pancreatic Diseases; Sodium Chloride Symporter Inhibitors; Tyrosinemias

Islet transplantation can restore endogenous beta-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 +/- 1.2 years, their mean duration of diabetes was 27.1 +/- 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 +/- 30,220 IE (11,910 +/- 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority ( approximately 80%) have C-peptide present post-islet transplant, but only a minority ( approximately 10%) maintain insulin independence. The median duration of insulin independence was 15 months (interquartile range 6.2-25.5). The HbA(1c) (A1C) level was well controlled in those off insulin (6.4% [6.1-6.7]) and in those back on insulin but C-peptide positive (6.7% [5.9-7.5]) and higher in those who lost all graft function (9.0% [6.7-9.3]) (P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 +/- 0.06 vs. 0.76 +/- 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed, bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant. There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up to 5 years, al

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Humans; Hypoglycemia; Insulin; Islets of Langerhans Transplantation; Male; Postoperative Complications; Survival Analysis; Time Factors; Treatment Outcome

Clinical history and inappropriate insulin secretion during hypoglycemic episodes permit the diagnosis of hyperinsulinism. We report 2 cases of factitious hyperinsulinism leading to partial pancreatectomy. Case 1 was an 8-year-old girl who presented with severe hypoglycemia and elevated insulin and C-peptide levels. Catheterization of pancreatic veins was performed to localize the excess insulin secretion. Insulinoma was suspected, and partial pancreatectomy was performed. Ten days after surgery, severe hypoglycemia recurred with severely elevated plasma insulin levels (x100) but very low C-peptide plasma levels, suggesting factitious hyperinsulinemia. Hypoglycemic episodes before surgery were provoked by oral sulfonamides; postoperative episodes were caused by parenteral insulin. Falsified prescriptions for sulfonamides and insulin by the mother, a nurse, were found. Case 2 was a 6-month-old girl who presented with seizures and hypoglycemia but had a symptom-free interval of many months afterward. At 2 years of age, repeated hypoglycemic seizures and elevated insulin plasma levels suggested congenital hyperinsulinism. C-peptide plasma level, measured once, was normal, but blood sampling was performed 15 minutes after a hypoglycemic episode. Partial pancreatectomy was performed. Two weeks after surgery, hypoglycemic seizures recurred, and the patient was admitted for pancreatic vein catheterization. This investigation was performed during hypoglycemia and revealed high insulin levels and undetectable C-peptide levels, suggesting factitious hypoglycemia. Insulin/C-peptide ratio analysis is crucial to assess factitious hypoglycemia, although sulfonamide-induced hypoglycemia is not thereby detected. One percent (2 of 250) of all cases of hyperinsulinemic hypoglycemia in our unit have been identified as Munchausen syndrome by proxy. Atypical disease history should raise the question of factitious hypoglycemia.

Topics: Blood Glucose; C-Peptide; Child; Child, Preschool; Congenital Hyperinsulinism; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Munchausen Syndrome by Proxy; Pancreatectomy

Non islet cell tumour hypoglycaemia (NICTH) is a rare cause of hypoglycaemia associated with malignancy and can be considered as a paraneoplastic syndrome. The hormonal factor associated with this condition is big IGF II, which exerts negative feedback effect and decreases the production of growth hormone and insulin. Due to low growth hormone levels, hepatic production of IGFBP 3 (the main binding protein of IGF II) is impaired. Excess free big IGF II is thus available for binding with insulin receptors to cause hypoglycaemia. Treatment options are either surgical removal of the tumour, administration of growth hormone, glucocorticoids or combination of treatments. A case of metastatic Leydig cell tumour causing NICTH has been discussed and the mechanism of NICTH hypoglycaemia and the treatment is outlined.

Topics: Aged; C-Peptide; Glucocorticoids; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leydig Cell Tumor; Male; Pancreatic Neoplasms; Testicular Neoplasms

Thioredoxin-interacting protein (Txnip) is a ubiquitous protein that binds with high affinity to thioredoxin and inhibits its ability to reduce sulfhydryl groups via NADPH oxidation. HcB-19 mice contain a nonsense mutation in Txnip that eliminates its expression. Unlike normal animals, HcB-19 mice have approximately 3-fold increase in insulin levels when fasted. The C-peptide/insulin ratio is normal, suggesting that the hyperinsulinemia is due to increased insulin secretion. Fasted HcB-19 mice are hypoglycemic, hypertriglyceridemic, and have higher than normal levels of ketone bodies. Ablation of pancreatic beta-cells with streptozotocin completely blocks the fasting-induced hypoglycemia/hypertriglyceridemia, suggesting that these abnormalities are due to excess insulin secretion. This is supported by increased hepatic mRNA levels of the insulin-inducible, lipogenic transcription factor sterol-responsive element-binding protein-1c and two of its targets, acetyl-CoA carboxylase and fatty acid synthase. During a prolonged fast, the hyperinsulinemia up-regulates lipogenesis but fails to down-regulate hepatic phosphoenolpyruvate carboxykinase mRNA expression. Hepatic ratios of reduced:oxidized glutathione, established regulators of gluconeogenic/glycolytic/lipogenic enzymes, were elevated 30% in HcB-19 mice, suggesting a loss of Txnip-enhanced sulfhydryl reduction. The altered hepatic enzymatic profiles of HcB-19 mice divert phosphoenolpyruvate to glyceroneogenesis and lipogenesis rather than gluconeogenesis. Our findings implicate Txnip-modulated sulfhydryl redox as a central regulator of insulin secretion in beta-cells and regulation of many of the branch-points of gluconeogenesis/glycolysis/lipogenesis.

Topics: Animals; C-Peptide; Carrier Proteins; Disulfides; DNA-Binding Proteins; Down-Regulation; Galactose; Glucose; Glucose-6-Phosphate; Glutathione; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Ketones; Liver; Mice; Mice, Inbred C3H; Models, Biological; Oxidation-Reduction; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Streptozocin; Sulfhydryl Compounds; Thioredoxins; Time Factors; Transcription Factors; Up-Regulation

To compare the outcome of different treatment options used in several cases of non-islet cell tumour hypoglycaemia (NICTH).. Eight cases of NICTH were referred for diagnosis and monitoring following either surgical or medical treatment.. Serum samples collected throughout the time-course of each case were analysed for glucose, insulin, C-peptide, IGF-I, total IGF-II, total IGF-II to IGF-I ratio and, in most of the cases, big IGF-II.. Surgical excision was successful in the relief of symptoms and normalization of the biochemical parameters. Therapeutic treatment with glucocorticoids confirmed previous studies showing the suppressive effect on tumour (big) IGF-II production. The present data show that the effect was dose-dependent and reversible if doses were below a critical level.. Within the limits of the cases studied, and the time-scales involved, moderate- to high-dose glucocorticoid therapy had immediate beneficial influence on symptomatic hypoglycaemia and, if tolerated in the long term, was effective in correcting the underlying biochemical dysfunction, unlike other therapeutic regimens. This effectiveness was only achieved when the dose exceeded a threshold level specific to the patient. In addition, reduction of the dose or withdrawal of the drug caused a return of the abnormal biochemical profile. Surgical removal of the malignancy, where this was an option, was successful within the periods studied.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Glucocorticoids; Human Growth Hormone; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Middle Aged; Neoplasms; Prednisolone; Protein Precursors

Transient hyperinsulinism (HI) occurs in infants born to diabetic mothers, in infants experiencing perinatal asphyxia and in infants with intrauterine growth retardation. The precise mechanism of transient HI in these different aetiologies is not fully understood. Lactic acidosis is commonly seen in neonates as a secondary phenomenon due to hypoxia, hypovolaemia, anaemia and infection. The combination of transient HI and lactic acidosis is rare. We present the clinical and biochemical features of five infants presenting with transient HI associated with hyperlactataemia in the absence of markers of perinatal stress. This combination lasted for 3-4 weeks with complete resolution except in one patient in whom the hyperinsulinism lasted until 6 months before resolution. The precise mechanism of this association is not clear but may be related either to immaturity of the pyruvate dehydrogenase complex or to the accumulation of abnormal intramitochondrial intermediary metabolites. Infants presenting with HI should have a free flowing blood sample drawn for the measurement of plasma lactate levels.

Topics: Acidosis; Age of Onset; Blood Glucose; C-Peptide; Chlorothiazide; Diazoxide; Diuretics; Fasting; Fatty Acids, Nonesterified; Female; Fibroblasts; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Ketone Bodies; Lactates; Male; Skin

A 53-year-old Caucasian woman presented with repeated episodes of hypoglycemia. Self-monitored blood glucose levels during the attacks were between 40 and 60 mg/dl (2.2-3.3 mmol/l).. An oral glucose tolerance test performed over 210 minutes showed normal baseline glucose levels, markedly elevated levels of serum insulin and slightly elevated C-peptide concentrations. During the test, a marked increase of insulin and a normal increment of C-peptide were observed. The tentative diagnosis of an insulinoma was raised and a 72 h fasting test performed, throughout which the insulin-glucose-ratio was pathologically elevated, whereas C-peptide levels were only slightly elevated.. Strongly positive levels of insulin antibodies led to the diagnosis of an insulin autoimmune syndrome.. This syndrome is caused by IgG-insulin-complexes with prolonged plasma half-life in the presence of reduced insulin action. The therapy consisted of fractionated meals to avoid hyperinsulinism and following hypoglycemic episodes. After four months a spontaneous clinical remission was observed.. The autoimmune insulin syndrome is a rare cause of recurrent, spontaneous hypoglycemia in Europe in non diabetic patients. Its prognosis is good as there is a high rate of spontaneous clinical remission in up to 80 % of patients.

Topics: Autoimmune Diseases; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Immunoglobulin G; Insulin; Insulin Antibodies; Middle Aged; Prognosis; Remission, Spontaneous; Syndrome

Mice bearing IL-1beta-secreting tumor were used to study the chronic effect of IL-1beta on glucose metabolism. Mice were injected with syngeneic tumor cells transduced with the human IL-1beta gene. Serum IL-1beta levels increased exponentially with time. Secretion of IL-1beta from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Body composition analysis revealed that IL-1beta caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities and mRNA levels of these enzymes were reduced, and 2-deoxy-glucose uptake by peripheral tissues was enhanced. mRNA levels of glucose transporters (Gluts) in the liver were determined by real-time PCR analysis. Glut-3 mRNA levels were up-regulated by IL-1beta. Glut-1 and Glut-4 mRNA levels in IL-1beta mice were similar to mRNA levels in pair-fed mice bearing nonsecreting tumor. mRNA level of Glut-2, the major Glut of the liver, was down-regulated by IL-1beta. We concluded that both decreased glucose production by the liver and enhanced glucose disposal lead to the development of hypoglycemia in mice bearing IL-1beta-secreting tumor. The observed changes in expression of hepatic Gluts that are not dependent on insulin may contribute to the increased glucose uptake.

Topics: Animals; Anorexia; Blood Glucose; Body Composition; Body Weight; C-Peptide; Cell Line, Tumor; Eating; Female; Fibrosarcoma; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Glycogen; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Interleukin-1; Leptin; Liver; Mice; Mice, Inbred C57BL; Monosaccharide Transport Proteins; Neoplasm Transplantation; Protein Serine-Threonine Kinases; RNA, Messenger

We present the case of an elderly non-diabetic female who was admitted to hospital as an emergency due to loss of consciousness. Her clinical presentation was consistent with hypoglycaemia due to a massive insulin overdose. However, the patient refuted the possibility of insulin administration, and the circumstances were reported to the police for investigation. This case demonstrates the clinical and biochemical characteristics of insulin overdose. Furthermore, it serves to illustrate the sequence of events that may be created when foul play is suspected, and the factors related to patient confidentiality that require consideration by the responsible physician.

Topics: Aged; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Suicide, Attempted

Insulin autoimmune syndrome (IAS, Hirata disease) is a rare cause of hypoglycemia in Western countries. It is characterized by hypoglycemic episodes, elevated insulin levels, and positive insulin antibodies. Our objective is to report a case of IAS identified in South America.. A 56-year-old Caucasian male patient started presenting neuroglycopenic symptoms during hospitalization due to severe trauma. Biochemical evaluation confirmed hypoglycemia and abnormally high levels of insulin. Conventional imaging examinations were negative for pancreatic tumor. Insulin antibodies were above the normal range. Clinical remission of the episodes was not achieved with verapamil and steroids. Thus, a subtotal pancreatectomy was performed due to the lack of response to conservative treatment and because immunosuppressants were contraindicated due to bacteremia. Histopathological examination revealed diffuse hypertrophy of beta cells. The patient continues to have high insulin levels but is almost free of hypoglycemic episodes.

Topics: Autoimmune Diseases; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Antibodies; Male; Middle Aged; Syndrome

A diabetic patient with chronic renal failure who developed recurrent and prolonged episodes of hypoglycemia associated with use of sulfonylurea agent is presented here. This patient was hospitalized with neuroglycopenic symptoms of hypoglycemia that persisted in spite of large doses of parenteral glucose replacement. On administration of somatostatin analogue octreotide, hypoglycemia resolved and, blood glucose levels were maintained even after cessation of parenteral glucose. The patient received 2 subcutaneous doses of octreotide 12 hours apart, and made a complete recovery. Our experience suggests that use of octerotide to treat refractory or prolonged sulfonylurea-included hypoglycemia in renal failure patients is safe and effective; large prospective studies would be needed to validate these findings.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Gastrointestinal Agents; Glipizide; Humans; Hypoglycemia; Hypoglycemic Agents; Kidney Failure, Chronic; Male; Octreotide; Seizures

In patients with type 1 diabetes, measurement of connecting peptide (C-peptide), cosecreted with insulin from the islets of Langerhans, permits estimation of remaining beta-cell secretion of insulin. In this retrospective analysis to distinguish the incremental benefits of residual beta-cell activity in type 1 diabetes, stimulated (90 min following ingestion of a mixed meal) C-peptide levels at entry in the Diabetes Control and Complications Trial (DCCT) were related to measures of diabetic retinopathy and nephropathy and to incidents of severe hypoglycemia. Based on the analytical sensitivity of the assay (0.03 nmol/l) and study entry criteria, the DCCT subjects were divided into four groups of stimulated C-peptide responses: 40 mg/24 h once and repeated at the next annual visit). There were also differences in severe hypoglycemia across C-peptide levels in both treatment groups. In the intensively treated cohort there were essentially identical prevalences of severe hypoglycemia ( approximately 65% of participants) in the first three groups; however, those subjects with mixed-meal stimulated C-peptide level >0.20 nmol/l for at least baseline and the first annual visit in the DCCT experienced a reduced prevalence of approximately 30%. Therefore, even modest levels of beta-cell activity at entry in the DCCT were associated with reduced incidences of retinopathy and nephropathy. Also, continuing C-peptide (insulin) secretion is important in avoiding hypoglycemia (the major complication of intensive diabetic therapy).

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Islets of Langerhans; Male; Retrospective Studies

We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACEgene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively.. We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists.. There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACEgene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia.. High ACE activity and the presence of the D allele of the ACE gene predict a high rate of severe hypoglycaemia in Type 1 diabetes.

Topics: Adult; Alleles; Awareness; C-Peptide; Diabetes Mellitus, Type 1; Female; Genotype; Humans; Hypoglycemia; Male; Middle Aged; Multivariate Analysis; Peptidyl-Dipeptidase A; Prognosis; Retrospective Studies; Risk Factors; Severity of Illness Index

The work-up of fasting hypoglycemia may be difficult but is crucially important because a wrong diagnosis can lead to either unnecessary pancreatectomy or a missed pancreatic tumor. We describe a patient with severe fasting hypoglycemia [22-32 mg/dl (1.2-1.8 mmol/liter) after 6-10 h of fasting] in which the diagnosis of a secretory islet-cell tumor was obscured, rather than facilitated, by use of a new, highly specific serum insulin assay. Insulin measured by the specific assay suppressed normally during fasting hypoglycemia [undetectable at < 2.0-3.8 micro IU/ml (26.4 pmol/liter)], whereas insulin measured by older, less specific assays was diagnostically elevated [34, 73 micro IU/ml (236.1, 507.0 pmol/liter)]. Serum proinsulin and C-peptide levels were abnormal, and further work-up revealed an islet-cell tumor that secreted predominantly proinsulin. The tumor was surgically removed, relieving the fasting hypoglycemia. We conclude that insulin levels as measured by new, highly specific insulin assays may obscure the diagnosis of a functional, proinsulin-secreting islet-cell tumor. Because proinsulin cross-reacts with insulin in older insulin assays, C-peptide or proinsulin should be measured to rule out a proinsulin-secreting islet-cell tumor. Normative values for new insulin assays must be established during prolonged fasting.

Topics: Adenoma, Islet Cell; Adult; Anemia, Sickle Cell; Biopsy, Needle; C-Peptide; Fasting; Humans; Hypoglycemia; Insulin; Male; Pancreatectomy; Pancreatic Neoplasms; Proinsulin; Sensitivity and Specificity; Ultrasonography

Given that iatrogenic hypoglycemia often occurs during the night in people with type 1 diabetes, we tested the hypothesis that physiological, and the resulting behavioral, defenses against developing hypoglycemia-already compromised by absent glucagon and attenuated epinephrine and neurogenic symptom responses-are further compromised during sleep in type 1 diabetes. To do so, we studied eight adult patients with uncomplicated type 1 diabetes and eight matched nondiabetic control subjects with hyperinsulinemic stepped hypoglycemic clamps (glucose steps of approximately 85, 75, 65, 55, and 45 mg/dl) in the morning (0730-1230) while awake and at night (2100-0200) while awake throughout and while asleep from 0000 to 0200 in random sequence. Plasma epinephrine (P = 0.0010), perhaps norepinephrine (P = 0.0838), and pancreatic polypeptide (P = 0.0034) responses to hypoglycemia were reduced during sleep in diabetic subjects (the final awake versus asleep values were 240 +/- 86 and 85 +/- 47, 205 +/- 24 and 148 +/- 17, and 197 +/- 45 and 118 +/- 31 pg/ml, respectively), but not in the control subjects. The diabetic subjects exhibited markedly reduced awakening from sleep during hypoglycemia. Sleep efficiency (percent time asleep) was 77 +/- 18% in the diabetic subjects, but only 26 +/- 8% (P = 0.0109) in the control subjects late in the 45-mg/dl hypoglycemic steps. We conclude that autonomic responses to hypoglycemia are reduced during sleep in type 1 diabetes, and that, probably because of their reduced sympathoadrenal responses, patients with type 1 diabetes are substantially less likely to be awakened by hypoglycemia. Thus both physiological and behavioral defenses are further compromised during sleep. This sleep-related hypoglycemia-associated autonomic failure, in the context of imperfect insulin replacement, likely explains the high frequency of nocturnal hypoglycemia in type 1 diabetes.

Topics: Blood Glucose; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Humans; Hypoglycemia; Insulin; Reference Values; Sleep; Sleep Stages; Sleep, REM; Wakefulness

During liver transplantation and after both meal ingestion and prolonged fasting, renal glucose release (RGR) increases while hepatic glucose release (HGR) decreases. These and other observations have led to the concept of hepatorenal reciprocity. According to this concept, reciprocal changes in hepatic and renal glucose release may occur to minimize deviations from normal glucose homeostasis. We further assessed this concept by testing the hypothesis that during counterregulation of hypoglycemia in patients with type 2 diabetes, who would be expected to have reduced HGR, RGR would be increased. Accordingly, we performed hypoglycemic hyperinsulinemic clamp experiments (approximately 3.1 mmol/l) in 12 type 2 diabetic and in 10 age-weight-matched nondiabetic volunteers and measured total endogenous glucose release (TEGR) and RGR using a combined isotopic net balance approach. HGR was calculated as the difference between TEGR and RGR since only these organs are capable of releasing glucose. We found that during comparable hypoglycemia and hyperinsulinemia, TEGR was reduced in type 2 diabetes (6.6 +/- 0.6 vs. 10.2 +/- 1.1 micromol. kg(-1). min(-1) in nondiabetic volunteers, P = 0.01) due to reduced HGR (3.9 +/- 0.5 vs. 8.6 +/- 1.0 micromol. kg(-1). min(-1) in nondiabetic volunteers, P = 0.0015). In contrast, RGR was increased approximately twofold in type 2 diabetes (3.3 +/- 0.5 vs. 1.6 +/- 0.3 micromol. kg(-1). min(-1) in nondiabetic volunteers, P = 0.015). Plasma epinephrine, lactate, and free fatty acid concentrations, which would promote RGR, were also greater in type 2 diabetes (all P < 0.01). Our results provide further support for hepatorenal reciprocity and may explain at least in part the relatively low occurrence of severe hypoglycemia in type 2 diabetes compared with type 1 diabetes where both HGR and RGR counterregulatory responses are reduced.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose; Homeostasis; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kidney; Lactates; Liver; Male; Middle Aged; Reference Values

We report a case of an 82 year-old woman who had two episodes of documented hypoglycemia. Initial laboratory testing revealed hyperinsulinemia and a negative serum sulfonylurea screen. While these data suggested the presence of an insulinoma, further evaluation of the case revealed inadvertent ingestion of glimepiride, a sulfonylurea not included in the standard serum sulfonylurea screen.

Topics: Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Overdose; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Sulfonylurea Compounds

Adult spontaneous hypoglycaemia is not a diagnosis per se but a manifestation of a disease. Although rare, it is important to identify spontaneous hypoglycaemia and its causes because treatment may be preventative or curative. Hypoglycaemia can occur as an epiphenomenon in many serious diseases. It is sufficient to recognise the disease's association with hypoglycaemia and then take appropriate action to prevent the recurrence of hypoglycaemia. In investigating apparently healthy individuals, common pitfalls to avoid are: failure to recognise subacute neuroglycopenia clinically; failure to document hypoglycaemia adequately during symptoms; failure to measure pancreatic hormones, counter-regulatory hormones, and ketones in hypoglycaemic samples; failure to recognise pre-analytical and analytical limitations of laboratory assays; and failure to abandon obsolete and inappropriate investigations. Providing these caveats are met, appropriate laboratory and radiological investigations will almost always uncover the cause of spontaneous hypoglycaemia.

Topics: Acute Disease; Adult; Autoantibodies; Blood Glucose; C-Peptide; Clinical Laboratory Techniques; Diagnosis, Differential; Exercise Test; Fasting; Homeostasis; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Postprandial Period; Proinsulin; Receptor, Insulin

The aim of the present study was to determine whether a decrease in the portal vein insulin level during non-insulin-induced hypoglycemia is sensed and is responsible for the normal increase in glucagon release from the alpha cell. To address this aim, a glycogen phosphorylase inhibitor was used to create mild, non-insulin-induced hypoglycemia in 2 groups of 18-hour fasted conscious dogs. Arterial insulin was clamped at a basal level in both groups, but in one group (PE) the portal vein insulin level was permitted to fall by approximately 65% while in the other group (POR) it was clamped at a basal level. In both groups glucose was infused at a variable rate to clamp the plasma glucose level at approximately 70 mg/dL. Plasma glucagon (pg/mL) rose to indistinguishable maxima in both groups (56 +/- 3 in PE and 67 +/- 9 in POR). Likewise, glucagon secretion (pg/kg/min) increased similarly (189 +/- 32 to 455 +/- 203 in PE and 192 +/- 50 to 686 +/- 237 in POR). Thus, the increase in glucagon release was not inhibited when the portal vein insulin level was prevented from decreasing (POR group). Clearly, a fall in the portal vein insulin level is not required for a normal alpha-cell response to mild, non-insulin-induced hypoglycemia.

Topics: Animals; Biosensing Techniques; Blood Glucose; C-Peptide; Dogs; Female; Glucagon; Glycogen Phosphorylase; Hypoglycemia; Insulin; Islets of Langerhans; Male; Norepinephrine; Portal Vein

We report a case of insulinoma in which the diagnosis was very challenging as some of the biochemical data were consistently equivocal. In order to assess the relative reliability of the analytical tests, retrospective biochemical data on 45 other cases of histologically confirmed insulinoma were evaluated, enabling the most secure diagnostic process to be identified.. The data showed that insulin concentrations alone, although measurable, were equivocal in 17% of cases. The addition of C-peptide values clarified the diagnosis in about 50% of the borderline cases, whilst ketone (beta-hydroxybutyrate) concentrations were low during the prevailing hypoglycaemia in all cases.. The combination of these three tests is suggested as the most effective method for the biochemical diagnosis of hypoglycaemia due to insulinoma.

Topics: 3-Hydroxybutyric Acid; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Predictive Value of Tests; Reference Values; Reproducibility of Results; Retrospective Studies

An end-stage renal disease patient on long-term peritoneal dialysis was admitted with dizziness, fatigue, hypoglycemia, and hypotension. The hypotension resolved with intravenous normal saline, but the hypoglycemia persisted for 3 days despite an intravenous dextrose drip and discontinuation of gabapentin. The patient became normoglycemic on the fourth day of admission. None of the known causes for the hypoglycemia were identified except gabapentin, the dose of which was recently doubled 1 month before admission. Insulin and C-peptide levels were high during the hypoglycemic episode and returned to normal after discontinuation of gabapentin. The patient remains off gabapentin and has had no further episodes of hypoglycemia. To our knowledge, this is the first case of hypoglycemia induced by gabapentin.

Topics: Acetates; Amines; C-Peptide; Cyclohexanecarboxylic Acids; Female; Gabapentin; gamma-Aminobutyric Acid; Gluconeogenesis; Humans; Hypoglycemia; Hypotension; Insulin; Kidney Cortex; Kidney Failure, Chronic; Liver; Middle Aged; Pancreas; Parathyroidectomy; Peritoneal Dialysis; Postoperative Complications

Hyperinsulinemic hypoglycemia associated with trimethoprim-sulfamethoxazole (TMP-SMX) has generally been reported in adults who had renal impairment or in patients with AIDS using high dose TMP-SMX. We present a 5 month-old infant with immunodeficiency due to major histocompatibility complex class II expression defect, developing hypoglycemic convulsion on the third day of high dose TMP-SMX administration. High insulin and C-peptide levels were documented at the time of hypoglycemia. To overcome hypoglycemia while TMP-SMX tapered off, diazoxide was administered which resolved hypoglycemia in 2 months.

Topics: Blood Glucose; C-Peptide; Diazoxide; Drug Administration Schedule; Female; Gene Expression; Genes, MHC Class II; Glucose; Histocompatibility Antigens Class II; Hospitalization; Humans; Hyperinsulinism; Hypoglycemia; Immunologic Deficiency Syndromes; Infant; Infusions, Intravenous; Pneumonia; Seizures; Time Factors; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

The most important cause of hypoglycaemia in the presence of high insulin and C-peptide concentrations is insulinoma. However, a similar picture arises from use of sulphonylureas, which is sometimes covert. All specimens received in two years by a supraregional assay service laboratory from adults with low glucose and inappropriately high insulin and C-peptide concentrations were tested for sulphonylureas by a radioimmunoassay that employed antibodies to glibenclamide. In sulphonylurea-positive cases a questionnaire was sent to the consultant responsible for the patient, to elicit further information. Samples from 93 adult patients met the criteria, and 34 (37%) of these gave a positive result on screening for sulphonylureas. The consultants provided further information on 31 of the 34, and in 20 the presence of a sulphonylurea was unexpected. In 10 the features were such as to raise the possibility of factitious drug ingestion. A simple screening technique applied to specimens from patients with hyperinsulinaemic hypoglycaemia indicated that, in a substantial proportion of cases, the patient was taking a sulphonylurea.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; C-Peptide; Child; Female; Humans; Hypoglycemia; Insulin; Male; Mass Screening; Middle Aged; Radioimmunoassay; Sensitivity and Specificity; Sulfonylurea Compounds

To evaluate the influence of residual beta-cell function on glucagon secretion and glucose counter-regulation following hypoglycaemia in type 1 diabetes.. The hormonal counter-regulatory responses to standardized insulin-induced hypoglycaemia were investigated, 18 patients with type 1 diabetes of long duration and 12 healthy subjects were investigated. Nine of the diabetic patients (diabetes duration 17 +/- 1 years) had residual insulin secretion, as reflected by persistent urinary C-peptide excretion. The other nine diabetic patients (diabetes duration 21 +/- 1 years) were C-peptide negative.. Similar hypoglycaemic nadirs were found in all groups (2.1-2.3 mmol L-1), whereas the recovery of plasma glucose levels was delayed similarly in the diabetic groups. In the control subjects, plasma glucagon increased ( approximately 50%). No significant glucagon response was registered in either of the two diabetic groups. The maximum plasma adrenaline and pancreatic polypeptides (PP) responses to hypoglycaemia were comparable in the two diabetic patient groups; the peak values being lower (P < 0.05) than in the controls. Plasma noradrenaline, growth hormone and cortisol responses to hypoglycaemia were similar in all three groups.. Residual beta-cell function in patients with long-term type 1 diabetes is not accompanied by preservation of the glucagon response to hypoglycaemia. As the two markers of autonomic function (adrenaline and PP) were similarly reduced in the two diabetic groups, the findings instead favour the concept that the defective glucagon secretory response to hypoglycaemia is because of autonomic nervous dysfunction.

Topics: Adult; Autonomic Nervous System; Blood Glucose; C-Peptide; Data Interpretation, Statistical; Diabetes Mellitus, Type 1; Epinephrine; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Infusions, Intravenous; Injections, Subcutaneous; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Pancreatic Polypeptide; Radioimmunoassay; Time Factors

Islet allotransplantation can provide prolonged insulin independence in selected individuals with type 1 diabetes. Whether islet transplantation also restores hypoglycemic counterregulation is unclear. To determine if hypoglycemic counterregulation is restored by islet transplantation, we studied hormone responses and hypoglycemic symptom recognition in seven insulin-independent islet transplant recipients using a 3-h stepped hypoglycemic clamp, and compared their responses to those of nontransplanted type 1 diabetic subjects and nondiabetic control subjects. Glucagon responses of islet transplant recipients to hypoglycemia were significantly less than that observed in control subjects (incremental glucagon [mean +/- SE]: -12 +/- 12 vs. 64 +/- 22 pg/ml, respectively; P < 0.05), and not significantly different from that of nontransplanted type 1 diabetic subjects (-17 +/- 10 pg/ml). Epinephrine responses and symptom recognition were also not restored by islet transplantation (incremental epinephrine [mean +/- SE]: 195 +/- 128 [islet transplant recipients] vs. 238 +/- 73 [type 1 diabetic subjects] vs. 633 +/- 139 pg/ml [nondiabetic control subjects], P < 0.05 vs. control; peak symptom scores: 3.3 +/- 0.9 [islet transplant recipients] vs. 3.1 +/- 1.1 [type 1 diabetic subjects] vs. 6.7 +/- 0.8 [nondiabetic control subjects]). Thus the results indicate that despite providing prolonged insulin independence and near-normal glycemic control in these patients with long-standing type 1 diabetes, hypoglycemic hormonal counterregulation and symptom recognition were not restored by intrahepatic islet transplantation.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Epinephrine; Female; Glucagon; Hormones; Humans; Hypoglycemia; Insulin; Islets of Langerhans Transplantation; Liver; Male; Middle Aged

To review patients records operated with the diagnosis of insulinoma and to discuss their clinical presentations, diagnostic and therapeutic modalities.. Retrospective study.. Ankara Numune Teaching and Research Hospital, Turkey.. Eight cases were operated in the Department of 6th Surgery, Ankara Numune Teaching and Research Hospital between 1994 and 2000. All patients had neuroglycopenic symptoms. Six patients had blood glucose levels of lower than 50 mg/dL during the admission. The other two patients had hypoglycaemia in the prolonged fasting test. Serum insulin/glucose ratio was diagnostic in all patients except one. Abdominal ultrasonography and computerised tomography could successfully localise the tumour in one case. In six patients tumours could be localised by endoscopic pancreatic ultrasonography. In one patient none of the studies could localise the tumour. Three tumours were located at the pancreatic head, one in the neck, two at the body and two at the tail. All tumours except one were palpable. Enucleation was the procedure of choice in four cases and distal pancreatectomy was the procedure of choice in four.. Post-operative course was uneventful in seven patients. One patient died due to intra-abdominal sepsis. Hypoglycaemia was controlled in all patients after the surgery.. Surgery is the mainstay of treatment of insulinoma. Enucleation should be the procedure of choice if possible. Endoscopic pancreatic ultrasonography has promising results and may replace invasive angiographic studies in the future.

Topics: Adult; Blood Glucose; C-Peptide; Confusion; Diagnosis, Differential; Dizziness; Endosonography; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Muscle Weakness; Pancreatectomy; Pancreatic Neoplasms; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome; Turkey; Unconsciousness

We tested the hypotheses that the glucagon response to hypoglycemia is reduced in patients who are approaching the insulin-deficient end of the spectrum of type 2 diabetes and that recent antecedent hypoglycemia shifts the glycemic thresholds for autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia to lower plasma glucose concentrations in type 2 diabetes. Hyperinsulinemic stepped hypoglycemic clamps (85, 75, 65, 55, and 45 mg/dl steps) were performed on two consecutive days, with an additional 2 h of hypoglycemia (50 mg/dl) in the afternoon of the first day, in 13 patients with type 2 diabetes---7 treated with oral hypoglycemic agents (OHA R(X); mean [+/- SD] HbA(1c) 8.6 +/- 1.1%) and 6 requiring therapy with insulin for an average of 5 years and with reduced C-peptide levels (insulin R(X), HbA(1c) 7.5 +/- 0.7%)---and 15 nondiabetic control subjects. The glucagon response to hypoglycemia was virtually absent (P = 0.0252) in the insulin-deficient type 2 diabetic patients (insulin R(X) mean [+/- SE] final values of 52 plus minus 16 vs. 93 plus minus 15 pg/ml in control subjects and 98 +/- 16 pg/ml in type 2 diabetic patients, OHA R(X) on day 1). Glucagon (P = 0.0015), epinephrine (P = 0.0002), and norepinephrine (P = 0.0138) responses and neurogenic (P = 0.0149) and neuroglycopenic (P = 0.0015) symptom responses to hypoglycemia were reduced on day 2 after hypoglycemia on day 1 in type 2 diabetic patients; these responses were not eliminated, but their glycemic thresholds were shifted to lower plasma glucose concentrations. In addition, the glycemic thresholds for these responses were at higher-than-normal plasma glucose concentrations (P = 0.0082, 0.0028, 0.0023, and 0.0182, respectively) at baseline (day 1) in OHA R(X) type 2 diabetic patients, with relatively poorly controlled diabetes. Because the glucagon response to falling plasma glucose levels is virtually absent and the glycemic thresholds for autonomic and symptomatic responses to hypoglycemia are shifted to lower glucose concentrations by recent antecedent hypoglycemia, patients with advanced type 2 diabetes, like those with type 1 diabetes, are at risk for hypoglycemia-associated autonomic failure and the resultant vicious cycle of recurrent iatrogenic hypoglycemia.

Topics: Adult; Autonomic Nervous System; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Kinetics; Male; Middle Aged; Norepinephrine

We tested the hypothesis that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia. Twelve healthy young adults were studied on two separate occasions, once after infusions of a pharmacological dose of alpha-(1-24)-ACTH (100 microg/h) from 0930 to 1200 and 1330 to 1600, which raised plasma cortisol levels to approximately 45 microg/dl on day 1, and once after saline infusions on day 1. Hyperinsulinemic (2.0 mU x kg(-1) x min(-1)) stepped hypoglycemic clamps (90, 75, 65, 55, and 45 mg/dl glucose steps) were performed on the morning of day 2 on both occasions. These markedly elevated antecedent endogenous cortisol levels reduced the adrenomedullary (P = 0.004, final plasma epinephrine levels of 489 +/-64 vs. 816 +/-113 pg/ml), sympathetic neural (P = 0.0022, final plasma norepinephrine levels of 244 +/-15 vs. 342 +/-22 pg/ml), parasympathetic neural (P = 0.0434, final plasma pancreatic polypeptide levels of 312 +/- 37 vs. 424 +/- 56 pg/ml), and neurogenic (autonomic) symptom (P = 0.0097, final symptom score of 7.1 +/-1.5 vs. 10.6 +/- 1.6) responses to subsequent hypoglycemia. Growth hormone, but not glucagon or cortisol, responses were also reduced. The findings that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia are potentially relevant to cortisol mediation of hypoglycemia-associated autonomic failure, and thus a vicious cycle of recurrent iatrogenic hypoglycemia, in people with diabetes mellitus.

Topics: 3-Hydroxybutyric Acid; Adrenal Medulla; Adult; C-Peptide; Cosyntropin; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Glucose Clamp Technique; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin; Male; Neurosecretory Systems; Norepinephrine; Pancreatic Polypeptide; Parasympathetic Nervous System

To evaluate the C-peptide suppression test as a screening test in patients with symptoms of hypoglycemia as compared to the standard fasting test.. Retrospective discriminant analysis of data from C-peptide suppression tests.. Clinical study.. Patients with insulinomas and patients without insulinomas but having symptoms compatible with hypoglycemia.. The results from C-peptide suppression tests of 26 patients with insulinomas and 100 patients without insulinomas were compared.. A classification plot which introduces two discriminant parameters for the C-peptide suppression test: the ratio of [blood glucose]/[C-peptide] at the lowest C-peptide concentration and mean glycemia during insulin infusion.. In patients with insulinomas, minimal serum C-peptide levels were higher (1.81+/- 0.87 ng/mL; median 1.83 ng/mL; maximal suppression 37 +/- 24% of basal C-peptide levels) as compared to patients without insulinoma (0.40 +/- 0.15 ng/mL; median 0.30 ng/mL; maximal suppression of 75 +/- 9%; P<0.001). Mean glycemia during the test was lower in patients with insulinomas (30.8 +/- 3.3 vs. 47.5 +/- 8.3 mg/dL; P<0.001) as was the [blood glucose]/[C-peptide] ratio (21.9 +/- 14.6 vs. 139.2 +/- 43.8; P<0.001). Discriminant analysis revealed a specificity of 96% to rule out the diagnosis of 'insulinoma' at a 1% probability threshold with a sensitivity of 100%.. We developed a new classification plot for the C-peptide suppression test in order to accurately identify those patients whose symptoms of hypoglycemia are not due to endogenous hyperinsulinemia/insulinomas. Thus, the need for fasting tests and hospitalization costs can be reduced.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Aged, 80 and over; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Insulin Antagonists; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms

To assess the extent to which biochemical analytical services contribute to the diagnosis and management of clinical cases of hypoglycaemia.. All cases of confirmed hypoglycaemia, referred during a six month period, were included in the survey. Questionnaires were sent to each referring laboratory requesting information on the clinical progress and current status of the patient.. The level of influence exerted by analytical data was assigned in each case and those with similar outcomes combined. Identifiable case groups were: (1) Results not recorded in the patients' notes (15.7%). (2) Inappropriate requesting of insulin and C peptide measurements in cases of diabetes (11.4%). (3) Patient died soon after investigation (20.0%). (4) Patient recovered spontaneously (17.1%). (5) Patient received effective medical or surgical treatment (12.9%). (6) Patient awaiting or not requiring pathology based treatment (31.4%). (7) Inconclusive outcome prompting further investigation (5.7%).. Within the timescale of the survey (approximately 12 months), positive progress had been made towards diagnosis and subsequent treatment in only 10% of cases. Another 30% were either awaiting some form of treatment or further diagnostic tests. The remaining 60% did not appear to benefit in any way from the biochemical investigations.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Autopsy; C-Peptide; Child; Child, Preschool; Diagnostic Services; England; Enzyme-Linked Immunosorbent Assay; Health Care Surveys; Health Services Research; Humans; Hypoglycemia; Infant; Infant, Newborn; Insulin; Laboratories, Hospital; Middle Aged; Treatment Outcome

In great part of the investigations of endocrine system functions in astronauts during space flights the plasma levels of hormones and metabolites were determined only in resting conditions, usually from one blood sample collection. Such levels reflected the psychical and physical state and new hormonal homeostasis of organism at the time of blood collection, however, the functional capacity of neuroendocrine system to respond to various stress stimuli during space flight remained unknown. The aim of present investigations was to study dynamic changes of hormone levels during the stress and metabolic loads (insulin induced hypoglycemia, physical exercise and oral glucose tolerance test) at the exposure of human subject to microgravity on the space station MIR. The responses of sympatico-adrenomedullary system to these stress and workloads were presented by Kvetnansky et al.

Topics: Adaptation, Physiological; Blood Glucose; C-Peptide; Exercise Test; Growth Hormone; Hormones; Humans; Hydrocortisone; Hypoglycemia; Insulin; Male; Prolactin; Space Flight; Stress, Physiological; Weightlessness

To establish reference intervals for the pancreatic beta-cell response and the counterregulatory hormone response to prolonged fasting, we studied 33 healthy subjects (16 males, 17 females) during a 72-h fast. Glucose, insulin, C-peptide, and proinsulin levels decreased (P < 0.001), and the levels of counterregulatory factors increased during the fast [P < 0.05; glucagon and free fatty acids (FFA) with a linear increase and epinephrine, norepinephrine, and cortisol with a clear underlying circadian rhythm]. Growth hormone secretion increased from the first to third day of fasting (P < 0.05) but actually decreased from the second to third day of fasting (P = 0.03). Males had higher glucose and glucagon levels and lower FFA levels during the fast (P < 0.05), whereas no effect of gender on beta-cell polypeptides was observed. A high body mass index resulted in higher insulin and C-peptide levels during the fast (P < 0.05). In conclusion, we have provided reference intervals for glucoregulatory factors during a 72-h fast. We observed a diminished beta-cell response concomitant with an increased secretion of counterregulatory hormones. These results should be of clinical and scientific value in the investigation of hypoglycemic disorders.

Topics: Adult; Aged; B-Lymphocytes; Blood Glucose; Body Mass Index; C-Peptide; Chemistry, Clinical; Epinephrine; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Insulin; Male; Middle Aged; Norepinephrine; Peptides; Proinsulin; Reference Values; Serum Albumin; Sex Factors

It has previously been shown that intravenous and subcutaneous administration of glucagon-like peptide (GLP)-1 concomitant with intravenous glucose results in reactive hypoglycaemia in healthy subjects. Since GLP-1 is also effective in Type 2 diabetic patients and is presently being evaluated as a therapeutic agent in this disease, it is important to investigate whether GLP-1 can cause hypoglycaemia in such patients.. Eight Type 2 diabetic patients (age 54 (49-67) years; body mass index 31 (27-38) kg/m2; HbA1c 9.4 (7.0-12.5)%) and seven matched non-diabetic subjects (HbA1c 5.5 (5.2-5.8)%, fasting plasma glucose 5.4 (5.0-5.7) mmol/l) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body weight (maximally tolerated dose), and 15 min later, plasma glucose (PG) was raised to 15 mmol/l with an intravenous glucose bolus.. Hypoglycaemia with a PG at or below 2.5 mmol/l was seen in five of the seven healthy subjects after 60-70 min, but PG spontaneously increased again, reaching 3.7 (3.3-4.0) mmol/l at 90 min. In the patients, PG fell slowly and stabilized at 8.6 (4.2-12.1) mmol/l after 80 min. In both groups, glucagon levels initially decreased, but later increased, exceeding basal levels in healthy subjects, in spite of persistent, high concentrations of GLP-1 (P < 0.02).. Subcutaneous GLP-1 plus intravenous glucose induced reactive hypoglycaemia in healthy subjects, but not in Type 2 diabetic patients. Therefore, a GLP-1-based therapy would not be expected to be associated with an increased risk of hypoglycaemia in Type 2 diabetes mellitus.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Injections, Subcutaneous; Insulin; Kinetics; Male; Middle Aged; Peptide Fragments; Protein Precursors; Reference Values

Set point errors in glucose homeostasis that result in chronic, mild hyperglycemia in the setting of maturity onset diabetes of the young have been described. Similar set point errors may exist that result in chronic, asymptomatic glucopenia.. A healthy 39-year-old female was referred for evaluation of chronic, persistent, and asymptomatic glucopenia that persisted over the prior several years with a record of numerous random plasma glucose concentrations between 35 and 45 mg/dL. She denied ethanol intake and family history of hypoglycemia or diabetes. She was not taking any medications known to cause hypoglycemia, and a urine sulfonylurea screen was negative. Fasting insulin and C-peptide levels were not elevated, and pancreatic imaging studies were normal. We hypothesized that this patient possessed an error in glucose metabolism that resulted in chronic, asymptomatic glucopenia.. In a series of clinical studies, we demonstrated a nadir plasma glucose concentration of 35 mg/dL in the absence of symptoms during a 60-hour fast. C-peptide secretion was appropriately suppressed during symptomatic hypoglycemia with exogenous insulin infusion, and counterregulatory hormone secretion was intact during insulin-induced symptomatic hypoglycemia. Finally, the patient demonstrated an incremental increase in insulin concentration in response to minimal increases in plasma glucose during a sequential, stepped infusion of 10% dextrose.. We conclude that this patient exhibits features of a set point error in glucose homeostasis that manifests as chronic, asymptomatic glucopenia. Although the mechanism for this condition remains to be elucidated, such set point errors do exist and should be considered in the differential diagnosis of chronic hypoglycemia.

Topics: Adult; C-Peptide; Chronic Disease; Diagnosis, Differential; Female; Glucose; Homeostasis; Humans; Hypoglycemia

A 43-year-old man presented with attacks of altered behaviour over a short period of time; they were associated with episodes of hypoglycaemia. The clinical suspicion of insulinoma prompted investigations that quickly established serum insulin and C-peptide levels to be elevated at the times when blood glucose values were low. A physical lesion was found in the head of the pancreas by means of computerised tomography and endo-duodenal ultrasound scan; an octreotide scan was negative. The patient underwent laparotomy and enucleation of a benign tumour, measuring 2.6 cm in diameter, lying within the head of the pancreas; histological examination confirmed it to be an insulinoma. Postoperatively, the patient's personality gradually became more normal and his fasting blood glucose concentrations returned to within normal limits. The diagnosis and management of insulinoma are discussed in the context of this clinical case; there is also reference to the protean clinical manifestations that may occur in this condition- and its differential diagnosis.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Dizziness; Endosonography; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Mental Disorders; Pancreatic Neoplasms; Personality; Tomography, X-Ray Computed

To investigate the frequency of macrosomia in an homogeneous cohort of type 1 diabetic mothers and to analyze the influence of maternal factors and glycemic control on the incidence of fetal macrosomia.. Fifty-five consecutive type 1 diabetic first-pregnancies were prospectively studied. Macrosomia was defined by a ponderal index above the 90(th) percentile. Venous cord blood levels of insulin, C peptide and leptin were measured at delivery. The influence of HbA1c levels and other maternal variables on the occurrence of macrosomia and on the ponderal index was assessed using a stepwise regression logistic model.. The mean (+/- SD) birth weight was 3482 (+/- 497) g at 37.4 +/- 1.0 weeks gestation. Macrosomia occurred in 29 cases (53.7%). Fetal insulin, C peptide and leptin levels were significantly higher in macrosomic than in non macrosomic infants. Maternal age, duration of diabetes, pregravid body mass index, parity, weight gain during pregnancy, presence of a microangiopathy, nephropathy, smoking habits, gestational hypertension or preeclampsia, and HbA1c levels throughout pregnancy did not differed between mothers of macrosomic and non macrosomic infants. In the stepwise analysis none of these covariates was explanatory of the ponderal index.. The frequency of macrosomia remains very high in infants of type 1 diabetic mothers despite a reasonable degree of glycemic control. The variability of the fetal growth response to mild hyperglycemia prompts for the identification of other factors involved in the modulation of fetal growth.

Topics: Adult; Birth Weight; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Embryonic and Fetal Development; Female; Fetal Macrosomia; Gestational Age; Glycated Hemoglobin; Humans; Hypoglycemia; Infant, Newborn; Insulin; Leptin; Maternal Age; Placenta; Pregnancy; Pregnancy in Diabetics; Prospective Studies; Reference Values

We report the case of a 69-year-old woman with insulin autoimmune syndrome first misdiagnosed as insulinoma. The case demonstrates the difficulties to correctly diagnose this rare disorder as both insulin and proinsulin levels were increased by crossreactive autoantibodies. No known triggering agent could be identified. We suggest that this diagnosis should be considered more often also in caucasian patients to avoid useless operations for such patients.

Topics: Aged; Antibody Specificity; Autoantibodies; Autoimmune Diseases; C-Peptide; Diagnosis, Differential; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin

Topics: Adult; Blood Glucose; C-Peptide; False Negative Reactions; Female; Fingers; Forearm; Humans; Hypoglycemia; Insulin; Raynaud Disease

Characterization of metabolically inadequate insulin secretion is essential for insulinoma diagnostics. Hyperinsulinaemic, eu- and hypoglycaemic clamp procedures have been used to suppress endogenous insulin secretion in healthy subjects. The use of exogenous insulin precluded the use of insulin as a parameter to be measured. We now suggest to use exogenous insulin lispro and an insulin-specific ELISA not cross reacting with insulin lispro. Thus, determination of insulin by ELISA in this experimental setting reflects endogenous insulin. A 39-year-old man with a surgically confirmed pancreatic insulinoma was studied under hyperinsulinaemic [lispro insulin 40 mU x m(-2) body surface x min(-1)] clamp conditions. Euglycaemia was achieved (3.8 +/- 0.5 mmol/L) for 1 h and hypoglycaemia (2.36 +/- 0.49 mmol/L) was achieved for another 30 min. Insulin was evaluated by ELISA (cross-reaction with lispro insulin < 0.006%, C-peptide < 0.01%, proinsulin < 0.001%) and by a nonselective RIA (cross-reaction with proinsulin 40%). In control subjects the euglycaemic hyperinsulinaemia suppressed C-peptide to 0.36 +/- 0.03 ng/ml and hypoglycaemic hyperinsulinaemia to 0.29 +/- 0.03 ng/ml. Endogenous insulin was suppressed to 2.8 +/- 0.03 mU/L under euglycaemia and to 2.6 +/- 0.03 mU/L under hypoglycaemia in control subjects. In the insulinoma patient apparently irregular but small changes in both C-peptide (1.43 +/- 0.1 ng/ml) and more pronounced changes in endogenous insulin concentrations 4.41 +/- 0.1 mU/l under euglycaemia and 5.35 +/- 0.3 mU/l under hypoglycaemic conditions, were observed. The basal level of insulin (ELISA insulin 4.6 mU/L) and C-peptide (1.7 ng/ml) were not markedly elevated. Determination of insulin allowed better characterization of irregular pulses because of the shorter half-life of insulin relative to C-peptide. The new modification of sequential eu- and hypoglycaemic clamp procedures should also be useful in pharmacological studies of insulinotropic substances. Direct measurement of peripheral insulin may be more sensitive than C-peptide to detect low levels of autonomous insulin secretion in small insulinomas.

Topics: Adult; C-Peptide; Enzyme-Linked Immunosorbent Assay; Fasting; Glucose; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Lispro; Insulin Secretion; Insulinoma; Male; Pancreatic Neoplasms; Proinsulin

The aim of this study was to examine hormonal counterregulation during insulin-induced hypoglycemia in type-1 diabetic patients during long-term near normoglycemic insulin therapy and intensive clinical care.. Type-1 diabetic patients (age 35.3 +/- 2 years, body mass index 22.8 +/- 1 kg x m(-2), mean diabetes duration 13.6 (11-17 years), mean HbA1c during the last year 6.6 +/- 0.1%) and nondiabetic subjects were studied during (0-120 min) and after (120-240 min) hypoglycemic (3.05 mmol/l) hyperinsulinemic (approximately 330 pmol/l) clamp tests.. During hypoglycemia peak plasma concentrations of glucagon (199 +/- 16 vs. 155 +/- 11 ng/l, p < 0.05), epinephrine (4,514 +/- 644 vs. 1,676 +/- 513 pmol/l, p < 0.001), norepinephrine (2.21 +/- 0.14 vs. 1.35 +/- 0.19 nmol/l, p < 0.01) and cortisol (532 +/- 44 vs. 334 +/- 61 nmol/l) were reduced in the diabetic patients. Plasma lactate did not change from baseline values (0.51 +/- 0.06 mmol/l) in diabetic but doubled in healthy subjects (1.13 +/- 0.111 mmol/l, p < 0.001 vs. control). During the posthypoglycemic recovery period plasma concentrations of free fatty acids were higher in diabetic patients at 240 min (1.34 +/- 0.12 vs. 2.01 +/- 0.23 mmol/l, p < 0.05).. Despite long-term near physiologic insulin substitution and the low incidence of hypoglycemia, hormonal hypoglycemia counterregulation was impaired in type-1 diabetic patients after a diabetes duration of more than 10 years.

Topics: 3-Hydroxybutyric Acid; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Glucose; Hormones; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Lactic Acid; Male; Middle Aged; Reference Values

Topics: Biopsy; Blood Glucose; C-Peptide; Female; Humans; Hypoglycemia; Insulinoma; Magnetic Resonance Imaging; Middle Aged; Pancreatic Neoplasms; Tomography, X-Ray Computed

Subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4alpha gene (RW pedigree/maturity-onset diabetes of the young [MODY]-1) have diminished insulin and glucagon secretory responses to arginine. To determine if pancreatic polypeptide (PP) secretion is likewise involved, we studied PP responses to insulin-induced hypoglycemia in 17 RW pedigree members: 6 nondiabetic mutation-negative [ND(-)], 4 nondiabetic mutation-positive [ND(+)], and 7 diabetic mutation-positive [D(+)]. Subjects received 0.08 U/kg body wt human regular insulin as an intravenous bolus to produce moderate self-limited hypoglycemia. PP areas under the curve (PP-AUCs) were compared among groups. With hypoglycemia, the PP-AUC was lower in the D(+) group (14,907 +/- 6,444 pg/ml, P = 0.03) and the ND(+) group (14,622 +/- 6,015 pg/ml, P = 0.04) compared with the ND(-) group (21,120 +/- 4,158 pg/ml). In addition, to determine if the beta-cell secretory defect in response to arginine involves amylin in addition to insulin secretion, we analyzed samples from 17 previously studied RW pedigree subjects. We compared the AUCs during arginine infusions for the 3 groups both at euglycemia and hyperglycemia as well as their C-peptide-to-amylin ratios. The D(+) and ND(+) groups had decreased amylin AUCs during both arginine infusions compared with the ND(-) group, but had similar C-peptide-to-amylin ratios. These results suggest that the HNF-4alpha mutation in the RW/MODY1 pedigree confers a generalized defect in islet cell function involving PP cells in addition to beta- and alpha-cells, and beta-cell impairment involving proportional deficits in insulin and amylin secretion.

Topics: Adult; Amyloid; Arginine; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Female; Glucagon; Hepatocyte Nuclear Factor 4; Humans; Hypoglycemia; Insulin; Islet Amyloid Polypeptide; Male; Mutation; Pancreatic Polypeptide; Phosphoproteins; Transcription Factors

Topics: Adult; Blood Glucose; C-Peptide; Calcium Gluconate; Chronic Disease; Female; Glucose Clamp Technique; Humans; Hypoglycemia; Infusions, Intravenous; Insulin; Insulinoma; Pancreatic Neoplasms; Portal Vein

Although both insulin and hypoglycemia are known to inhibit endogenous insulin secretion, their potency to suppress insulin secretion has not been directly compared thus far. The serum C-peptide concentration was measured during 28 euglycemic and 28 stepwise hypoglycemic (4.1,3.6, 3.1, and 2.6 mmol/L) clamp experiments using either a low-rate (1.5 mU x min(-1) x kg(-1)) or high-rate (15.0 mU x mU(-1) x kg(-1)) insulin infusion. The experiments lasted 6 hours and were performed in 28 lean healthy men. During both the euglycemic and hypoglycemic clamps, serum insulin was approximately 40-fold higher during the high-rates versus low-rate insulin infusion (euglycemia, 24,029 +/- 1,595 v 543 +/- 34 pmol/L; hypoglycemia, 23,624 +/- 1,587 v 622 +/- 32 pmol/L). Under euglycemic conditions, serum C-peptide decreased from 0.54 +/- 0.04 to 0.41 +/- 0.05 nmol/L during the low-rate insulin infusion (P < .05) and from 0.55 +/- 0.07 to 0.27 +/- 0.09 nmol/L during the high-rate insulin infusion (P < .001). Under hypoglycemic conditions, serum C-peptide decreased from 0.50 +/- 0.03 to 0.02 +/- 0.01 nmol/L during the low-rate insulin infusion (P< .001) and from 0.46 +/- 0.07 to 0.02 +/- 0.01 nmol/L during the high-rate insulin infusion (P< .001). In the euglycemic clamp condition, the high-rate insulin infusion reduced the C-peptide concentration more than the low-rate insulin infusion (P < .05). Independent of the rate of insulin infusion, the decrease in C-peptide was distinctly more pronounced during hypoglycemia versus euglycemia (P < .001). These data indicate that insulin inhibits insulin/C-peptide secretion in a dose-dependent manner. Hypoglycemia is a much stronger inhibitor of insulin secretion than insulin itself.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Hypoglycemia; Insulin; Insulin Secretion; Male

In response to hypoglycemia, healthy individuals rapidly antagonize insulin action on glucose and lipid metabolism, but the effects on protein metabolism are unclear. Because amino acids are an important substrate for gluconeogenesis and a fuel alternative to glucose for oxidation, we evaluated whether hypoglycemia antagonizes the hypoaminoacidemic and the antiproteolytic effects of insulin and changes the de novo synthesis of glutamine, a gluconeogenic amino acid. To this purpose, in 7 healthy subjects, we performed 2 studies, 3.5 h each, at similar insulin but different glucose concentrations (i.e., 4.9 +/- 0.1 mmol/l [euglycemic clamp] or 2.9 +/- 0.2 mmol/l [hypoglycemic clamp]). As expected, hypoglycemia antagonized the insulin suppression of glucose production achieved in euglycemia (from 21 +/- 15 to 116 +/- 12% of basal, P < 0.001), the stimulation of glucose uptake (from 207 +/- 28 to 103 +/- 7% of basal, P < 0.01) and the suppression of circulating free fatty acids (from 30 +/- 5 to 80 +/- 17% of basal, P < 0.001). In contrast, hypoglycemia increased the insulin suppression of circulating leucine (from 63 +/- 1 to 46 +/- 2% of basal, P < 0.001) and phenylalanine (from 79 +/- 3 to 64 +/- 3% of basal, P < 0.001) concentrations. Hypoglycemia did not change the insulin suppression of proteolysis (from 79 +/- 2 to 82 +/- 4% of basal, P < 0.001). However, hypoglycemia doubled the insulin suppression of the glutamine concentrations (from 84 +/- 3 to 63 +/- 3% of basal, P < 0.01) in the absence of significant changes in the glutamine rate of appearance, but it also caused an imbalance between glutamine uptake and release. This study demonstrates that successful counterregulation does not affect proteolysis. Moreover, it does not increase the availability of circulating amino acids by de novo synthesis. In contrast, despite the lower concentration of circulating amino acids, hypoglycemia increases the uptake of glutamine that can be used for gluconeogenesis and as a fuel alternative to glucose.

Topics: Adult; Blood Glucose; C-Peptide; Carbon Isotopes; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glutamine; Humans; Hypoglycemia; Insulin; Insulin Secretion; Kinetics; Leucine; Male; Nitrogen Isotopes; Proteins; Reference Values; Sodium Bicarbonate

Augmented glucose utilisation or secretion of insulin-like-growth-factor II (IGF-II) are discussed as important pathogenetic factors in tumor-associated hypoglycemia (Doege-Potter Syndrome) with suppressed insulin and C-peptide levels. Primary malignant fibrous histiocytoma of the lung is an uncommon neoplasia and its association with hypoglycemia is rare and the causal relationship remains unclear. - We report a 57-year-old male with spontaneous hypoglycemia (1.67 mmol/l) due to a primary malignant fibrous histiocytoma of the lung, secreting IGF-II. Insulin (0.10 nmol/l; normal range 0.33-1.2) and C-peptide (3.0 mIU/l; 5-25) levels were suppressed in combination with low levels of growth hormone (<0.5 ng/ml; <7 ng/ml) and IGF-I (<66.0 ng/ml; 70-246). The elevated IGF-II level (787 ng/ml; 300-500) and decreased IGF-binding protein 3 (1.6 mg/l; 2-5) indicated a high free IGF-II activity. After surgery (resection of the right upper lobe), glucose (4.4 mmol/l), insulin (9.0 mIU/L) and C-peptide (0.84 nmol/l) levels returned to normal. Serum IGF-I (289 ng/ml) and the IGF-I/IGF-II ratio (<0.08 preoperative vs. 0.41 postoperative; >0.20) increased to the normal reference range. - In conclusion, malignant fibrous histiocytoma (MFH) is rarely described presenting as tumor-induced hypoglycemia. Doege-Potter Syndrome in MFH seems to be related to tumor-associated IGF-II production.

Topics: Adult; C-Peptide; Histiocytoma, Benign Fibrous; Human Growth Hormone; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Lung Neoplasms; Male; Tomography, X-Ray Computed

The magnitude of the counterregulatory response to insulin-induced hypoglycemia is primarily determined by the degree of hypoglycemia. We examined whether the route of acute insulin delivery (portal or peripheral venous) is also important in determining the magnitude of the counterregulatory response to hypoglycemia in nine healthy nondiabetic men. Pancreatic insulin secretion, stimulated by an i.v. tolbutamide infusion (portal insulin study), was matched with an exogenous insulin infusion into the peripheral vein 4-6 weeks later (peripheral insulin study). Each study consisted of a 150-min baseline tracer equilibration period, a 180-min euglycemic hyperinsulinemic (portal or peripheral insulin delivery) period, a 60-min hypoglycemic period in which insulin secretion diminished during tolbutamide or was reduced during exogenous insulin, and a 30-min recovery period. Peripheral venous glucose concentrations were well matched in the portal and peripheral studies during euglycemia and hypoglycemia (glucose nadir, 2.9 +/- 0.1 mmol/L in the portal and 2.7 +/- 0.1 mmol/L in the peripheral; mean +/- SEM; P = NS), and insulin concentrations were about 1.5-fold higher throughout the experiment in the peripheral vs. the portal insulin study due to the first pass extraction of insulin in the portal study. There was a much greater increment (P < 0.0001) in FFA in the portal vs. the peripheral study (area under the curve: portal, 19.5 +/- 3.9 mmol/L x 90 min; peripheral, 3.3 +/- 1.1 mmol/L x 90 min), whereas plasma glucagon and GH were higher in the peripheral study (P = 0.01 for glucagon; P = 0.015 for GH). There was no significant difference between studies in epinephrine and norepinephrine responses to hypoglycemia or stimulation of endogenous glucose production (area under the curve: portal, 636 +/- 103 micromol/kg x 90 min; peripheral, 705 +/- 69 micromol/kg x 90 min; P = NS). In summary, we have shown that the glucagon, GH, and FFA responses to hypoglycemia during insulin dissipation are affected by the route of insulin delivery and are not controlled exclusively by the nadir blood glucose level. The clinical importance of these observations in diabetic subjects as they relate to route of insulin delivery (portal or peripheral) during insulin dissipation remains to be determined.

Topics: Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Glucose; Hormones; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Injections, Intravenous; Insulin; Lactic Acid; Male; Portal Vein; Reference Values; Tolbutamide; Veins

Topics: Adolescent; Age Factors; Blood Glucose; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemia; Infant; Islets of Langerhans; Randomized Controlled Trials as Topic; Risk

In adults, endogenous hyperinsulinemic hypoglycemia is almost invariably due to insulinoma. In these patients with insulinoma, neuroglycopenic episodes exclusively after meal ingestion and negative 72-h fasts are extraordinarily rare. We describe five adults with neuroglycopenic episodes from hyperinsulinemic hypoglycemia within 4 h of meal ingestion and negative 72-h fasts. Each had negative transabdominal ultrasonography, spiral computed tomographic scanning, and celiac axis angiography of the pancreas. However, all showed positive selective arterial calcium stimulation tests indicative of pancreatic beta-cell hyperfunction. At pancreatic exploration, no insulinoma was detected by intraoperative ultrasonography and complete mobilization and palpation of the pancreas. Moreover, the resected pancreata showed islet hypertrophy and nesidioblastosis, but no insulinoma. No definite disease-causing mutation was detected in Kir6.2 and SUR1 genes, which encode the subunits of the pancreatic ATP-sensitive potassium channel responsible for glucose-induced insulin secretion. Four patients who underwent gradient-guided partial pancreatectomy have been free of hypoglycemic symptoms for up to 3 yr follow-up; the other, who underwent a limited distal pancreatectomy, has had brief recurrence of symptoms. The unique clinical features and responses to dynamic testing in these adults with hyperinsulinemic hypoglycemia in the absence of insulinoma may constitute a new syndrome of postprandial hypoglycemia from diffuse beta-cell hyperfunction.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Calcium; Female; Glycosyltransferases; Humans; Hyperinsulinism; Hypoglycemia; Islets of Langerhans; Male; Membrane Proteins; Mutation; Pancreas; Pancreatectomy; Postprandial Period; Potassium Channels; Potassium Channels, Inwardly Rectifying; Regional Blood Flow; Repressor Proteins; Saccharomyces cerevisiae Proteins; Syndrome; Tomography, X-Ray Computed; Ultrasonography

Topics: Adult; Antidepressive Agents, Second-Generation; Blood Glucose; C-Peptide; Depressive Disorder; Diabetes Mellitus, Type 1; Female; Glucagon; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Maprotiline

Superior mesenteric artery blood flow (SMABF) increases significantly during and after the hypoglycaemia reaction in healthy humans. To investigate the mechanisms controlling this phenomenon, SMABF and plasma catecholamines were measured in healthy human volunteers. In 10 controls, hypoglycaemia was induced by insulin infusion (2.5 m-units.min-1.kg-1). In six subjects, beta-blockade by propranolol infusion (0.7 microgram.min-1.kg-1) preceded insulin infusion and was continued throughout the study. Following the hypoglycaemia reaction, the glucose nadir was similar in both groups. In controls, increases in SMABF [42.4+/-6.1% (mean+/-S.E.M.); P<0. 001], cardiac output (34.3+/-2.3%; P<0.001) and pulse rate (from 63. 9+/-2.7 to 82.5+/-3.1 beats/min; P<0.001) occurred. Superior mesenteric artery resistance fell by 32.4+/-3.3% (P<0.001). Under beta-blockade, decreases in SMABF (34.8+/-2.9%; P<0.001) and pulse rate (from 59.5+/-0.2 to 51.8+/-2.2 beats/min; P<0.001) occurred. Superior mesenteric artery resistance increased (peak +30.8+/-12.3%; not significant). Subjects showed greater increases in adrenaline (P<0.006) and noradrenaline (P<0.022) concentrations than controls. Mesenteric hyperaemia associated with hypoglycaemia in man appears to be mediated by a beta-adrenergic mechanism that is activated by increased circulating levels of adrenaline.

Topics: Acute Disease; Adult; Blood Glucose; C-Peptide; Epinephrine; Hemodynamics; Humans; Hypoglycemia; Insulin; Mesenteric Artery, Superior; Norepinephrine; Splanchnic Circulation

Topics: 3-Hydroxybutyric Acid; Adrenal Gland Diseases; Adrenocorticotropic Hormone; C-Peptide; Coma; Female; Humans; Hypoglycemia; Insulin; Ketones; Thyroid Hormones

We tested the hypotheses that 1) hypoglycemia per se stimulates the sympathetic neural as well as the adrenomedullary component of the sympathochromaffin system, and 2) sympathetic neural responses to hypoglycemia, like adrenomedullary responses, are reduced after recent hypoglycemia. To this end, we studied 10 healthy young adults on 2 consecutive days on two separate occasions, on one occasion with euglycemia (5.0 mmol/l) and on the other occasion with hypoglycemia (2.8 mmol/l) from 1000 to 1200 and 1400 to 1600 on day 1 of each occasion. On day 2 of each occasion, plasma epinephrine and norepinephrine (NE) concentrations and rates of systemic NE spillover (SNESO) and forearm NE spillover (FNESO) were measured during hyperinsulinemic (12.0 pmol x kg(-1) x min(-1)) euglycemia (5.0 mmol/l) and hypoglycemia (2.8 mmol/l). Compared with values during euglycemia, plasma epinephrine and NE and rates of SNESO and FNESO all increased during hypoglycemia (P < 0.01). After day 1 hypoglycemia, there were reductions during hypoglycemia on day 2 in plasma epinephrine (2,050 +/- 500 vs. 2,960 +/- 400 pmol/l; P < 0.02), plasma NE (1.35 +/- 0.16 vs. 1.92 +/- 0.20 nmol/l; P < 0.01), and SNESO rates (5.13 +/- 0.84 vs. 6.87 +/- 0.81 nmol/min; P < 0.02). However, FNESO rates were unaltered (1.16 +/- 0.25 vs. 1.27 +/- 0.17 pmol x min(-1) x 100 ml tissue(-1). Thus we conclude that 1) hypoglycemia per se stimulates both the sympathetic neural and adrenomedullary components of the sympathochromaffin system and 2) adrenomedullary, but not forearm sympathetic neural, responses to hypoglycemia are reduced after recent hypoglycemia. The extent to which the lower plasma NE levels and reduced SNESO responses to hypoglycemia after day 1 hypoglycemia reflect reduced NE release from the adrenal medullae, sympathetic nerves other than those in the forearm, or both cannot be determined from these data.

Topics: Adrenal Medulla; Adult; C-Peptide; Case-Control Studies; Female; Forearm; Glucose Clamp Technique; Humans; Hypoglycemia; Insulin; Male; Sympathetic Nervous System

Haemangiopericytoma is a rare soft tissue tumour originating from the contractile pericapillary cells. Relatively little is known about its molecular pathogenesis. To address this issue, the insulin-like growth factor family (IGFs) was analysed in 19 tumours collected from a human tumour bank network. Seven of the tumours were associated with severe hypoglycaemia. Of these, six were retroperitoneal and one was located in the leg. 3 out of the 19 tumours (15.8 per cent) were positive for insulin-like growth factor I (IGF I) mRNA and 11 were positive for IGF II mRNA (57.9 per cent). Almost 90 per cent of haemangiopericytomas expressed IGF I receptor (IGF IR) mRNA (17 out of 19), five (26.3 per cent) expressed IGF binding protein 1 (IGF BP1), three (15.8 per cent) expressed IGF BP2, and four (21 per cent) exhibited IGF BP3 mRNA. All of the 14 haemangiopericytomas examined with regard to specific receptor binding were IGF IR positive, ranging from 1.2 to 16.2 per cent. Binding was much higher in IGF I/IGF IR positive tumours (15.3+/-0. 7) than in IGF I negative/IGF IR positive tumours (5.1+/-3.3). The potential role of IGF IR as a growth promoting factor in malignant haemangiopericytoma was studied using antisense oligonucleotides and monoclonal antibody alphaIR3 that specifically inhibit IGF IR synthesis or activity. 10 microM IGF IR antisense oligonucleotides significantly inhibited the growth of haemangiopericytoma cells in culture, by around 50 per cent; monoclonal antibody against IGF IR (alphaIR3) also significantly inhibited proliferation. The data suggest that IGF IR may play an important role in the genesis and progression of malignant haemangiopericytomas.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Cell Division; Child, Preschool; Female; Hemangiopericytoma; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Lung Neoplasms; Male; Middle Aged; Pelvic Neoplasms; Receptor, IGF Type 1; Retroperitoneal Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatomedins; Tumor Cells, Cultured

Topics: Adult; C-Peptide; Carcinoma, Small Cell; Fatal Outcome; Female; Glucose; Humans; Hypoglycemia; Insulin; Insulin Secretion; Proinsulin; Uterine Cervical Neoplasms

Intensifying pharmacological therapy in patients with type 2 diabetes increases the risk of hypoglycemia and often requires the simultaneous use of more than one agent. Combining insulin and sulfonylurea is an effective and frequently used therapy in such patients. However, sulfonylurea derivatives have been shown to affect the release of glucagon, indicating a possible effect of such therapy on hormonal counterregulation to hypoglycemia. Thirteen patients receiving combined therapy were studied on two occasions: 1) after a wash-out period of glibenclamide (-GLIB), and 2) after resuming combined treatment for 6 months (+GLIB). We performed nonstep-wise, hyperinsulinemic hypoglycemic clamps using a constant i.v. insulin infusion and clamping blood glucose at 2.7 mmol/L (48 mg/dL) for 60 min. C Peptide levels were significantly higher during + GLIB, but no significant differences were seen in peripheral plasma insulin levels (+GLIB mean +/- SD, 70 +/- 17 mU/L vs. -GLIB, 75 +/- 14; P = 0.26). Epinephrine responses were similar in the two tests, but when glibenclamide was present the glucagon response was smaller, both the peak value (P = 0.016) and the incremental area under the curve (P = 0.011) as well as the total area under the curve (P = 0.016). These results suggest that intraislet insulin secretion is of importance for the alpha-cell responsiveness to hypoglycemia in these patients.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Kinetics; Male; Middle Aged

We report the case of a Caucasian patient with insulin autoimmune syndrome (IAS), defined as the association of hypoglycaemic attacks with insulin autoantibodies in individuals not previously treated with exogenous insulin. This rare syndrome (more than 200 published cases) has been reported mainly in Japan. Most affected patients present with other autoimmune disorders, most often Graves' disease. In most cases, insulin autoantibodies appear a few weeks after the beginning of treatment with a drug containing a sulphyldryl group. A significant increase in insulin and C-peptide plasma concentrations and the presence of other antiorgan antibodies are observed. The susceptibility haplotype is present in the Japanese population, which may account for the high frequency of IAS. Spontaneous remission is observed in 80% of cases, with cessation of hypoglycaemic attacks and disappearance of insulin autoantibodies some months after withdrawal of the drug. This rare cause of hypoglycaemia in Caucasian subjects should be considered in aetiologic investigation of spontaneous hypoglycaemia.

Topics: Antithyroid Agents; Autoantibodies; Autoimmune Diseases; C-Peptide; Carbimazole; Humans; Hyperthyroidism; Hypoglycemia; Insulin; Japan; Male; Middle Aged; Morocco; Paris; Propylthiouracil; Syndrome; White People

A case of a previously healthy 48-year-old man murdered by exogenous insulin administration is reported. The patient was delivered unconscious to the emergency unit. Initially, treatment with hyperbaric oxygen was commenced because decompression sickness was suspected. However, the treatment was aborted as the patient was found to be hypoglycaemic (nadir serum glucose 0.3 mmol/l) and treatment and diagnostics of hypoglycaemia commenced. Brain damage due to hypoglycaemia was severe, and the patient remained in a vegetative state for 2 months before he died of multiorgan failure. Serum samples drawn at admittance were stored frozen, whereby it was possible to show retrospectively, that while the concentration of insulin in serum was high (75 mU/l, increasing further to over 240 mU/l in the next few hours) concentration of C-peptide was low (below detection limit of 0.1 nmol/l) at the hypoglycaemic stage. It was concluded that the patient had received exogenous insulin somehow, and the police was informed. Circumstantial evidence obtained during ensuing criminal investigation was considered by the court to prove the patient's wife (a nurse) guilty of murder. The availability of stored frozen serum samples drawn at the early stage of hospitalization helped to uncover the crime involved in our case.

Topics: Blood Glucose; C-Peptide; Forensic Medicine; Homicide; Humans; Hypoglycemia; Insulin; Male; Middle Aged

Topics: Adult; Angiography; Blood Glucose; C-Peptide; Cognition Disorders; Diagnosis, Differential; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Syncope; Tomography, X-Ray Computed

Pancreatic transplantation is an established treatment for patients with insulin-dependent diabetes mellitus. Side-effects are mainly related to surgical complications, immunosuppressive therapy and graft rejection. We report on two patients having recurrent hypoglycaemic events following pancreatic transplantation. The cause of hypoglycaemia in our patients remained obscure. Hypoglycaemia following pancreatic transplantation has been described. Hypoglycaemic events may appear years after transplantation. In the article we review three possible mechanisms of hypoglycaemia: hyperinsulinaemia, secondary to systemic drainage (due to loss of first pass hepatic insulin clearance), presence of anti-insulin antibodies and persistence of counter-regulatory abnormalities. Physicians and patients should be aware of possible hypoglycaemia events following transplantation.

Topics: Adult; Blood Glucose; C-Peptide; Glucagon; Growth Hormone; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Pancreas Transplantation; Transplantation, Homologous

We describe a sensitive two-site sandwich enzyme-linked immunosorbent assay for the measurement of intact human proinsulin in 100 microL of serum or plasma. The assay is based on the use of two monoclonal antibodies specific for epitopes at the C-peptide/insulin A chain junction and at the insulin B chain/C-peptide junction, respectively. Cross-reactivities with insulin, C-peptide, and the four proinsulin conversion intermediates were negligible. The detection limit in buffer was 0.2 pmol/L (3 standard deviations from zero). The working range was 0.2-100 pmol/L. The mean intra- and interassay coefficients of variation were 2.4% and 8.9%, respectively. The mean recovery of added proinsulin was 103%. Dilution curves of 40 serum samples are parallel to the proinsulin calibration curve. Proinsulin concentrations in 20 fasting healthy subjects were all above the limit of detection: median (range), 2.7 pmol/L (1.1-6.9 pmol/L). Six fasting non-insulin-dependent diabetes mellitus and five insulinoma patients had proinsulin concentrations significantly higher than healthy subjects: median (range), 7.7 pmol/L (3.2-18 pmol/L) and 153 pmol/L (98-320 pmol/L), respectively.

Topics: Adult; Aged; Antibodies, Monoclonal; C-Peptide; Cross Reactions; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypoglycemia; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin; Reproducibility of Results; Sensitivity and Specificity

Arginine-vasopressin (AVP) and oxytocin (OT) secretions are abnormally stimulated by hypoglycaemia in patients with IDDM. Since previous studies showed that AVP secretion is influenced by the persistence of residual endogenous insulin secretion, we wondered whether this factor also regulates OT secretion.. Case-control study: the OT response to insulin-induced hypoglycaemia was measured in normal and diabetic patients with or without residual endogenous insulin secretion.. Ten normal male subjects, 10 C-peptide positive (CpP) and 11 C-peptide negative (CpN) male diabetic patients.. plasma C-peptide levels were measured after intravenous administration of 1 mg glucagon. Insulin tolerance test (ITT): diabetics were studied after optimization of their metabolic status by 3 days of treatment with constant subcutaneous insulin infusion. CpP and CpN diabetics and normal controls were tested with an intravenous administration of 0.15 IU per kg body weight insulin. Blood samples for OT assay were taken just before the rapid injection of insulin (time 0) and at time 15, 30, 45 and 60 min.. The basal concentrations of OT were similar in all groups. Insulin induced a similar hypoglycaemic nadir in all groups at 30 min, even though diabetic groups showed a delayed recovery in blood glucose levels. The glycaemic pattern was similar in all diabetic patients. Hypoglycaemia-induced OT rise was significantly higher in the two diabetic groups than in the normal group. However, CpN patients showed significantly higher OT increments than CpP subjects.. These data indicate that a residual endogenous insulin secretion exerts a partial protective action against the hypothalamic-pituitary disorder affecting the OT secretory system in IDDM.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 1; Glucagon; Humans; Hypoglycemia; Injections, Intravenous; Insulin; Insulin Secretion; Male; Oxytocin

We have investigated the potential for the human brain to use lipid fuels during acute hypoglycemia. Nine healthy male subjects underwent hyperinsulinemic (1.5 mU/kg x min) stepped hypoglycemic clamps on two occasions, infusing Intralipid (20%) and heparin (0.1 U/kg x min) on one occasion only (ILH), with an identical study without infusion of ILH acting as a control. Five subjects also underwent euglycemic clamping with Intralipid/heparin infusion. During hypoglycemia, ILH raised circulating levels of nonesterified fatty acids, glycerol, and beta-hydroxybutyrate, although the latter did not rise until after the onset of counterregulation. With ILH, epinephrine responses [area under the curve (AUC), 127.9 +/- 31.7 vs. 175.1 +/- 27.4 nmol/L x 180 min; P = 0.03] and GH responses (AUC, 260 +/- 91 vs. 1009 +/- 150, P < 0.01) were reduced and delayed (glucose thresholds, 2.8 +/- 0.04 vs. 3.0 +/- 0.1 mmol/L; P = 0.04), with a trend toward reduced cortisol responses. Similarly, hypoglycemic symptom scores were diminished during ILH (AUC, 647 +/- 162 vs. 1222 +/- 874; P = 0.03). However, there was no significant effect on the deterioration in four-choice reaction time, one measure of cognitive deterioration [glucose thresholds, 2.6 +/- 0.1 vs. 2.7 +/- 0.1 mmol/L, ILH vs. control (P = 0.75); AUC, 1420 +/- 710 vs. 2250 +/- 1080 ms/min (P = 0.59)]. During euglycemic clamping with Intralipid/heparin infusion studies, there was no rise in hormones, four-choice reaction time, or symptoms other than hunger and tiredness. Both nonesterified fatty acids and glycerol can penetrate the mammalian brain and be metabolized. Raised levels were able to reduce neurohumoral responses to hypoglycemia, but could not protect cognitive function. This suggests that regional differences exist in human brain metabolism between glucose-sensing and cognitive areas of brain, which may be important in the understanding of the mechanisms of glucose sensing and in the genesis of hypoglycemia unawareness in insulin-dependent diabetes.

Topics: 3-Hydroxybutyric Acid; Adult; Blood Glucose; Blood-Brain Barrier; Brain; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Glucose Clamp Technique; Glycerol; Homeostasis; Human Growth Hormone; Humans; Hydroxybutyrates; Hypoglycemia; Insulin; Kinetics; Lipids; Male; Triglycerides

The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects, it is impossible to induce hypoglycaemia in normal subjects in the basal state by exogenous GLP-1, regardless of dose. To further assess the role of the incretin hormones in reactive hypoglycaemia, we reproduced the glucose and hormone profiles of the patients with reactive hypoglycaemia in 8 healthy volunteers in 4 separate protocols: 1) i.v. infusion of glucose (25 g) alone, 2) glucose together with i.v. GLP-1 infusion, and 3) and 4) glucose together with i.v. infusion of the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), at two different infusion rates. The plasma glucose, GLP-1 and GIP concentrations (low dose) obtained were comparable with those of the patients. With GLP-1, infusion of a total of 33.4 +/- 1.3 g glucose was required to obtain plasma glucose concentrations similar to those obtained by glucose infusion alone; with low GIP, 28.0 +/- 1.2 g and with high GIP 38.4 +/- 3.5 g. Insulin concentrations increased 10-fold with GLP-1 compared with i.v. glucose alone, but less with high and low GIP. In contrast, C-peptide concentrations were similar after GLP-1 and high GIP. After termination of i.v. glucose the lowest glucose concentrations were 4.5 (3.7-4.9) (median, range) for glucose alone; 2.4 (1.9-2.8) mmol/l with GLP-1; 3.7 (2.6-4.0) with low GIP and 3.3 (2.1-4.2) with high GIP. Thus, the exaggerated GLP-1 response to nutrients in patients with accelerated gastric emptying could be responsible for their high incidence of postprandial reactive hypoglycaemia.

Topics: Adult; Blood Glucose; C-Peptide; Dumping Syndrome; Female; Gastrectomy; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Kinetics; Male; Peptide Fragments; Protein Precursors

Plasma norepinephrine (NE) concentrations are a fallible index of sympathetic neural activity because circulating NE can be derived from sympathetic nerves, the adrenal medullas, or both and because of regional differences in sympathetic neural activity. We used isotope dilution measurements of systemic and forearm NE spillover rates (SNESO and FNESO, respectively) to study the sympathochromaffin system during prolonged standing, hyperinsulinemic euglycemia, and hyperinsulinemic hypoglycemia in healthy humans. Prolonged standing led to decrements in blood pressure without increments in heart rate, the pattern of incipient vasodepressor syncope. FNESO was not increased (0.58 +/- 0.20 to 0. 50 +/- 0.21 pmol. min-1. 100 ml tissue-1), suggesting that the approximately twofold increments in plasma NE and SNESO were derived from sympathetic nerves other than those in the forearm (with a possible contribution from the adrenal medullas). Hyperinsulinemia per se (euglycemia maintained) stimulated sympathetic neural activity, as evidenced by increments in FNESO (0.57 +/- 0.11 to 1.25 +/- 0.25 pmol. min-1. 100 ml tissue-1, P < 0.05), but not adrenomedullary activity. Hypoglycemia per se stimulated adrenomedullary activity (plasma epinephrine from 190 +/- 70 to 1720 +/- 320, pmol/l, P < 0.01). Although SNESO (P < 0.05) and perhaps plasma NE (P < 0.06) were raised to a greater extent during hyperinsulinemic hypoglycemia than during hyperinsulinemic euglycemia, FNESO was not. Thus these data do not provide direct support for the concept that hypoglycemia per se also stimulates sympathetic neural activity.

Topics: Adult; Blood Pressure; C-Peptide; Chromaffin System; Female; Forearm; Glucagon; Glucose Clamp Technique; Heart Rate; Hormones; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Infusions, Intravenous; Insulin; Male; Muscle, Skeletal; Norepinephrine; Pancreatic Polypeptide; Posture; Regional Blood Flow; Sympathetic Nervous System

A 36-year-old woman without significant medical history complained of "spells" of diplopia, fatigue, and dizziness. On formal fasting, her glucose dropped to 40 mg/dL, with simultaneous insulin levels of 15 microU/mL (normal <6 microU/mL) and C-peptide of 2.5 ng/ml (normal <2 ng/mL). An isolated plasma sulfonylurea screen done during the fast was positive for tolbutamide, suggesting the diagnosis of factitious hypoglycemia, but further workup revealed multiple pancreatic masses resulting in an eventual diagnosis of multiple insulinomas that was confirmed surgically. We discuss the approach to hypoglycemia caused by insulin excess and distinguishing clinical and biochemical features.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Sick Role

Hypoglycaemia is an important complication of insulin treatment in Type 1 diabetes mellitus (DM). Pancreas transplantation couples glucose sensing and insulin secretion, attaining a distinctive advantage over insulin treatment. We tested whether successful transplantation can avoid hypoglycaemia in Type 1 DM. Combined kidney and pancreas transplanted Type 1 DM who complied with good function criteria (KP-Tx, n = 55), and isolated kidney or liver transplanted non-diabetic subjects on the same immunosuppressive regimen (CON-Tx, n = 14), underwent 1-day metabolic profiles in the first 3 years after transplantation, sampling plasma glucose (PG) and pancreatic hormones every 2 hours. KP-Tx had lower PG than CON-Tx in the night and in the morning and higher insulin concentrations throughout the day. KP-Tx had lower PG nadirs than CON-Tx (4.40+/-0.05 vs 4.96+/-0.16 mmol l(-1), ANOVA p = 0.001). Nine per cent of KP-Tx had hypoglycaemic values (PG < or = 3.0 mmol l(-1)) in the profiles, both postprandial and postabsorptive, whereas none of CON-Tx did (p < 0.02). In conclusion, after pancreas transplantation, mild hypoglycaemia is frequent, although its clinical impact is limited. Compared to insulin treatment in Type 1 DM, pancreas transplantation improves but cannot eliminate hypoglycaemia.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Humans; Hypoglycemia; Insulin; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Male; Pancreas Transplantation; Postoperative Complications; Time Factors

Acarbose, a potent alpha-glucosidase inhibitor, provides a new concept for the treatment of metabolic disorders, and particularly diabetes mellitus. It reduces the postprandial blood glucose increment and insulin response. For this reason the drug has been successfully used not only in the treatment of type 1 and type 2 diabetes, but also in the management of reactive hypoglycemia and dumping syndrome. The primary aim of the present study is to evaluate the long-term effect of acarbose in reducing hypoglycemic symptoms and influencing laboratory measurements in patients with the diagnosis of reactive hypoglycemia.. 21 non-obese (BMI < 27 kg/m2) patients (6 males, 15 females) complaining of postprandial symptoms suggesting hypoglycemia and who showed blood glucose values of < 54 mg/dl on one or more occasions during a 5 h oral glucose tolerance test (OGTT) were selected.. Before treatment, ingestion of glucose decreased plasma glucose levels at the 3rd and 4th hours, the lowest levels being 39 mg/dl and 45 mg/dl respectively. Eighteen patients had hypoglycemic symptoms during OGTT. Following 3 months of acarbose treatment, the lowest plasma glucose levels at the 3rd and 4th hours increased to 67 mg/dI and 75 mg/dI respectively. Plasma insulin and c-peptide levels were reduced between the 1st and 5th hours, but only the 1st and 2nd hour decrements were statistically significant. The area under the curve (AUC) between 0-300 minutes for insulin was not significant. Plasma glucose levels were significantly increased during the last 3 hours. The AUC for glucose was not significantly changed. Frequency of hypoglycemic attacks was reduced from 4 times a week to 1. C-peptide levels in 24-hour urine collection did not change significantly: 45 micrograms/I and 56 micrograms/I respectively before and after treatment.. These results confirm that acarbose may be of value in preventing reactive hypoglycemia by reducing the early hyperglycemic stimulus to insulin secretion, and in the treatment of reactive hypoglycemia.

Topics: Acarbose; Adult; C-Peptide; Enzyme Inhibitors; Female; Glucose Tolerance Test; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Insulin; Male; Middle Aged

We describe a case of non-islet cell tumour hypoglycaemia (NICTH) associated with a renal cell carcinoma. Serum insulin-like growth factors (IGFs) (including IGF-II E peptide), IGF-binding proteins (IGFBPs), insulin and C-peptide were measured before and after surgical removal of the tumour. IGFBPs were visualized by Western ligand blotting. Preoperatively 'big' IGF-II and IGFBP-2 levels were raised. IGF-I, IGFBP-1 and IGFBP-3 were low, while insulin, C-peptide and GH were undetectable. These changes were reversed by 2 days postoperatively. Protease assays showed little IGFBP-3 protease activity preoperatively. Preoperatively, neutral chromatography demonstrated most of the immunoassayable IGFBP-3 in a high molecular weight form with a small amount of IGF-II. Most of the IGF-II and big IGF-II eluted in lower molecular weight forms. Postoperative samples showed a shift in IGF-II which became increasingly associated with IGFBP-3 in both low and high molecular weight complexes. By Northern blotting, expression of all species of IGF-II mRNA in the tumour was 10-fold greater than in normal human liver. The tumour did not express IGFBP-1 or IGFBP-2. IGFBP-3 was expressed in small amounts, while the expression of IGFBP-4 was two-fold higher than in liver. In conclusion, we have confirmed high levels of big IGF-II and IGFBP-2 in NICTH, changes which are reversed postoperatively. The IGF-II is derived from the tumour which overexpresses these genes but IGFBP-2 probably arises from extratumour upregulation.

Topics: Aged; Blotting, Northern; C-Peptide; Carcinoma, Renal Cell; Female; Follow-Up Studies; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Kidney Neoplasms; RNA, Messenger

In this paper we describe for the first time late post-prandial hypoglycaemia as the sole presenting feature of an insulinoma in a patient who had previously undergone subtotal gastrectomy. The symptoms of hypoglycaemia always occurred 1-3 h after meals, not in the fasting state. Because of the history of gastrectomy and because post-prandial hypoglycaemia was reproduced by an oral glucose tolerance test, the diagnosis of reactive hypoglycaemia was made. Eighteen months later a fasting test was performed: venous plasma glucose decreased from 3.8 mmol/l to 2.7 mmol/l between 14 and 20 h of fast while plasma immunoreactive insulin did not decrease and plateaued at 185 pmol/l. Plasma C-peptide (0.9 nmol/l) and proinsulin (70 pmol/l, split 64, 65) were also elevated. All islet hormones increased in response to i.v. glucose and were suppressed after diazoxide. Although pre-operative procedures were negative in localizing an insulinoma, the patient underwent an operation and an insulinoma was detected at the body level of the pancreas. Thus, insulinoma should be considered in the differential diagnosis of reactive hypoglycaemia in gastrectomized patients. Response of islet hormones to glucose and their suppression by diazoxide are evidence of a secreting insulinoma even in the absence of preoperative localization of the pancreatic adenoma.

Topics: Blood Glucose; C-Peptide; Diagnosis, Differential; Follow-Up Studies; Gastrectomy; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Postprandial Period

Some patients with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) are positive for antibodies to glutamic acid decarboxylase (anti-GAD), which have been shown to be a useful marker for the diagnosis and prediction of insulin-dependent (Type 1) diabetes mellitus (IDDM). Anti-GAD positive NIDDM patients tend to develop insulin deficiency. We investigated the prevalence of anti-GAD in 200 NIDDM with secondary failure of oral hypoglycaemic therapy (SF) and 200 NIDDM well controlled by diet and/or sulphonylurea agents (NSF). Twenty-two of 200 (11%, p < 0.05) SF patients and 6 of 200 (3%) NSF patients were anti-GAD positive. The positive. The positive rate for anti-GAD was as high as 23.8% in the non-obese and insulin deficient SF patients. The SF patients with anti-GAD tended to be non-obese and to have an impaired release of endogenous insulin. The internal before development of secondary failure was not associated with the presence of anti-GAD in this study. In conclusion we found that anti-GAD was positive in as many as 11% of the SF patients, suggesting that autoimmune mechanisms may play an important role in the pathogenesis of secondary failure or sulphonylurea therapy.

Topics: Analysis of Variance; Antibodies; Autoantibodies; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Fasting; Female; Glutamate Decarboxylase; Humans; Hypoglycemia; Insulin; Japan; Male; Middle Aged; Obesity; Time Factors; Treatment Failure; Urine

Topics: Adult; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Pancreatic Neoplasms; Ultrasonography

Topics: Adolescent; Adult; Autoantibodies; Blood Glucose; C-Peptide; Cohort Studies; Diabetes Mellitus, Type 1; Diseases in Twins; Female; Glucose Intolerance; Humans; Hypoglycemia; Insulin; Longitudinal Studies; Self Administration; Time Factors; Twins, Monozygotic

To investigate the effect of normal aging on the protective responses against hypoglycemia, in view of the fact that type II diabetes is primarily a disease of aging, and its treatment is associated with risk of hypoglycemia with cognitive impairment.. Plasma glucose was lowered stepwise from 5 to 2.4 mmol/l and restored by manipulation of an infusion of 20% glucose during 220-min intravenous infusion of 1.5 mU.kg-1.min-1 soluble insulin in 14 men; 7 were aged 60-70 years and the other 7 were 22-26 years. Changes in neurohumoral responses, subjective awareness, and choice reaction time were assessed.. Hormonal responses were similar in the two groups, but symptoms began earlier in the younger men (at a plasma glucose of 3.6 +/- 0.1 vs. 3.0 +/- 0.2 mmol/l, P = 0.02) and were more intense (P = 0.03). Four-choice reaction time, a measure of psychomotor coordination, deteriorated earlier in the older men (at a plasma glucose of 3.0 +/- 0.1 vs. 2.6 +/- 0.1 mmol/l, P = 0.07) and to a greater degree. The difference between the glucose level for subjective awareness of hypoglycemia and the onset of cognitive dysfunction was lost in the older men (0.0 +/- 0.2 vs. 0.8 +/- 0.1 mmol/l, P < 0.007).. Older men are prone to more severe cognitive impairment during hypoglycemia than younger men and are less likely to experience prior warning symptoms if blood glucose falls. This effect of normal aging may contribute to the risk of severe hypoglycemia in older diabetic patients treated with sulfonylureas and insulin.

Topics: Adult; Aged; Aging; Blood Glucose; Blood Pressure; C-Peptide; Cognition; Cohort Studies; Epinephrine; Glucagon; Glucose Clamp Technique; Heart Rate; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin; Male; Middle Aged; Psychomotor Performance

The long-term follow-up of chronic hyperinsulinemic seizures, epileptogenesis and other neurological complications in five patients who were treated with conservative therapy followed by pancreatectomy during the neonatal period and infancy, who were confirmed to have diffuse nesidioblastosis are described. The reaction pattern of the C-peptide (CPR) suppression test and its relation to the final extent of pancreatectomy was examined in four patients. The chronological change in electro-encephalography (EEG) and its epileptogenesis was also examined in each patient during hyperinsulinemic hypoglycemia, and during normoglycemia in a long-term post-pancreatectomy follow-up. All patients demonstrated several types of hypoglycemic seizures, ranging from apnea, erratic seizures, evolving to generalized/unilateral tonic-clonic or tonic seizures, myoclonic seizures and EEG abnormalities. Four of five patients still suffered from epilepsy at the age of 4-22 years. The reaction pattern of the CPR suppression test showed dichotomy, with a hyper-reactive pattern in two patients who required total pancreatectomy to control hypoglycemia, and a suppression pattern in two other patients treated with 90-95% pancreatectomy. Neonatal onset and subsequent myoclonic seizures were ominous signs of epileptogenesis to various types of intractable epilepsy and other neurological sequelae. A prompt diagnosis and pancreatectomy of a sufficient extent at the first operation are essential. The CPR suppression test may be useful for a prompt diagnosis and selection of the extent of pancreatectomy.

Topics: Blood Chemical Analysis; C-Peptide; Epilepsy; Female; Humans; Hyperinsulinism; Hypoglycemia; Infant; Infant, Newborn; Male; Pancreatectomy; Pancreatic Diseases; Pancreatic Function Tests; Prospective Studies

The pathogenetic mechanisms behind insulin resistance in polycystic ovary syndrome (PCOS) are far from fully elucidated. Aberrant counterregulatory responses to hypoglycaemia have been reported in patients with insulin resistance, and recent reports suggest that plasma glucose may be regulated at lower levels in women with PCOS. In this study we investigated the complete hormonal counterregulatory response to hypoglycaemia in women with PCOS.. Prospective cross-sectional study.. Eight obese (BMI > or = 25) and 10 non-obese (BMI < 25) women with PCOS, diagnosed by means of ultrasonography and clinical signs of chronic anovulation. Eight obese and 9 non-obese controls.. Hypoglycaemia was induced by an intravenous bolus of soluble insulin (0.15 IU/kg body weight). The counterregulatory responses of cortisol, GH, catecholamines, glucagon, chromogranin A (CGA), and neuropeptide Y (NPY) were studied together with symptoms of hypoglycaemia.. The obese women with PCOS had a more pronounced truncal-abdominal body fat distribution (waist hip ratio, WHR) and were hyperinsulinaemic, compared with the obese controls. All the women exhibited blood glucose levels (< 2 mmol/l) well below the threshold for the hormonal counterregulatory response and for the appearance of clinical symptoms. The non-obese women with PCOS showed a greater increase in serum concentrations of GH than the lean controls. The obese women with PCOS exhibited blunted responses of noradrenaline and NPY, but similar increases of adrenaline and CGA, compared with the obese controls. They also showed a lower symptom score during hypoglycaemia. The response of noradrenaline to hypoglycaemia correlated inversely with fasting insulin levels in the women with PCOS. Among all the obese women (PCOS and controls pooled) basal levels of noradrenaline correlated inversely with the WHR.. All the women with PCOS, independent of BMI, body fat distribution and insulin levels, showed preserved counterregulatory responses to hypoglycaemia. The reduced plasma levels of noradrenaline and the lower perception of hypoglycaemic symptoms in the obese women with PCOS could both reflect a lower activation of the sympathetic nervous system. This aberration seems related to truncal-abdominal obesity and hyperinsulinaemia. The finding of an increased response of GH in the lean women with PCOS could support previous suggestions of an altered activity of the GH/IGF-I system in these women.

Topics: Adult; Body Mass Index; C-Peptide; Chromogranin A; Chromogranins; Cross-Sectional Studies; Female; Growth Hormone; Humans; Hypoglycemia; Insulin; Neuropeptide Y; Norepinephrine; Obesity; Polycystic Ovary Syndrome; Prospective Studies

Disruption of intraislet mechanisms could account for the impaired glucagon response to hypoglycemia in type 1 diabetes. However, in contrast to animals, there is conflicting evidence that such mechanisms operate in humans. We have used i.v. tolbutamide (T) (1.7 g bolus + 130 mg/h infusion) to create high portal insulin concentrations and compared this with equivalent hypoglycemia using an i.v. insulin infusion (I) (30 mU/m2 x min). Ten normal subjects underwent two hypoglycemic clamps; mean glucose; I (53 +/- 1 mg/dL); and T (53 +/- 1 mg/dL) (2.9 +/- 0.04 mmol/L vs. 2.9 +/- 0.05 mmol/L), held for 30 min. During hypoglycemia, mean peripheral insulin levels were greater with I (59 +/- 4 mU/L) than T (18 +/- 3 mU/L), P < 0.001. Calculated peak portal insulin concentrations were greater during T (282 +/- 28 mU/L) than I (78 +/- 4 mU/L), P < 0.00005. The demonstration of a reduced glucagon response during T-induced hypoglycemia (111 +/- 8 ng/L vs. 135 +/- 12 ng/L, P < 0.05) with higher portal insulin concentrations suggests that intraislet mechanisms may contribute to the release of glucagon during hypoglycemia in man.

Topics: Adult; Blood Glucose; C-Peptide; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Kinetics; Male; Tolbutamide

To evaluate the prevalence and risk factors of nocturnal hypoglycemia (NH) in children and adolescents with insulin-dependent diabetes mellitus.. A total of 150 patients, 87% of whom were receiving conventional therapy, were admitted to the hospital for one night. Blood glucose (BG) levels were measured hourly from 10 PM to 8 AM.. The prevalence of NH was 47%; NH was asymptomatic in 49% of the cases. Risk factors were as follows: at least two episodes of severe hypoglycemia from onset of insulin-dependent diabetes mellitus (p = 0.0004), insulin dosage > 0.85 IU/kg per day (p = 0.02), more than 5% of BG measurements < or = 3.3 mmol/L during the last month of monitoring (p = 0.04). The risk decreased significantly with age (p = 0.0001). Both high predictive values and significant relative risk were found for BG thresholds < or = 5.2 mmol/L at dinner time (p < 0.0001) and < or = 6.7 mmol/L at 7 AM (p < 0.0001). When BG values at 10 PM were used, prediction of NH was weak.. Nocturnal hypoglycemia occurred frequently in children and adolescents with insulin-dependent diabetes mellitus. Our study found risk factors that will help pediatricians to identify those children with a high risk of NH. Especially in these patients, counseling based on the BG values before dinner and early in the morning is indicated to reduce the prevalence of NH.

Topics: Adolescent; Age Factors; Blood Glucose; C-Peptide; Child; Child, Preschool; Circadian Rhythm; Cohort Studies; Counseling; Diabetes Mellitus, Type 1; Eating; Female; Forecasting; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Male; Predictive Value of Tests; Prevalence; Puberty; Risk Factors; Time Factors

The diagnosis of hypoglycemia caused by hyperinsulinism may be difficult because insulin levels are not uniformly elevated at the time of hypoglycemia. Insulin-like growth factor binding protein-1 (IGFBP-1) is a 28 kd protein whose secretion is acutely inhibited by insulin. We hypothesized that serum levels of IGFBP-1 would be a useful marker of hyperinsulinism. We measured IGFBP-1 levels during the course of standardized fasting studies in hospitalized children; 36 patients became hypoglycemic during the fasting studies, and samples obtained at the point of hypoglycemia were analyzed. On the basis of the currently used diagnostic criteria, 13 children had hyperinsulinism, 16 had ketotic hypoglycemia or no disorder, 3 had hypopituitarism or isolated growth hormone deficiency, 2 had glycogen storage disease type 1 and 2 had fatty acid oxidation disorders. In control subjects (children with ketotic hypoglycemia or no disorder), IGFBP-1 levels rose during fasting to a mean of 343.8 +/- 71.3 ng/ml in the sample drawn at the time of hypoglycemia. Mean IGFBP-1 levels at hypoglycemia for the entire group with hyperinsulinism were 52.4 +/- 11.5 ng/ml, significantly different from levels seen in control subjects (p < 0.0001). In children with moderately controlled hyperinsulinism (fasting tolerance > 4 hours), mean IGFBP-1 levels at the time of hypoglycemia were 71.5 +/- 16.9 ng/ml. IGFBP-1 levels in the children with poorly controlled hyperinsulinism (fasting tolerance < 4 hours) failed to rise during fasting, with a mean of 30.1 +/- 10.4 ng/ml in the final sample. IGFBP-1 levels were inversely correlated with serum insulin and C-peptide levels (r = -0.71 and -0.72, respectively; p < 0.0001). Patients with other endocrinologic or metabolic diseases that result in fasting hypoglycemia demonstrated a rise in IGFBP-1 levels similar to that seen in ketotic hypoglycemia. Low serum levels of IGFBP-1 at the time of hypoglycemia provide an additional marker of insulin action that might help to differentiate hyperinsulinism from other hypoglycemic disorders.

Topics: Adolescent; Biomarkers; C-Peptide; Child; Child, Preschool; Fasting; Fatty Acids; Female; Glycogen Storage Disease Type I; Human Growth Hormone; Humans; Hyperinsulinism; Hypoglycemia; Hypopituitarism; Infant; Infant, Newborn; Insulin; Insulin-Like Growth Factor Binding Protein 1; Ketosis; Lipid Metabolism, Inborn Errors; Male

The purpose of the present study was to evaluate the role of muscle glycogen synthase activity in the reduction of glucose uptake during hypoglycaemia. Six healthy young men were examined twice; during 120 min of hyperinsulinaemic (1.5 mU.kg-1. min-1) euglycaemia followed by: 1)240 min of graded hypoglycaemia (plasma glucose nadir 2.8 mmol/l) or 2) 240 min of euglycaemia. At 350-360 min a muscle biopsy was taken and indirect calorimetry was performed at 210-240 and 330-350 min. Hypoglycaemia was associated with markedly increased levels of adrenaline, growth hormone and glucagon and also with less hyperinsulinaemia. During hypoglycaemia the fractional velocity for glycogen synthase was markedly reduced; from 29.8 +/- 2.3 to 6.4 +/- 0.9%, p < 0.05. Total glucose disposal was decreased during hypoglycaemia (5.58 +/- 0.55 vs 11.01 +/- 0.75 mg.kg-1. min-1 (euglycaemia); p < 0.05); this was primarily due to a reduction of non-oxidative glucose disposal (2.43 +/- 0.41 vs 7.15 +/- 0.7 mg.kg-1 .min-1 (euglycaemia); p < 0.05), whereas oxidative glucose disposal was only suppressed to a minor degree. In conclusion hypoglycaemia virtually abolishes the effect of insulin on muscle glycogen synthase activity. This is in keeping with the finding of a marked reduction of non-oxidative glucose metabolism.

Topics: Adult; Biopsy; Blood Glucose; C-Peptide; Calorimetry, Indirect; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Glucose Clamp Technique; Glycogen Synthase; Glycolysis; Growth Hormone; Humans; Hypoglycemia; Infusions, Intravenous; Insulin; Kinetics; Male; Muscle, Skeletal; Reference Values; Time Factors

Topics: C-Peptide; Female; Fetal Blood; Fetal Macrosomia; Humans; Hypoglycemia; Infant, Newborn; Pregnancy

3 patients with recurrent, symptomatic hypoglycemia associated with increased insulin and C-peptide blood levels are described. 2 men aged 37 and 21-years had mental and social problems and although they had access to sulfonylurea drugs, both denied intake. 1 was scheduled for pancreatectomy, but as a result of the vigilance of the surgeon, the operation was canceled. By demonstrating sulfonylurea in their urine, a definitive diagnosis of factitious hypoglycemia was established, and further invasive procedures were avoided. The third was a woman aged 40-years had malignant insulinoma with liver metastases, proven by cytology. The common and differentiating clinical and laboratory characteristics of hypoglycemia due to insulinoma and factitious hypoglycemia secondary to sulfonylurea intake are discussed, and the importance of urine analysis demonstrating the presence of sulfonylurea is emphasized.

Topics: Adult; C-Peptide; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Mental Disorders; Pancreatic Neoplasms; Sulfonylurea Compounds

There is little information concerning the physiological response to hypoglycaemia induced by sulphonylureas. We compared the physiological and symptomatic responses to insulin and tolbutamide induced hypoglycaemia in 8 normal subjects. While infusing either insulin or tolbutamide, we used a glucose clamp to maintain blood glucose at 4.5 mmol l-1 for 30 min and lowered it to 2.9 mmol l-1 for a further 30 min. Mean peripheral insulin levels during the insulin infusion arm in comparison with the tolbutamide infusion were not significantly different during the euglycaemic plateau: 106 +/- 4 vs 77 +/- 15 mU l-1 (mean +/- SEM) (mean difference 29 mU l-1, 95% CI -22 to 80; p = NS) but were greater during the hypoglycaemic plateau: 106 +/- 3.5 vs 21.0 +/- 4.0 mU l-1 (mean difference 85 mU l-1, 95% CI 72 to 98; p < 0.0001). Portal insulin concentrations, calculated from C-peptide data were not significantly different during the euglycaemic plateau with insulin as compared to tolbutamide. However, during hypoglycaemia portal insulin concentrations were significantly higher 15 min from the start of the plateau, during insulin infusion. During hypoglycaemia induced by either insulin or tolbutamide there were similar peak responses of glucagon: 124 +/- 14 vs 128 +/- 7 ng l-1 (mean difference -4, 95% CI -39 to 31; p = NS) and adrenaline: 2.9 +/- 0.4 vs 2.8 +/- 0.3 nmol l-1, (mean difference 0.1, 95% CI -0.9 to 1.0; p = NS). Increases in tremor and sweating and deterioration in reaction time were similar during both periods of hypoglycaemia as were increases in total: 18.5 +/- 1.4 vs 19.6 +/- 2.2 (mean difference -1.0, 95% CI -3.8 to 1.8; p = NS) and autonomic: 8.9 +/- 0.9 vs. 9.9 +/- 1.3 (mean difference -1.1, 95% CI -5.9 to 3.6; p = NS) symptom scores. We conclude that there is no difference in the glucagon, sympathoadrenal, cognitive or symptomatic response during hypoglycaemia induced by either insulin or tolbutamide. This suggests that the different insulin concentrations produced by these contrasting models of hypoglycaemia had no effect on the physiological response and patients taking sulphonylureas can be expected to develop similar warning symptoms to those on insulin.

Topics: Adult; Blood Glucose; C-Peptide; Cognition; Dose-Response Relationship, Drug; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Hemodynamics; Humans; Hypoglycemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin, Regular, Pork; Male; Reaction Time; Recombinant Proteins; Sweating; Tolbutamide; Tremor

The author describe a rare case of pancreatic beta-cell hyperplasia. The patient was referred to us because of serious hypoglycemic crises. During hospitalization, endogenous hyperinsulinism was confirmed by hematochemical and instrumental tests. AngioCT of the pancreas evidenced a small lesion of the corpus, suspected of insulinoma. The patient underwent a corpus caudalis pancreatectomy: a small nodule with histologic neuroendocrine traits was ablated. A few days after the operation, new symptomatic hypoglycemia appeared. The hormonal tests confirmed a recurrence of endogenous hyperinsulinism. The patient underwent a new operation for pancreaticoduodenectomy: histological examination confirmed a pancreatic beta-cells hyperplasia. This condition has to be taken into account in the differential diagnosis of post prandial hypoglycemia. Besides, the observation of an insulinoma doesn't exclude the presence of a diffused disorder of islet cells as in the case above described.

Topics: C-Peptide; Diagnosis, Differential; Female; Humans; Hyperinsulinism; Hyperplasia; Hypoglycemia; Insulinoma; Islets of Langerhans; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy

The C-peptide suppression test employing the euglycemic hyperinsulinemic clamp technique has been proposed as a useful diagnostic measure for insulinoma. To examine the specificity of the C-peptide suppression, we applied this test to subjects with symptoms suggesting reactive hypoglycemia. Five subjects studied had never experienced fasting hypoglycemia, and were negative in ultrasound, CT and MRI of the pancreas. Plasma C-peptide was not suppressed by physiological (50-100 microU/ml) and supraphysiological (200-500 microU/ml) hyperinsulinemia (% of baseline: 97.3 +/- 8.6% and 90.6 +/- 10.4%, +/- SEM, respectively, both NS). Three subjects were re-examined one year later, when their hypoglycemic episodes were noticeably attenuated. No significant suppression was found. Significant suppression was observed when plasma glucose was clamped at 50-60 mg/dl in four of five subjects (61.7 +/- 11.5%, P < 0.05), but one subject responded to neither higher plasma insulin nor low-normal glucose. In contrast, normal glucose tolerance (n = 13), IGT (n = 12) and obese NIDDM (n = 31) subjects showed highly significant suppression during euglycemic and physiological hyperinsulinemia (37.1 +/- 3.8%, 46.3 +/- 5.6%, 39.9 +/- 2.6%, respectively, all P < 0.001). In conclusion, the results of the present study indicate that a failure of hyperinsulinemic suppression of C-peptide in euglycemia is not specific for insulinoma, and that suppression of C-peptide by insulin at lower plasma glucose levels (50-60 mg/dl) would be a better diagnostic test.

Topics: Adolescent; Adult; Aged; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Middle Aged; Obesity

Mutations in the insulin receptor gene can cause genetic syndromes associated with extreme insulin resistance. We have investigated a patient with leprechaunism (leprechaun/Qatar-1) born of a consanguineous marriage. Postnatally, the proband had episodes of severe hypoglycemia and hyperinsulinernia, with blood glucose levels ranging from 0.9 to 9.9 mmol/L. The C peptide concentration with 1880 nmol/L, and the total insulin concentration was 1409 mU/L. The patient died outside the hospital at the age of four months. All 22 exons of the patient's insulin receptor gene were screened for mutations using denaturing gradient gel electrophoresis. Thereafter, the nucleotide sequences of selected exons were determined directly. The patient was homozygous for a mutation in exon 13; thirteen base pairs were deleted and replaced by a 5 b.p. sequence. This mutation shifts the reading frame and introduces a premature chain termination codon downstream in exon 13. Thus, the mutant allele is predicted to be a null allele that encodes a truncated receptor lacking both transmembrane and tyrosine kinase domains.

Topics: Alleles; Blood Glucose; C-Peptide; Chromosome Mapping; DNA Mutational Analysis; Female; Humans; Hypoglycemia; Infant; Molecular Sequence Data; Qatar; Receptor, Insulin; Williams Syndrome

The mechanism(s) of an inappropriate secretion of insulin is poorly understood. We report a case of reactive hypoglycemia associated with an unusually exaggerated insulin secretion. The patient, a 32-year-old man, developed frequent episodes of postprandial hypoglycemia after interferon treatment was begun for chronic type C hepatitis. Oral glucose challenge test confirmed the patient's extremely high plasma IRI response, i.e., more than 1000 microU/ml, and that of plasma C-peptide 56.9 ng/ml at 90 min, followed by symptomatic hypoglycemia (plasma glucose 34 mg/dl) at 240 min. The plasma proinsulin level also was high, but the molar ratio of immuno reactive insulin (IRI)/plasma C-peptide and IRI/proinsulin was within the normal range. Antibodies to insulin or insulin-receptor were negative. Plasma IRI response was apparently greater when the glucose was given orally than when given intravenously. The response of plasma glucagon-like-peptide (GLP)-1 to oral glucose was quite high (from baseline of 45.5 to 303.2 pmol/L) and showed a close parallel with the change in the plasma IRI concentration. The greatly enhanced insulin secretion leading to reactive hypoglycemia in this patient may therefore be attributed to the increased secretion of GLP-1.

Topics: Adult; C-Peptide; Fasting; Food; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Secretion; Male; Peptide Fragments; Proinsulin

Octreotide, a long-acting somatostatin analogue, has been used to alleviate hypoglycaemia in patients with insulinomas. Transient worsening of fasting hypoglycaemia following octreotide has also been described (Stehouwer et al., 1989). We describe a patient with a 'proinsulinoma' in whom octreotide caused rapid and prolonged symptomatic worsening of fasting hypoglycaemia. Catecholamine and cortisol counterregulatory hormonal responses were normal but those of glucagon and GH were impaired. Acute neuroglycopaenic symptoms were present during octreotide induced hypoglycaemia, which was accompanied by and attributed to an acute reduction in pancreatic glucagon secretion in the presence of persistent and unsuppressed hyperproinsulinaemia. This suggests that glucagon may be important in maintaining glucose homeostasis in chronic hypoglycaemia due to endogenous hyperinsulinism even though its concentration in the peripheral blood is not raised.

Topics: Blood Glucose; C-Peptide; Female; Glucagon; Growth Hormone; Humans; Hypoglycemia; Insulin; Middle Aged; Octreotide; Pancreatic Neoplasms; Proinsulin

C-peptide concentrations in the cord blood of 29 macrosomic neonates born of nondiabetic mothers were higher than in 23 control infants whose birth weight was appropriate for gestational age, and there was a significant direct correlation between birth weight and C-peptide concentration. Six of the macrosomic infants studied (20%) had hypoglycemia in the first 24 hours of life, compared with none of the infants born with appropriate weight. We conclude that chronic fetal hyperinsulinemia may be one of the causes of macrosomia and neonatal hypoglycemia in infants of nondiabetic mothers.

Topics: Birth Weight; C-Peptide; Diabetes, Gestational; Female; Fetal Blood; Fetal Macrosomia; Gestational Age; Humans; Hypoglycemia; Infant, Newborn; Pregnancy; Radioimmunoassay

Topics: Blood Glucose; C-Peptide; Fasting; Humans; Hypoglycemia

Hypoglycemia secondary to a meningioma that has not metastasized to the liver has not been reported previously. A 41-year-old woman with a spinal cord meningioma first diagnosed 5 years previously with 3 recurrences in the spinal cord resulting in 4 neurosurgical procedures was admitted with a serum glucose of 23 mg/dL. Six months before the current admission, the patient was noted to have an abdominal mass of 10 cm not present on previous computed tomography. Three months later, the mass was 15.2 cm, and on the current admission, had increased to 23 cm and encased both the aorta and inferior vena cava. A needle biopsy of this mass before referral to the authors' hospital with hypoglycemia revealed that it was a meningioma. Evaluation of the etiology of the hypoglycemia, which required continuous intravenous glucose therapy, revealed that circulating insulin, C-peptide (i.e., connecting peptide), insulin-like growth factor-I (i.e., somatomedin-C) and insulin-like growth factor-II were all normal or low. Serum cortisol also was not low. Based on her endocrine evaluation, the hypoglycemia was secondary to the large mass of tumor cells, requiring a large glucose uptake to sustain its growth. After radiation therapy of 3,770 CGy to the meningioma, the patient became euglycemic without glucose supplementation.

Topics: Adult; Biopsy, Needle; C-Peptide; Female; Glucose; Humans; Hydrocortisone; Hypoglycemia; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Magnetic Resonance Imaging; Meningioma; Neoplasm Recurrence, Local; Spinal Cord Neoplasms

The medical history of a 43-year-old non-insulin-dependent diabetic patient is presented. The exact diagnosis of the cause of repetitive and severe hypoglycaemic episodes proved to be difficult. Finally, high serum insulin and low C-peptide values were found in peripheral venous blood during hypoglycaemia resulting in an elevated (> 1.0) molar ratio of insulin to C-peptide. The laboratory findings were assessed as consequences of surreptitious insulin administration. Factitious hypoglycaemia could be considered as a clinical manifestation of Munchhausen syndrome. Confronting the patient with evidences of surreptitious insulin injections, hypoglycaemic episodes abruptly discontinued to occur.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemia; Insulin; Insulin Coma; Munchausen Syndrome; Self Medication

To compare postprandial metabolic control after subcutaneous injection of a short-acting insulin analog [Lys(B289),Pro(B29)] (Lispro) or human regular insulin (Humulin R U-100 [Hum-R]) in insulin-dependent diabetes mellitus (IDDM) of short duration with residual beta-cell function.. Six IDDM patients (age 25 +/- 2 years, diabetes duration 14 +/- 2 months, HbA1c 6.4 +/- 0.5%) with residual pancreatic beta-cell function (fasting plasma C-peptide 0.19 +/- 0.02 nmol/l) were studied on three different occasions. Postbreakfast plasma glucose was maintained at approximately 7.1 mmol/l by means of intravenous insulin until either 1200 when 0.1 U/kg Hum-R was injected or until 1225 when 0.1 U/kg of either Hum-R or Lispro was injected subcutaneously. Lunch (mixed meal, 692 Kcal) was served at 1230 (0 min). Six nondiabetic control subjects were also studied.. After Lispro administration, the 120-min plasma glucose decreased more (6.1 +/- 0.3 mmol/l) than after injection of Hum-R at -30 min (7.7 +/- 0.3 mmol/l) or -5 min (9.9 +/- 0.2 mmol/l). By the end of the study, plasma glucose was still lower after Lispro was injected (6.7 +/- 0.3 mmol/l) than after Hum-R was injected at -30 min (7.6 +/- 0.3 mmol/l) or -5 min (7.3 +/- 0.2 mmol/l) (P < 0.05). Two IDDM patients required glucose to prevent hypoglycemia after being injected with Lispro, but four required glucose after being injected with Hum-R at -5 min (Lispro approximately 27 mmol glucose infused between 90 and 240 min; Hum-R approximately 80 mmol between 240 and 390 min). After Lispro, plasma insulin peaked earlier (at 30 min, 342 +/- 29 pmol/l) than after Hum-R injection at -30 min (at 90 min, 198 +/- 28 pmol/l) and was superimposable on that of nondiabetic subjects. In Hum-R injected at -5 min, plasma insulin peaked later (at 120 min) and subsequently remained greater than in the two other studies.. Despite the lack of a time interval between injection and meal, Lispro controls postprandial plasma glucose concentration better than Hum-R given 30 min before meals and, to an even greater extent, better than Hum-R given 5 min before meals. In addition, Lispro minimizes the risk of postprandial hypoglycemia, thus closely mimicking the postprandial glucose homeostasis of nondiabetic subjects. IDDM patients with residual pancreatic beta-cell function are the ideal candidates for prandial use of Lispro because they can maintain near-normoglycemia longer after subcutaneous analog injection because of residual endogenous insulin secretion.

Topics: 3-Hydroxybutyric Acid; Adult; Alanine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Drug Administration Schedule; Eating; Fatty Acids, Nonesterified; Female; Glucagon; Glycerol; Humans; Hydroxybutyrates; Hypoglycemia; Injections, Subcutaneous; Insulin; Insulin Lispro; Islets of Langerhans; Lactates; Male; Recombinant Proteins; Reference Values; Time Factors

A 67-year-old woman was admitted in hypoglycemic coma, with fever and signs of hyperthyroidism. Diagnosis was made of both an insulinoma and subacute ("De Quervain") thyroiditis. This rare coincidence of two diseases with opposite effects on serum glucose levels, offered a rare opportunity to study glucose metabolism in this peculiar physiopathological situation. During the day abnormally high postprandial blood glucose levels were seen, pointing to the glucose intolerance usually seen in the hyperthyroid state. During the night and after prolonged fasting, however, hypoglycemia predominated, consistent with the clinical picture typical of an insulinoma. After resection of the insulinoma and spontaneous healing of hyperthyroidism, glucose metabolism reverted to normal. As shown in this case, concurrent hyperthyroidism and an insulinoma may lead to consecutive episodes of glucose intolerance and hypoglycemia within the same 24-hour period.

Topics: Aged; Blood Glucose; C-Peptide; Female; Humans; Hyperthyroidism; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Thyroiditis, Subacute

To assess the relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses, symptoms and deterioration of cognitive function (12 cognitive tests) during progressive decreases in plasma glucose, and to quantitate glycaemic thresholds, 22 normal, non-diabetic subjects (11 males, 11 females) were studied on four occasions: prolonged fast (n = 8, saline euglycaemia study, SA-EU), stepped hypoglycaemia (plasma glucose plateaus of 4.3, 3.7, 3 and 2.3 mmol/l) or euglycaemia during insulin infusion at 1 and 2 mU.kg-1.min-1 (n = 22, high-insulin hypoglycaemia and euglycaemia studies, HI-INS-HYPO and HI-INS-EU, respectively), and stepped hypoglycaemia during infusion of insulin at 0.35 mU.kg-1.min-1 (n = 9, low-insulin hypoglycaemia study, LO-INS-HYPO). Insulin per se (SA-EU vs HI-INS-EU), suppressed plasma glucagon (approximately 20%) and pancreatic polypeptide (approximately 30%), whereas it increased plasma noradrenaline (approximately 10%, p < 0.05). Hypoglycaemia per se (HI-INS-HYPO vs HI-INS-EU) induced responses of counterregulatory hormones (CR-HORM), symptoms and deteriorated cognitive function. With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44 +/- 0.06 mmol/l, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (approximately 3.8-3.6 mmol/l); noradrenaline (3.1 +/- 0.0 mmol/l), autonomic (3.05 +/- 0.06 mmol/l) and neuroglycopenic (3.05 +/- 0.05 mmol/l) symptoms had higher thresholds. All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45 +/- 0.06 mmol/l, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89 +/- 0.06 mmol/l. Although all CR-HORM had a similar glycaemic threshold, the lag time of response (the time required for a given parameter to increase) of glucagon (15 +/- 1 min) and growth hormone (14 +/- 3 min) was shorter than adrenaline (19 +/- 3 min) and cortisol (39 +/- 4 min) (p < 0.05). With the exception of glucagon (which was suppressed) and noradrenaline (which was stimulated), insulin per se (HI-INS-HYPO vs LO-INS-HYPO) did not affect the responses of CR-HORM, and did not influence the symptoms or the cognitive function during hypoglycaemia. Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia.

Topics: Adult; Autonomic Nervous System; Blood Glucose; C-Peptide; Cognition; Cognition Disorders; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Growth Hormone; Hormones; Humans; Hydrocortisone; Hypoglycemia; Insulin; Insulin Secretion; Male; Norepinephrine; Pancreatic Polypeptide; Reference Values; Sex Factors; Time Factors

To determine the reason patients with insulinoma are unable to cease insulin secretion during hypoglycemia.. Five patients with insulinoma.. All patients fasted for up to 25 hours, during which blood was obtained serially for determination of glucose and insulin concentrations. Insulinomas were surgically removed from all patients and Glut 1 and Glut 2 transporter proteins were measured in solubilized tumor membranes by immune blotting.. In all patients, serum insulin concentrations failed to decrease to less than 30.0 pmol/L (< 5.0 microU/mL) and C-peptide concentrations to less than 0.08 nmol/L during hypoglycemia (glucose concentration, < 2.2 mmol/L) that was induced by fasting. The islet cell tumors from all five patients contained Glut 1, a low-Km glucose transporter protein, which is not normally present in beta-cells. Glut 2, a high-Km glucose transporter protein, which is normally prevalent in beta-cells, was undetectable in one patient and was present in what appeared to be low concentrations in the remaining four patients.. Our data are compatible with the concept that continued glucose transport, mediated by the low-Km Glut 1 glucose transporter, was responsible for continued insulin release during hypoglycemia in these patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cell Membrane; Female; Glucose Transporter Type 4; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Membrane Glycoproteins; Middle Aged; Monosaccharide Transport Proteins; Muscle Proteins; Neoplasm Proteins; Pancreatic Neoplasms

Increased thyroid hormone concentrations have been reported to have disparate effects on insulin sensitivity in man. We describe a 72-year-old lady who initially presented with episodic hypoglycemia secondary to an insulinoma that was controlled by diazoxide. She re-presented 12 months later with a recurrence of the hypoglycemia following the development of thyrotoxicosis. The diazoxide treatment was maintained and propranolol was introduced, which prevented further episodes of hypoglycemia. This appeared to be due to a direct effect of propranolol on endogenous insulin secretion, while whole body insulin sensitivity remained unchanged as assessed using the hyperinsulinemic-euglycemic clamp technique. She was later rendered biochemically euthyroid with a combination of blocking carbimazole therapy and thyroxine replacement, and this was associated with a marked decrease in insulin sensitivity. Thus, the principal effect of thyroid hormone excess in this patient was an increase in insulin sensitivity that led to the clinical relapse of the insulinoma.

Topics: Aged; C-Peptide; Diazoxide; Female; Humans; Hypoglycemia; Insulin; Insulin Resistance; Insulinoma; Pancreatic Neoplasms; Propranolol; Recurrence; Thyrotoxicosis

Glucagon-like peptide-1 is a peptide hormone from the distal small intestine which stimulates insulin secretion and inhibits glucagon secretion and thereby lowers blood glucose. This hormone, therefore, could be involved in the pathogenesis of postprandial reactive hypoglycemia. We subjected 8 patients showing symptoms of early dumping after partial gastrectomy to an oral 100 g glucose load and measured blood glucose and plasma insulin, C-peptide, glucagon, enteroglucagon and GLP-1 concentrations for 3.5 h after ingestion. Ten matched controls were treated similarly. The patients had higher blood glucose concentrations for the initial 60 min, but lower values for the remaining test period with a nadir of 2.76 +/- 0.19 mmol/l at 146 +/- 17 min after glucose (controls: 3.36 +/- 0.21 mmol/l at 210 +/- 9 min). GLP-1 and enteroglucagon responses were grossly elevated in patients compared to controls and insulin and C-peptide levels were higher during the initial 60 min. Glucagon concentrations increased in patients and decreased in controls. When hypoglycemia occurred, GLP-1 levels were only moderately elevated and insulin and C-peptide levels were lower and glucagon levels higher in patients than in controls. Thus, mechanisms other than release of GLP-1 seem to be responsible for the observed changes in the concentrations of glucose and glucoregulatory hormones.

Topics: Administration, Oral; Adult; Blood Glucose; C-Peptide; Chromatography, Gel; Data Interpretation, Statistical; Female; Gastrectomy; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemia; Insulin; Insulin Secretion; Male; Middle Aged; Peptide Fragments; Protein Precursors; Radioimmunoassay

An insulinoma was diagnosed in a 26 year-old woman who suddenly went into hypoglycemic coma in the 38th week of an apparently uncomplicated pregnancy. On review of the history it became apparent that symptoms due to hypoglycemia had been present since the 16th week of pregnancy. Continuous intravenous infusion of glucose was administered and the patient was delivered of a healthy child 5 days later. Investigations revealed 2 insulinoma nodules in the tail of the pancreas which were successfully removed 2 weeks post partum.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Female; Humans; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Trimester, Third

Although successful pancreas transplantation in humans with type I diabetes mellitus restores glucose-induced insulin secretion, provides freedom from insulin treatment, and normalizes fasting glucose levels, much less is known about its effects on counterregulation of hypoglycemia. To determine whether pancreas transplantation normalizes glucagon secretion and hepatic glucose production (HGP) during hypoglycemia, we performed hyperinsulinemic hypoglycemic clamps in successful recipients of pancreas allografts. Recipients were found to have glucagon secretory responses during hypoglycemia that were similar to those of control subjects (incremental glucagon response: recipients, 147 +/- 34 ng/L; control subjects, 161 +/- 43 ng/L, NS) but were significantly higher than those of matched subjects with type I diabetes (23 +/- 9 ng/L, P < 0.01). HGP rates at the end of 120 min of hypoglycemia were also significantly higher in recipients and control subjects than in subjects with diabetes (pancreas recipients, 1.92 +/- 0.33 mg.kg-1.min-1; control subjects, 2.05 +/- 0.18 mg.kg-1.min-1; subjects with type I diabetes, 0.58 +/- 0.12 mg.kg-1.min-1). A comparison with a third group of nondiabetic kidney transplant recipients demonstrated that the beneficial effects on glucose counterregulation were a result of pancreas transplantation and not the associated immunosuppressive therapy. We conclude that pancreas transplantation restores hypoglycemia-induced glucagon secretion and HGP, thereby allowing for normalization of glucose recovery from hypoglycemia.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon; Gluconeogenesis; Glucose; Glucose Clamp Technique; Humans; Hypoglycemia; Immunosuppressive Agents; Infusions, Intravenous; Insulin; Kidney Transplantation; Liver; Male; Pancreas Transplantation; Reference Values

We hypothesized, first, that recent antecedent hypoglycemia causes reduced autonomic responses to subsequent hypoglycemia in patients with well-controlled insulin-dependent diabetes mellitus (IDDM) and that the reduced responses are specific for the stimulus of hypoglycemia while the responses to other stimuli are unaltered and, second, that reduced autonomic responses, specifically sympathochromaffin, so-induced are not simply the result of prior activation of the system. To test the first hypothesis, eight patients with IDDM, selected for HbA1c levels < 8.0% and the absence of classic diabetic autonomic neuropathy, were studied twice. On one occasion, clamped hypoglycemia (approximately 2.8 mM) was produced at 1400-1600 on days 2 and 3; on the other occasion clamped euglycemia (approximately 5.6 mM) was produced at those times. On both occasions, autonomic responses to hypoglycemia (approximately 2.8 mM) were determined the morning of day 3 and those to standing, exercise, and a formula meal the morning of day 4. Following afternoon hypoglycemia, 1) the adrenomedullary epinephrine (EPI) response to hypoglycemia was reduced (P = 0.0397) but that to standing, exercise, and a meal were unaltered; 2) the sympathetic neural norepinephrine (NE) response to standing and to exercise was unaltered; and 3) the partially parasympathetic neural-mediated pancreatic polypeptide response to a meal was unaltered. To test the second hypothesis, seven nondiabetic subjects were studied twice, once with cycle exercise (60% peak VO2 x 60 min) and once without exercise 90 min before clamped hypoglycemia (approximately 2.8 mM). Prior exercise had no effect on the EPI, NE, or pancreatic polypeptide responses to hypoglycemia. We conclude, first, that the phenomenon of hypoglycemia-associated autonomic failure can be induced in patients with well-controlled IDDM and is specific for the stimulus of hypoglycemia and, second, that this is not simply the result of prior activation of the system.

Topics: 3-Hydroxybutyric Acid; Adult; Alanine; Analysis of Variance; Autonomic Nervous System; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 1; Epinephrine; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucose Clamp Technique; Growth Hormone; Heart Rate; Humans; Hydrocortisone; Hydroxybutyrates; Hypoglycemia; Insulin; Lactates; Male; Norepinephrine; Oxygen Consumption; Pancreatic Polypeptide; Physical Exertion; Posture; Reference Values; Time Factors

Metabolically well controlled insulin-dependent diabetic subjects (IDDM) have deficient autonomic adrenomedullary responses to hypoglycemia. This defect, coupled with the characteristic deficient glucagon response to hypoglycemia, predisposes well-controlled IDDM subjects to an increased incidence of severe hypoglycemic episodes. In this report we describe a physically trained subject with long-duration IDDM (9 years) who was rigorously well-controlled (normal HBA1c), yet had exaggerated epinephrine responses to hypoglycemia compared with normal controls. Steady state epinephrine levels during a low-dose insulin (9 pM/kg/min) hypoglycemic clamp (2.9 +/- 0.1 mM) were approximately 2-fold higher compared with normal controls (10.6 vs. 5.5 +/- 0.7 nM). Epinephrine levels during a high-dose insulin (30 pM/kg/min) hypoglycemic clamp (2.8 +/- 0.1 mM) were also increased compared with normal controls (13.1 vs. 8.8 +/- 0.6 nM). We conclude that physical training in this metabolically well-controlled IDDM subject was associated with an augmented autonomic adrenomedullary response to hypoglycemia.

Topics: 3-Hydroxybutyric Acid; Adult; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 1; Epinephrine; Exercise; Fatty Acids, Nonesterified; Glucagon; Growth Hormone; Heart Rate; Humans; Hydrocortisone; Hydroxybutyrates; Hypoglycemia; Insulin; Lactates; Liver; Male; Pancreatic Polypeptide; Physical Fitness; Reference Values; Sports

Octreotide is a recently available, FDA-approved, long-acting analog of somatostatin. The efficacy and tolerability of octreotide were evaluated in a series of protocols in healthy volunteers to assess its suitability for use in clinical investigations involving short-term inhibition of endogenous hormone secretion. Prolonged (270 minutes) hyperglycemic clamps were used to assess octreotide-mediated suppression of glucose-stimulated endogenous insulin secretion. Compared with a saline-control infusion, octreotide (30 ng/kg/min) suppressed stimulated insulin (P < .0001) and C-peptide (P < .0001) concentrations to basal levels. During insulin-induced hypoglycemia (plasma glucose < 40 mg/dL), octreotide (30 ng/kg/min) effectively suppressed the secretion of glucagon (P < .05) and growth hormone (P < .0005). In islet cell clamp studies, octreotide (30 ng/kg/min) suppressed C-peptide (P < .001), glucagon (P < .01), and growth hormone concentrations to below basal (fasting) levels in all subjects. Subsequent infusion of exogenous insulin, glucagon, and growth hormone resulted in predictable and stable concentrations of each hormone during octreotide-mediated suppression of their endogenous secretion. Consistent with the long half-life of octreotide (approximately 90 minutes), the concentrations of all three hormones remained suppressed below basal levels throughout a 60-minute observation period following the termination of octreotide infusion. In separate high-dose octreotide infusion studies, octreotide (60 ng/kg/min) did not produce any apparent additional metabolic effects, but was associated with an unacceptable degree of gastrointestinal side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Female; Glucagon; Growth Hormone; Humans; Hyperglycemia; Hypoglycemia; Infusions, Intravenous; Insulin; Insulin Resistance; Male; Octreotide; Radioimmunoassay; Time Factors

Recent animal studies have suggested that insulin-like growth factor binding protein (IGFBP)-1 may regulate the insulin-like actions of the circulating IGFs. In man, IGFBP-1 levels change rapidly with nutritional status and are inversely related to changes in insulin. In-vitro studies have shown that both insulin and glucose independently regulate IGFBP-1 secretion in an inverse manner. A rapid rise of serum IGFBP-1 levels following insulin-induced hypoglycaemia suggested that glucose or glucose availability, rather than insulin, may be the major regulator of IGFBP-1.. Three separate experiments both in patients and in normal volunteers were designed to examine the possibility that in these extreme circumstances glucose rather than insulin was the predominant regulator of IGFBP-1.. Insulin tolerance tests (ITT) were performed during the routine assessment of pituitary function in seven patients, four female and three male (mean age +/- SEM 36.8 +/- 6.3 years, range 20.7-69.3 years) with pituitary disease. Hypoglycaemic glucose clamp studies (insulin 2 mU/kg/min for 180 minutes) were performed in five normal volunteers, two female and three male (mean age 33.6 +/- 2.2 years, range 23.5-42.0 years). A three-part infusion study was performed in five volunteers, three female and two male (mean age 22.9 +/- 0.9 years, range 20.8-25.0 years) who received for 45 minutes on three occasions separated by at least 7 days either octreotide (long-acting somatostatin analogue) (1 microgram/min), adrenaline (3 micrograms/min) or control.. Serum levels of IGFBP-1, insulin, glucose, C-peptide and cortisol were measured at varying intervals during the three studies by radioimmunoassay (RIA).. Symptomatic hypoglycaemia (1.0 +/- 0.1 mmol/l) occurred at 30 minutes in all patients during the ITT. Serum IGFBP-1 levels rose from 28 +/- 7 to 86 +/- 15 micrograms/l at 180 minutes. During the hypoglycaemic glucose clamp study plasma glucose fell from 4.8 +/- 0.3 to 2.2 +/- 0.3 mmol/l. In contrast to the response observed during ITT, IGFBP-1 levels fell from 22 +/- 6 to 10 +/- 1 microgram/l by 180 minutes. During the octreotide infusion study there was no change in plasma glucose and plasma insulin levels fell from 5.8 +/- 1.9 to < 2.0 mU/l. Serum IGFBP-1 levels rose from 21 +/- 2 to 68 +/- 5 micrograms/l by 180 minutes. There was no change in IGFBP-1 during either the adrenaline infusion or the control study. The rise in IGFBP-1 following the octreotide infusion (68 +/- 5 micrograms/l) was similar to that in the patients undergoing the ITT (86 +/- 15 micrograms/l) (P = 0.3).. The rapid rise of serum IGFBP-1 levels induced by acute hypoglycaemia could be reproduced in euglycaemic conditions with octreotide when insulin secretion was suppressed, whereas IGFBP-1 levels did not rise with hypoglycaemia induced by a prolonged insulin infusion. These findings suggest that the surprising rise of IGFBP-1 levels observed during ITT is not secondary to changes in glucose. The rapid removal from the portal circulation of endogenous insulin with its inhibitory effect on IGFBP-1 secretion therefore appears to be the likely cause for the rapid rise of IGFBP-1 following an ITT. This conclusion supports the hypothesis that IGFBP-1 may inhibit the insulin-like actions of 'free' IGF when insulin secretion is low and so directly link the availability and hence actions of IGFs to acute but temporary changes in nutritional status.

Topics: Acute Disease; Adult; Aged; C-Peptide; Carrier Proteins; Female; Glucose Clamp Technique; Humans; Hydrocortisone; Hypoglycemia; Insulin; Insulin Secretion; Insulin-Like Growth Factor Binding Protein 1; Male; Middle Aged; Octreotide; Pituitary Gland; Somatomedins

Topics: Adult; Animals; Awareness; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glucose Clamp Technique; Heart Rate; Humans; Hypoglycemia; Insulin; Insulin-Like Growth Factor I; Liver; Male; Norepinephrine; Rats; Recombinant Proteins

We sought 1) to determine which symptoms of hypoglycemia are reproducible, 2) to pharmacologically distinguish neurogenic (autonomic) from neuroglycopenic symptoms, and 3) to test the hypothesis that awareness of hypoglycemia is the result of perception of neurogenic rather than neuroglycopenic symptoms. Awareness of hypoglycemia and 19 symptoms were quantitated in 10 normal, young adults, each studied on four occasions in random sequence, during 1) clamped euglycemia (approximately 5 mM), 2) clamped hypoglycemia (approximately 2.5 mM), 3) clamped hypoglycemia with combined alpha- and beta-adrenergic blockade (phentolamine and propranolol), and 4) clamped hypoglycemia with pan-autonomic blockade (phentolamine, propranolol and atropine). Significant (ANOVA, P < 0.001) treatment effects on the awareness of hypoglycemia ("blood sugar low") were noted. No change occurred in the score for this during euglycemia, but the mean +/- SE increase was 2.1 +/- 0.4 during hypoglycemia. This increase was not reduced significantly by adrenergic blockade (1.6 +/- 0.5), but was reduced significantly and substantially (approximately 70%) by pan-autonomic blockade (0.6 +/- 0.3). Significant neurogenic symptoms included shaky/tremulous (P < 0.001), heart pounding (P < 0.001), and nervous/anxious (P = 0.002), all adrenergic; and sweaty (P < 0.001), hungry (P < 0.001), and tingling (P = 0.009), all cholinergic. Significant neuroglycopenic symptoms, those produced by hypoglycemia but not reduced by pan-autonomic blockade, included warm (P < 0.001), weak (P = 0.011), difficulty thinking/confused (P = 0.004), and tired/drowsy (P = 0.003). We conclude that muscarinic cholinergic mechanisms mediate an important and previously uncharacterized component of the neurogenic symptoms of hypoglycemia and awareness of hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Hydroxybutyric Acid; Adult; Alanine; Atropine; Autonomic Nervous System; Awareness; Blood Glucose; Blood Pressure; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Glucose Clamp Technique; Growth Hormone; Heart Rate; Hormones; Humans; Hydrocortisone; Hydroxybutyrates; Hypoglycemia; Insulin; Lactates; Lactic Acid; Male; Norepinephrine; Pancreatic Polypeptide; Phentolamine; Propranolol; Receptors, Adrenergic, beta; Reference Values; Time Factors

The effects of peripheral autonomic neuropathy on the symptomatic, physiological, and hormonal responses to acute insulin-induced hypoglycaemia were studied in two groups of patients with Type 1 diabetes, matched for age, duration of diabetes, and prevailing glycaemic control. A group of eight patients who gave a history of normal awareness of hypoglycaemia and had normal cardiovascular autonomic function tests were compared to a group of six patients who had symptoms of autonomic dysfunction and gross abnormalities of cardiovascular autonomic function tests. An additional two patients with autonomic neuropathy who also had hypoglycaemia unawareness were studied. Acute hypoglycaemia was induced by intravenous infusion of insulin (2.5 mU kg-1 min-1) and the onset of the acute autonomic reaction (R) was identified objectively by the sudden rise in heart rate and onset of sweating. Cognitive function and hypoglycaemia symptom scores were estimated serially, and plasma counterregulatory hormones were measured. Acute autonomic activation was observed to occur in all subjects in response to hypoglycaemia and commenced at similar venous plasma glucose concentrations in both groups (neuropathic patients: 1.6 +/- 0.2 mmol l-1 vs non-neuropathic patients 1.6 +/- 0.2 mmol l-1, p = 0.9,). In the neuropathic patients plasma adrenaline responses were significantly lower at all time points from time R until time R + 30 min (MANOVA for repeated measures, F = 19.4, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Awareness; Blood Glucose; C-Peptide; Cardiovascular System; Cognition; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Diarrhea; Epinephrine; Female; Glucagon; Glycated Hemoglobin; Heart Rate; Humans; Hypoglycemia; Hypotension, Orthostatic; Insulin; Male; Middle Aged; Pancreatic Polypeptide; Reaction Time; Sweating; Valsalva Maneuver

Topics: Aged; C-Peptide; Humans; Hypoglycemia; Insulin; Leg; Male; Muscle Cramp; Quinine

To elucidate the mechanism of impaired pancreatic A cell function in hypoglycemia in diabetics, the effect of long-term strict glycemic regulations on hypoglycemia-induced glucagon secretion was studied. Firstly, the effect of plasma insulin concentrations on suppressing A cell was studied in healthy volunteers by injecting insulin at doses of 0.1 U/kg and 0.3 U/kg. With 0.3 U/kg of insulin, the rate of fall in glycemia and the nadir of blood glucose were made similar to those with 0.1 U/kg of insulin by glucose infusion with artificial endocrine pancreas. Plasma glucagon response after 0.3 U/kg of insulin was significantly suppressed as compared to that after 0.1 U/kg of insulin, demonstrating that not only hypoglycemic stimulus but also plasma insulin concentration were important determinants responsible for glucagon secretion in insulin-induced hypoglycemia. Secondly, effect of strict glycemic control was studied. Short-acting insulin at a dose of 0.1 U/kg was injected in an intravenous bolus form into 12 insulin-dependent (IDDM) and 9 non-insulin-dependent (NIDDM) diabetics before and 1-3 months after strict glycemic control with multiple insulin injections therapy. Before strict glycemic regulations in IDDM, no significant rise in plasma glucagon concentrations was observed during the insulin-induced hypoglycemia. In NIDDM, a rise in plasma glucagon concentrations was observed, though the response was delayed. After strict glycemic regulations, in patients with residual endogenous insulin secretion, the glucagon response to hypoglycemia improved considerably in IDDM and normalized in NIDDM. In IDDM and NIDDM, improvement in glucagon response to hypoglycemia related positively to daily urinary secretion rate of C-peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Insulin Infusion Systems; Insulin Secretion; Male; Middle Aged; Reference Values; Time Factors

To test the clinical use of octreotide in the treatment of sulfonylurea-induced hypoglycemia.. A case is reported of sulfonylurea-induced hypoglycemic coma in a nondiabetic subject, which was complicated by relapse of hypoglycemia after resuscitation with intravenous dextrose. Subcutaneous octreotide, 50 micrograms 12 hourly, suppressed stimulated endogenous insulin secretion, thereby preventing a further recurrence of hypoglycemia.. No adverse effects of treatment were observed.. These results suggest a significant role for octreotide as an adjunct to intravenous dextrose in the management of severe and refractory cases of sulfonylurea-induced hypoglycemia.

Topics: Adult; Blood Glucose; C-Peptide; Coma; Humans; Hypoglycemia; Male; Octreotide; Tolbutamide

Recombinant human insulin-like growth factor-1 (rhIGF-1) lowers blood glucose in humans but its effect on counterregulatory responses has not been established. We therefore compared infusions of rhIGF-1 (0.7 micrograms/kg per min) and insulin (0.8 mU/kg.min) for 120 min in 10 healthy volunteers (glucose allowed to fall freely). With both, glucose fell rapidly because of stimulation of glucose uptake and suppression of hepatic glucose production. Despite similar plasma glucose nadirs (2.6 +/- 0.1 vs. 2.7 +/- 0.1 mM), the glucagon response was absent (P < 0.005), growth hormone release was attenuated (P < 0.03), and norepinephrine levels were increased (P < 0.05) by rhIGF-1 compared with insulin. Absent glucagon responses were associated with a blunting of the rebound increase in glucose production (P < 0.05 vs. insulin). After stopping the infusions, glucose recovery was delayed with rhIGF-1 (P < 0.001 vs. insulin). To further evaluate the effects of rhIGF-1 during a standard hypoglycemic stimulus, eight additional healthy subjects received rhIGF-1 or insulin while glucose was clamped at 2.8 mM. Again the rise in glucagon during insulin-induced hypoglycemia was totally abolished by rhIGF-1. Growth hormone responses were delayed, whereas increases in norepinephrine, heart rate, and symptomatic awareness of hypoglycemia were greater with rhIGF-1 compared with insulin (P < 0.05). It was concluded that rhIGF-1 suppression of glucagon release during hypoglycemia impairs glucose recovery. Paradoxically, awareness of hypoglycemia is enhanced with rhIGF-1 in part due to stimulation of the sympathetic activity.

Topics: Adult; Analysis of Variance; Blood Glucose; Blood Pressure; C-Peptide; Epinephrine; Glucagon; Glucose; Glucose Clamp Technique; Growth Hormone; Heart Rate; Humans; Hypoglycemia; Infusions, Intravenous; Insulin; Insulin Secretion; Insulin-Like Growth Factor I; Kinetics; Norepinephrine; Recombinant Proteins; Time Factors

C-Peptide, a marker for insulin secretion, is purported to be elevated in patients with insulinoma but diagnostic criteria have not been established. Thirty-seven patients with histologically confirmed insulinoma studied preoperatively, 19 normal subjects, and 2 patients who subsequently acknowledged self-administration of insulin underwent the prolonged fast (< or = 72 h) according to a standard protocol. Plasma glucose, C-peptide, and insulin were measured every 6 h until plasma glucose was less than or equal to 3.3 mmol, then hourly until Whipple's triad was demonstrated or until 72 h without symptoms was reached. At the termination of the fasts, plasma was analyzed for sulfonylurea. Statistical analysis was by rank sum test. Data are expressed as median (range). The durations of fasts were 20 (2.5-68) h for patients with insulinomas and 72 h for normal subjects. At the end of fasts plasma glucose, C-peptide, and insulin concentrations were 2.2 (1.4-2.9) vs. 3.6 (2.7-5.5) mmol, P < 0.001; 0.60 (0.20-1.92) vs. 0.13 (0.07-0.43) nmol, P < 0.001; and 126 (35-840) vs. 35 (35-126) pmol, P < 0.001, respectively, for insulinoma patients and normal subjects. All plasma samples were negative for sulfonylurea. Insulinoma patients had C-peptide values at the end of the fasts greater than or equal to 0.20 nmol whereas normal subjects and patients with insulin factitial hypoglycemia had C-peptide concentrations less than or equal to 0.10 nmol when plasma glucose was less than or equal to 2.8 mmol. Insulinoma is confirmed in a sulfonylurea negative patient with Whipple's triad during the prolonged fast and a concomitant C-peptide concentration greater than or equal to 0.20 nmol.

Topics: Adolescent; Adult; Aged; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Radioimmunoassay; Reference Values

IDDM subjects lose the ability to release glucagon during hypoglycemia. Because replacement of basal levels of amino acids enhances the glucagon response to hypoglycemia in healthy subjects, we tested whether raising amino acid levels during hypoglycemia could reverse the defective alpha-cell response in IDDM patients. For this purpose, 11 IDDM patients (HbA1 9.4 +/- 0.6%) and 8 healthy, nondiabetic subjects received two hypoglycemic insulin clamp studies (0.8 mU.kg-1 x min-1) in which plasma glucose was clamped at 55 mg/dl (3.08 mM) for 180 min. During one of the studies, an infusion of amino acids was superimposed between 120 and 180 min (0.3 g.kg-1 x h-1). This dose of amino acids had a small effect on plasma glucagon levels during euglycemic hyperinsulinemia that was comparable in normal and IDDM subjects. In healthy control subjects, plasma glucagon rose by 80% during the initial hypoglycemic phase of the study. The addition of amino acids produced a further sharp (200-250 ng/L, P < 0.02) rise in plasma glucagon, such a change did not occur in the absence of amino acids. In contrast, plasma glucagon in IDDM patients failed to increase during hypoglycemia alone and rose by only 40-50 ng/L (P < 0.05 vs. controls) when amino acid infusion was superimposed, even though plasma amino acid levels rose to the same extent in IDDM and control subjects. More importantly, the rise in glucagon produced by amino acids was comparable during hypoglycemic and euglycemic hyperinsulinemia in the IDDM patients, results strikingly different from those observed in nondiabetic control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amino Acids; Amino Acids, Essential; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Glucagon; Glucose Clamp Technique; Humans; Hypoglycemia; Infusions, Intravenous; Insulin; Insulin Infusion Systems; Male; Reference Values

Patients with autoimmune insulin antibody are characterized by hypoglycemic attacks and antibodies to insulin in serum without prior insulin administration. In the present report, a patient with hypoglycemia due to autoimmune insulin antibody associated with primary empty sella syndrome and polymyositis appeared to have high urinary immunoreactive insulin (IRI) in the face of normal urinary C peptide. Consequently, the urinary IRI/C peptide ratio was apparently high. The amelioration of hypoglycemic attacks and polymyositis by prednisolone treatment was accompanied by the disappearance of the antibodies and complete normalization of the urinary IRI and IRI/C peptide ratio. No comparable rise in the urinary IRI and IRI/C peptide ratio was observed in the patients with other disorders studied. Glucose clamp and glucose tolerance study showed decreased sensitivity to exogenous or newly secreted insulin, prolonged half disappearance time of serum insulin, and normal disappearance of blood glucose. These results were consistent with the idea that autoantibodies buffered the effect of exogenous or newly secreted insulin and maintained a relatively constant level of serum free insulin which was not high enough when a large amount of glucose was loaded, but was too high after prolonged fasting, which eventually caused hypoglycemic attacks.

Topics: Autoantibodies; Autoimmune Diseases; Blood Glucose; C-Peptide; Child; Empty Sella Syndrome; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Middle Aged; Muscles; Myositis; Prednisolone; Time Factors

Topics: Alcohol Drinking; Alcoholism; Blood Glucose; C-Peptide; Glucagon; Humans; Hypoglycemia; Insulin; Radioimmunoassay

Topics: Adult; C-Peptide; Glucagon; Humans; Hypoglycemia; Insulin; Tolbutamide

To report a case of disopyramide-induced hypoglycemia and to discuss the observed inadequate adrenergic response in this patient. Risk factors, possible etiologies, and preventive measures are also discussed.. References from case reports and review articles as identified by MEDLINE.. A wide variety of drugs has been implicated as causing hypoglycemia. The mechanism for drug-induced hypoglycemia is known for the majority of these agents. Case reports of disopyramide-induced hypoglycemia have been reported in the literature, but the mechanism of action is unclear. We report a case of disopyramide-induced hypoglycemia in which counter-regulatory hormones, serum insulin, and C-peptide concentrations were obtained. From these data, it appears that disopyramide-induced hypoglycemia results from endogenous insulin secretion, with concomitant inadequate counterregulatory response.. Although a rare occurrence, disopyramide-induced hypoglycemia is potentially life-threatening. Patients at risk for this reaction need to be identified prior to the institution of disopyramide therapy. Patients at risk for hypoglycemia should be monitored while on disopyramide and disopyramide blood concentrations should be maintained at the lower end of the therapeutic range, or alternative agents should be considered.

Topics: Aged; C-Peptide; Disopyramide; Humans; Hypoglycemia; Insulin; Male

Advanced age is a risk factor for hypoglycemia caused by sulfonylureas (and insulin) used to treat diabetes mellitus. Therefore, we hypothesized that there is an age-associated impairment of glucose counterregulation and further that this is the result of a sedentary life-style. To test these hypotheses, glycemic and neuroendocrine responses to hypoglycemia, produced by 0.05 U/kg body wt insulin i.v. were measured in nondiabetic elderly subjects (age 65.1 +/- 0.9 yr n = 23)--and in a subset (n = 11) again after 1 yr of physical training (which increased VO2 max by 5.2 +/- 0.9 ml.kg-1.min-1, P less than 0.05)--and compared with these responses in nondiabetic young subjects (23.8 +/- 0.6 yr, n = 18). Recovery from hypoglycemia was attenuated (analysis of variance P less than 0.001) in the elderly (plasma glucose recovery rate 29.4 +/- 2.2 vs. 42.7 +/- 5.0 microM/min, P less than 0.02). This attenuation was the result of a smaller counterregulatory increment in glucose production (maximum increment 13.3 +/- 1.1 vs. 17.2 +/- 1.1 mumol.kg-1.min-1; P less than 0.05) rather than a greater increment in glucose utilization in the elderly. The attenuated glucose recovery was associated with higher plasma insulin concentrations (maximum increment 1385 +/- 122 vs. 940 +/- 72 pM, P less than 0.01) and reduced glucagon responses to hypoglycemia (maximum increment 43 +/- 6 vs. 66 +/- 12 ng/L). The epinephrine, norepinephrine, cortisol, and growth hormone responses were similar, although the epinephrine response was slightly delayed and the growth hormone response appeared smaller in the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Hydroxybutyric Acid; Adult; Age Factors; Aged; Alanine; Analysis of Variance; Blood Glucose; Blood Pressure; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Growth Hormone; Heart Rate; Humans; Hydrocortisone; Hydroxybutyrates; Hypoglycemia; Insulin; Lactates; Middle Aged; Norepinephrine

Three studies were performed on nine normal volunteers to assess whether catecholamine-mediated lipolysis contributes to counterregulation to hypoglycemia. In these three studies, insulin was intravenously infused for 8 h (0.30 mU.kg-1.min-1 from 0 to 180 min, and 0.40 mU.kg-1.min-1 until 480 min). In study I (control study), only insulin was infused; in study II (direct + indirect effects of catecholamines), propranolol and phentolamine were superimposed to insulin and exogenous glucose was infused to reproduce the same plasma glucose (PG) concentration of study I. Study III (indirect effect of catecholamines) was the same as study II, except heparin (0.2 U.kg-1.min-1 after 80 min), 10% Intralipid (1 ml.min-1 after 160 min) and variable glucose to match PG of study II, were also infused. Glucose production (HGO), glucose utilization (Rd) [3-3H]glucose, and glucose oxidation and lipid oxidation (LO) (indirect calorimetry) were determined. In all three studies, PG decreased from approximately 4.8 to approximately 2.9 mmol/liter (P = NS between studies), and plasma glycerol and FFA decreased to a nadir at 120 min. Afterwards, in study I plasma glycerol and FFA increased by approximately 75% at 480 min, but in study II they remained approximately 40% lower than in study I, whereas in study III they rebounded as in study I (P = NS). In study II, LO was lower than in study I (1.69 +/- 0.13 vs. 3.53 +/- 0.19 mumol.kg-1.min-1, P less than 0.05); HGO was also lower between 60 and 480 min (7.48 +/- 0.57 vs. 11.6 +/- 0.35 mumol.kg-1.min-1, P less than 0.05), whereas Rd was greater between 210 and 480 min (19 +/- 0.38 vs. 11.4 +/- 0.34 mumol.kg-1.min-1, respectively, P less than 0.05). In study III, LO increased to the values of study I; between 4 and 8 h, HGO increased by approximately 2.5 mumol.kg-1.min-1, and Rd decreased by approximately 7 mumol.kg-1.min-1 vs. study II. We conclude that, in a late phase of hypoglycemia, the indirect effects of catecholamines (lipolysis mediated) account for at least approximately 50% of the adrenergic contribution to increased HGO, and approximately 85% of suppressed Rd.

Topics: Adult; Blood Glucose; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glycerol; Humans; Hydrocortisone; Hydroxybutyrates; Hypoglycemia; Insulin; Kinetics; Lactates; Lipolysis; Male; Oxidation-Reduction

Improved blood glucose control by insulin treatment in patients with Type 2 (non-insulin dependent) diabetes mellitus increases the risk for hypoglycaemic episodes. Our objective was to investigate if hypoglycaemia causes electrocardiographic changes and cardiac arrhythmias in patients with Type 2 diabetes. Six insulin-treated patients with Type 2 diabetes and no known cardiac disease took part in the study. Hypoglycaemia was induced by insulin infusion aiming at a plasma glucose less than or equal to 2.0 mmol l-1 or hypoglycaemic symptoms. All patients experienced hypoglycaemic symptoms. The median lowest arterial plasma glucose was 2.0 mmol l-1. Arterial plasma adrenaline concentration increased from 0.4 +/- 0.1 (mean +/- SE) to 6.9 +/- 0.3 nmol l-1 (p less than 0.001) while serum potassium was lowered from 4.1 +/- 0.3 mmol l-1 to 3.5 +/- 0.2 mmol l-1 (p less than 0.001). The heart rate increased significantly during hypoglycaemia except in one patient who developed hypoglycaemic symptoms and a severe bradyarrhythmia at a plasma glucose of 4.4 mmol l-1. One patient developed frequent ventricular ectopic beats during hypoglycaemia while four patients showed no arrhythmia. ST-depression in ECG leads V2 and V6 was observed during hypoglycaemia in five patients (p less than 0.05) and four patients developed flattening of the T-wave. In conclusion, the study supports the hypothesis that hypoglycaemia in patients with Type 2 diabetes may be hazardous by causing cardiac arrhythmias.

Topics: Arrhythmias, Cardiac; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 2; Electrocardiography; Epinephrine; Fatty Acids, Nonesterified; Humans; Hypoglycemia; Insulin; Middle Aged; Norepinephrine; Potassium

To assess the effects of gender, age, and body mass index (BMI) on suppression of plasma C-peptide during insulin-induced hypoglycemia, 101 lean and obese, healthy men and women ages 20 to 80 yr underwent infusion of human regular insulin, 0.125 U/kg over 60 min after an overnight fast. Plasma glucose, insulin, and C-peptide were measured every 30 min for 120 min. C-peptide concentrations were influenced by gender at 30 min, by BMI at baseline and both BMI and age at all subsequent time points. Because of variations in baseline plasma C-peptide concentrations, percent decrease in C-peptide was evaluated. Significantly less percent decrease of C-peptide with increased age at 30, 60, and 90 min and with increased BMI at 30 and 60 min were noted with no effect of gender. From stepwise regression analysis using multiple, additional variables only the plasma glucose concentration at 30 min made a significant, albeit small (8%), contribution to the variability in percent decrease in C-peptide at 60 min. When C-peptide responses from eight histologically confirmed insulinoma patients were contrasted to values adjusted for age, gender, and BMI of normal subjects, all insulinoma patients had abnormal responses when percent decrease in C-peptide was used, whereas only four insulinoma patients had abnormal response when actual C-peptide concentrations were used.

Topics: Adult; Aged; Aged, 80 and over; Aging; Blood Glucose; Body Mass Index; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Osmolar Concentration; Pancreatic Neoplasms; Sex Characteristics

To assess the role of catecholamines in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal humans were studied with combined alpha- and beta-adrenergic blockade and with adrenergic blockade while changes in insulin and glucagon were prevented with the islet clamp technique (somatostatin infusion with insulin and glucagon infused at fixed rates). The results were compared with those from an islet clamp alone study. In contrast to a comparison study (saline infusion), adrenergic blockade resulted in a small initial decrease in plasma glucose during exercise, from 5.0 +/- 0.2 to 4.4 +/- 0.2 mmol/l (P less than 0.01), but the level then plateaued. There was a substantial exercise-associated decrement in plasma glucose when insulin and glucagon were held constant, i.e., from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.0001), but the level again plateaued. However, when insulin and glucagon were held constant and catecholamine actions were blocked simultaneously, progressive hypoglycemia, to 2.6 +/- 0.6 mmol/l (P less than 0.001), developed during exercise. Hypoglycemia was the result of an absent increase in glucose production and an exaggerated initial increase in glucose utilization. Thus we conclude that sympathochromaffin activation plays a minor role when insulin and glucagon are operative, but a catecholamine, probably epinephrine, becomes critical to the prevention of hypoglycemia during exercise when changes in insulin and glucagon do not occur.

Topics: 3-Hydroxybutyric Acid; Adult; Blood Glucose; Blood Pressure; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Growth Hormone; Heart Rate; Humans; Hydrocortisone; Hydroxybutyrates; Hypoglycemia; Infusions, Intravenous; Insulin; Kinetics; Male; Phentolamine; Physical Exertion; Propranolol; Reference Values; Somatostatin; Time Factors

In an attempt to clarify whether circulating insulin per se exerts an inhibitory effect on the hormonal responses to hypoglycemia, with special emphasis on glucagon secretion, nine healthy volunteers were exposed to low dose (244 pmol/kg.h) and high dose (1034 pmol/kg.h) iv insulin infusions for 3 h on two separate occasions. A close to identical arterial hypoglycemia of about 3.4 mmo/L was obtained in both tests by glucose clamping during the high dose test. The corresponding glucose concentration in the venous blood was significantly lower in the high dose test (2.5 +/- 0.1 vs. 3.0 +/- 0.1 mmol/L; P less than 0.01), while the plasma free insulin level was 4 times higher in the high dose test (897 +/- 50 vs. 208 +/- 14 pmol/L). Plasma glucagon was elevated in both experiments, but its rise was reduced during the high dose test after 1 h, yielding an incremental area under the glucagon curve that was significantly smaller than that obtained during the low dose test (213 +/- 70 vs. 348 +/- 81 ng/L.h; P less than 0.05). The plasma adrenaline, noradrenaline, GH, C-peptide, pancreatic polypeptide, and somatostatin profiles were similar in the two tests. We conclude that an inhibitory effect of circulating insulin on the glucagon response to hypoglycemia can be demonstrated in normal man during an infusion of insulin yielding a plasma concentration of about 900 pmol/L. The responses of other hormones studied are not significantly influenced by the circulating insulin level.

Topics: Adult; Blood Glucose; C-Peptide; Epinephrine; Female; Glucagon; Growth Hormone; Humans; Hypoglycemia; Infusions, Intravenous; Insulin; Kinetics; Male; Norepinephrine; Pancreatic Polypeptide; Somatostatin; Time Factors

All newborn children to mothers with gestational diabetes mellitus (GDM) in the county of Orebro were investigated during a one year prospective study. Neonatal macrosomia (birthweight greater than 3 SD) was observed in 27% of children of mothers with GDM and was significantly correlated to the cord C-peptide concentration. Hypoglycaemia (B-glucose less than 1.5 mmol/l) was observed in 38% of the children, most frequently two hours after delivery. Hypoglycaemia was not more common in macrosomic children and could not be predicted by the blood glucose concentration of the mother at delivery or by the cord C-peptide level. It is concluded that mothers with GDM must be intensively treated in order to avoid the occurrence of macrosomia in their infants and that the newborn child must be carefully observed and treated in order to avoid neonatal hypoglycaemia.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Fetal Macrosomia; Glycated Hemoglobin; Humans; Hypoglycemia; Infant, Newborn; Insulin; Pregnancy; Pregnancy in Diabetics

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Eating; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Secretion; Kidney Transplantation; Pancreas Transplantation; Transplantation, Heterotopic; Transplantation, Homologous

At physiological glucose concentrations, isolated pancreatic islets release a minor portion of their newly synthesized insulin and precursors in a phase of secretion which is largely complete by 4 h of chase. Discharge during this period can be amplified by secretagogues, yet is not abolished by conditions which fully suppress regulated release from dense core secretory granules. The ability to stimulate the secretion and the biochemical profile of released proinsulin-related peptides indicate that secretion during this period originates from immature granules. The stoichiometry of release of labeled C-peptide:insulin during this phase is 1:1 at high glucose concentrations. However, at physiologic or low concentrations, C-peptide is released in molar excess of insulin as if the exocytotic vesicles carrying this secretion were budding from a post-Golgi compartment in which the lumen was composed of condensing insulin and soluble C-peptide. These findings can be explained by a model for regulated secretory protein traffic in which direct exocytosis of young granules is stimulated by higher glucose concentrations and vesicle budding from immature granules occurs at lower concentrations. Thus, insulin targeting from immature granules exhibits both regulated and constitutive-like characteristics.

Topics: Animals; C-Peptide; Cytoplasmic Granules; Glucose; Hyperglycemia; Hypoglycemia; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Precipitin Tests; Rats; Rats, Inbred Strains

The content of hormones that regulate carbohydrate metabolism was studied during the early neonatal period in 80 full-term neonates with intrauterine hypotrophy. Early application to the breast (2 to 6 hours after the birth) was shown to promote the normalization of the hormonal content. The levels of blood serum C-peptide in the newborn depend on the degree of the rise of the mother's body weight during pregnancy and the presence of toxicosis. The levels of cortisol, somatotropic hormone, immunoreactive insulin and C-peptide were determined by the degree of morphological immaturity of the tissues whereas the content of STH and cortisol by the intensity of hypotrophy as well. The moment of the birth and the early neonatal period of children with intrauterine hypotrophy is characterized by a decrease of the activity of lactate dehydrogenase, alpha-hydroxybutyrate dehydrogenase, creatine kinase and aspartate aminotransferase.

Topics: Blood Glucose; C-Peptide; Female; Fetal Growth Retardation; Growth Hormone-Releasing Hormone; Humans; Hydrocortisone; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Oxidoreductases; Pregnancy

We studied a patient with systemic lupus erythematosus and type B insulin resistance, who progressed from extreme insulin resistance to fasting hypoglycemia. The plasma insulin level was 63.3 +/- 20.9 pmol/L in the fasting state and rose above 1440 pmol/L postprandially. Intravenous administration of human insulin caused almost no decline in plasma glucose. Therefore, it was concluded that the patient was still resistant to insulin and that plasma insulin did not play a crucial role in the development of hypoglycemia. Immunoglobulin G from this patient did not inhibit insulin binding to the insulin receptor; rather, it enhanced [125I]insulin binding in both the immunoprecipitate and the in vitro binding assay to intact cells. Antiinsulin receptor antibodies strongly inhibited insulin internalization in human adipocytes, slowed down the dissociation of [125I]insulin from receptors and failed to induce down-regulation of surface insulin receptors in both the presence and absence of insulin. Finally, autoantibodies mimicked the insulin stimulatory effect on human fat cell lipogenesis even after long term exposure, but inhibited the metabolic potency of insulin when added simultaneously with the natural ligand. We conclude that antiinsulin receptor antibodies induce fasting hypoglycemia, through their continuous receptor stimulatory action, and insulin resistance, possibly by a conformational perturbation of the receptor protein, which, in turn, uncouples insulin receptor binding from receptor function.

Topics: Antibodies; Blood Cells; Blood Glucose; C-Peptide; Down-Regulation; Female; Humans; Hypoglycemia; Immunoglobulin G; Injections, Intravenous; Insulin; Insulin Resistance; Lipid Metabolism; Lupus Erythematosus, Systemic; Middle Aged; Precipitin Tests; Receptor, Insulin

To identify the circulating species of insulin after separation by high-performance liquid chromatography (HPLC) in patients with factitious hypoglycemia.. In three of four patients presented, the diagnosis of surreptitious insulin injection was made by documenting the presence of animal insulin in the circulation after separation of the circulating insulin forms by HPLC.. Animal insulin was identified.. Thus, the identification of the circulating form of insulin in the circulation by HPLC may be a useful adjunct in the diagnosis of factitious hypoglycemia if animal insulin has been injected and if the simultaneously measured concentrations of insulin and C-peptide are inconclusive.

Topics: Adult; C-Peptide; Chromatography, High Pressure Liquid; Female; Humans; Hypoglycemia; Infant; Injections, Intramuscular; Insulin

We evaluated the effect of antecedent hypoglycemia on glucose counterregulation during hypoglycemia in non-diabetic human subjects. In single hypoglycemia studies, glucose production [( 3H]3-glucose) and counterregulatory hormone concentrations were measured (after a 3.5-h baseline period of euglycemia) during 120 min of hypoglycemia (glucose clamped at 3.0 mmol/L). During the final 60 min of hypoglycemia, counterregulation resulted in significant increments in glucose production (12.88 +/- 0.83 mumol/kg.min), and plasma glucagon (IRG; 185 +/- 22 ng/L), GH (29.3 +/- 7.0 micrograms/L), cortisol (630 +/- 100 nmol/L), epinephrine (3.44 +/- 0.76 nmol/L), and norepinephrine (2.02 +/- 0.21 nmol/L). In the recurrent hypoglycemia experiment, an antecedent period of identical hypoglycemia was induced. Glucose counterregulation during the second of two periods of hypoglycemia (HYPO 2) was then compared to that in single hypoglycemia studies. During HYPO 2, there were decreased responses in Ra (by 32%; P less than 0.03), GH (by 67%; P less than 0.05), F (by 41%; P less than 0.03), and norepinephrine (by 20%; P = 0.03) compared to those in the single hypoglycemia study. In contrast, plasma IRG values were similar in the single hypoglycemia studies and HYPO 2, but were reduced relative to those during the first hypoglycemic period of recurrent hypoglycemia (IRG, 263 +/- 18 ng/L; P less than 0.025 vs. HYPO 2 and P less than 0.05 vs. single hypoglycemia). Our results suggest that 1) antecedent hypoglycemia may alter glucose counterregulation during hypoglycemia; and 2) recurrent hypoglycemia may result in alterations in reduction of hepatic glucose production.

Topics: Acclimatization; Adult; Blood Glucose; C-Peptide; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin; Kinetics; Male; Norepinephrine; Reference Values; Time Factors

Eight Type 1 (insulin-dependent) diabetic patients with no diabetic complications were studied overnight for two consecutive and one subsequent night with continuous monitoring of electroencephalogram and serial hormone measurements. The aims were: 1) to evaluate the influence of spontaneous and insulin-induced hypoglycaemia on nocturnal electroencephalogram sleep-patterns and, 2) to evaluate counter-regulatory hormone responses. Spontaneous hypoglycaemia occurred on six nights (38%) with blood glucose concentrations less than 3.0 mmol/l and on four nights less than 2.0 mmol/l. All the patients experienced insulin-induced hypoglycaemia with a blood glucose nadir of 1.6 (range 1.4-1.9) mmol/l. The electroencephalogram was analysed by a new method developed for this purpose in contrast to the traditional definition of delta-, theta-, alpha- and beta-activity. The blood glucose concentration could be correlated to the rank of individual electroencephalogram-patterns during the whole night, and specific hypoglycaemic amplitude-frequency patterns could be assigned. Three of the eight patients showed electroencephalogram changes at blood glucose levels below 2.0 (1.6-2.0) mmol/l. The electroencephalogram classes representing hypoglycaemic activity had peak frequencies at 4 and 6 Hz, respectively, clearly different from the patients' delta- and theta-activity. The changes were not identical in each patient, however, they were reproducible in each patient. The changes were found equally in all regions of the brain. The three patients with electroencephalogram changes during nocturnal hypoglycaemia could only be separated from the other five patients by their impaired glucagon responses. Against this background the possibility of protection by glucagon, against neurophysiologic changes in the brain during hypoglycaemia may be considered.

Topics: Adult; Blood Glucose; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 1; Electrocardiography; Electroencephalography; Epinephrine; Glucagon; Glycated Hemoglobin; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin Antibodies; Norepinephrine

Counterregulatory hormone responses were evaluated in a 37-yr-old woman before and after removal of a benign insulin-producing islet cell tumor. Counterregulatory hormone concentrations were measured during a glucose clamp with graded reductions of plasma glucose from 5.2 to 2.6 mmol/L. In the study before surgery, the increase in plasma epinephrine concentration was markedly blunted (by greater than 90%) compared to that in the study after surgery. The peak plasma norepinephrine concentration was similarly reduced by 71%, and plasma cortisol by 63%. In addition, the glycemic thresholds for secretion of the counterregulatory hormones were lower before removal of the tumor. Peak plasma GH responses were equivalent before and after surgery, but the threshold for GH secretion was 21% lower in the first hypoglycemia study. We conclude 1) that there is evidence for abnormal glucose counterregulatory hormone secretion in this patient, which may contribute to the pathogenesis of hypoglycemia seen in patients with insulinoma; 2) the reversal of reduced counterregulatory hormone secretion after tumor resection suggests that these defective hormonal responses may be related to recurrent hypoglycemia, persistent hyperinsulinemia, or both; and 3) that abnormal glucose counterregulation may exist in the absence of type 1 diabetes.

Topics: Adult; Blood Glucose; C-Peptide; Female; Hormones; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Postoperative Period

To characterize pancreatic endocrine secretion and to examine interrelationships among alterations in alpha, beta, and pancreatic polypeptide cell function in patients with cystic fibrosis (CF), we studied 19 patients with exocrine insufficiency (EXO), including 9 receiving insulin therapy (EXO-IT); 10 patients with no exocrine insufficiency (NEXO); and 10 normal control subjects. First-phase C-peptide response to intravenously administered glucose was significantly impaired in CF patients with exocrine insufficiency (EXO-IT = 0.02 +/- 0.01; EXO = 0.11 +/- 0.02; NEXO = 0.25 +/- 0.05; control subjects = 0.30 +/- 0.04 nmol/L). Lowering fasting glucose levels with exogenous insulin administration in EXO-IT did not improve beta cell responsivity to glucose. The C-peptide response to arginine was less impaired (EXO-IT = 0.12 +/- 0.02; EXO = 0.15 +/- 0.02; NEXO = 0.23 +/- 0.06; control subjects = 0.28 +/- 0.04 nmol/L). Alpha cell function, measured as peak glucagon secretion in response to hypoglycemia, was diminished in EXO but not NEXO (EXO-IT = 21 +/- 10; EXO = 62 +/- 19; NEXO = 123 +/- 29; control subjects = 109 +/- 12 ng/L). Despite diminished glucagon response, EXO patients recovered normally from hypoglycemia. Peak pancreatic polypeptide response to hypoglycemia distinguished CF patients with exocrine insufficiency from those without exocrine insufficiency (EXO-IT = 3 +/- 2; EXO = 3 +/- 1; NEXO = 226 +/- 68; control subjects = 273 +/- 100 pmol/L). Thus CF patients with exocrine disease have less alpha, beta, and pancreatic polypeptide cell function than CF patients without exocrine disease. These data suggest either that exocrine disease causes endocrine dysfunction in CF or that a common pathogenic process simultaneously and independently impairs exocrine and endocrine function.

Topics: Adult; Arginine; C-Peptide; Cystic Fibrosis; Fasting; Glucagon; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Insulin; Pancreas; Pancreatic Polypeptide; Time Factors

Nine patients with food-relieved hypoglycaemic symptoms, in whom insulinoma and other organic diseases presenting with hypoglycaemia had been ruled out, and nine matched controls, participated in the study. Subjects were studied during a 5-h controlled (Biostator) insulin-induced (1-2 mU kg-1 min-1) hypoglycaemic clamp. After 1 h of euglycaemia, we aimed to lower the glucose level in arterialized venous blood in a stepwise manner at 30-min intervals to 3.5, 3.0, and 2.0 mmol l-1, and to withhold these levels for a further 30 min. At euglycaemia and at the end of the latter steps, the visual reaction time and cognitive function (digit span, letter cancellation and trail making) were tested, together with recording symptoms and signs of hypoglycaemia. Counter-regulatory hormones were measured at 20-min intervals. In the patients, clinical signs and symptoms of hypoglycaemia developed at median blood glucose levels of 2.6-2.8 and 2.8-3.1 mmol l-1, respectively. By contrast, the blood glucose levels were 0.4-0.8 mmol l-1 lower in control subjects (P less than 0.05). Similarly, the median threshold for deterioration of visual reaction time was 2.8 mmol l-1 in patients and 2.1 mmol l-1 in controls (P less than 0.01). A similar trend was observed for the results of the neuropsychological tests. Visual reaction time deteriorated in all subjects, whereas the cognitive function of some of the subjects in each group remained unchanged during hypoglycaemia. The glycaemic thresholds for release of cortisol, glucagon and growth hormone were significantly higher in patients (P less than 0.05), whereas the thresholds for catecholamine release showed no significant difference from controls. Despite the comparable glucose infusion rates required to sustain each of the hypoglycaemic levels in the two groups, the control subjects achieved lower glucose levels, suggesting that there is resistance to insulin or glucose in functional hypoglycaemia. In conclusion, the present study suggests that the existence of a higher threshold for symptoms and signs, as well as for deterioration of brain function, may explain every-day hypoglycaemic symptoms, despite normal glucose levels, in subjects with functional hypoglycaemia. However, the hypothesis should be tested further using a blinded approach, including euglycaemic control studies.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Catecholamines; Cognition; Evoked Potentials, Visual; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Male; Middle Aged; Reaction Time

To assess the roles of decrements in insulin and increments in glucagon in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal young men were studied during somatostatin infusions with insulin and glucagon infused to 1) hold insulin and glucagon levels constant, 2) decrease insulin, 3) increase glucagon, and 4) decrease insulin and increase glucagon during exercise. In contrast to a comparison study (saline infusion), when insulin and glucagon were held constant, glucose production did not increase and plasma glucose decreased from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.001) initially during exercise. Notably, plasma glucose then plateaued and was 3.3 +/- 0.2 mmol/l at the end of exercise. This decrease was at most only delayed when either insulin was decreased or glucagon was increased independently. However, when insulin was decreased and glucagon was increased simultaneously, there was an initial increase in glucose production, and the glucose level was 4.5 +/- 0.2 mmol/l at 60 min, a value not different from that in the comparison study. Thus we conclude that both decrements in insulin and increments in glucagon play important roles in the prevention of hypoglycemia during exercise and do so by signaling increments in glucose production. However, since hypoglycemia did not develop during exercise when changes in insulin and glucagon were prevented, an additional counterregulatory factor, such as epinephrine, must be involved in the prevention of hypoglycemia during exercise, at least when the primary factors, insulin and glucagon, are inoperative.

Topics: 3-Hydroxybutyric Acid; Adult; Analysis of Variance; Blood Glucose; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hydroxybutyrates; Hypoglycemia; Insulin; Male; Norepinephrine; Physical Exertion; Reference Values

Glycaemic status on hospital admission was compared in 97 children with severe falciparum malaria (36 with cerebral malaria) and 89 children with other serious illnesses (32 in coma; 57 with acute pneumonia, not in coma). The frequency of hypoglycaemia (blood glucose below 2.2 mmol/l) did not differ significantly between malarial and control patients (5.2% vs 11.2%) nor between the comatose (11.1% vs 18.8%) and conscious (1.6% vs 7.0%) malarial and control subgroups. Compared with normoglycaemic patients, hypoglycaemic patients had appropriately low serum insulin (3.0 vs 8.2 mU/l) and C-peptide (0.13 vs 0.42 mmol/l) and high plasma non-esterified fatty acids (1.42 vs 0.83 mmol/l). Hypoglycaemia, the level of consciousness, and death were all significantly associated with the time since the last meal. Hypoglycaemia is not a specific complication of malaria but is found in severely ill fasted children, resulting from glycogen depletion and perhaps impaired hepatic gluconeogenesis. It should be sought in all severely sick children. A single bolus dose of glucose may not be enough to correct it.

Topics: Alanine; Blood Glucose; Brain Diseases; C-Peptide; Child; Child, Preschool; Coma; Discriminant Analysis; Eating; Evaluation Studies as Topic; Fatty Acids, Nonesterified; Glasgow Coma Scale; Humans; Hypoglycemia; Infant; Infant, Newborn; Insulin; Malaria; Prognosis; Time Factors

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Glucagon; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Radioimmunoassay; Reference Values

This study compared the effects of saccharose and glucose on the recovery from insulin hypoglycemia. 17 normal volunteers (12 men, 5 women, 25-40 years old) received the same dose (0.1 IU i.v.) of semisynthetic rapid-acting human insulin on two different days after an overnight fast. Blood glucose and C peptide were measured in venous blood samples before as well as at regular time intervals after insulin administration. 30 min after the injection, 20 g saccharose or 20 g glucose p.o. (diluted in water) were given. The mean glucose values were at most time intervals higher after glucose than after saccharose administration. In addition, glucose ingestion resulted in an earlier and steeper blood glucose rise (mean recovery rates during the first 5 min 3.10 and 1.38 mg/dl/min for glucose and saccharose, respectively). The C peptide values decreased progressively and did not achieve baseline levels even at 120 min in spite of blood sugar normalization. It is concluded that glucose acts faster than saccharose in insulin-induced hypoglycemia. Exogenous insulin results in a prolonged depression of C peptide which lasts longer than the hypoglycemic effect.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucose; Humans; Hypoglycemia; Insulin; Kinetics; Male; Sucrose

We have studied a patient with fasting hypoglycaemia and skin lesions (sign of Leser-Trélat) related to a retroperitoneal haemangiopericytoma in whom removal of the tumour resulted in immediate cure of hypoglycaemia. Before removal of the tumour, severe fasting hypoglycaemia was associated with undetectable insulin and C-peptide levels. She required 16.9 mumol/kg/min (10.4 g/h) of glucose intravenously to prevent hypoglycaemia and endogenous glucose production (measured using tritiated glucose) was suppressed to 1.3 mumol/kg/min while the whole-body glucose utilization rate was elevated at 18.2 mumol/kg/min. After removal of the tumour both endogenous glucose production rate and utilization rate returned to normal (11.5 mumol/kg/min). Resting energy expenditure, measured by indirect calorimetry, was markedly elevated at 2109 kcal/day (161% of predicted) and fell to 1205 (97% of predicted) after the tumour was removed. Glucose oxidation was also enhanced at 8.5 mumol/kg/min and fell to 3.3 mumol/kg/min after removal of the tumour. Other metabolites and hormones measured, and their response to oral glucose, were all consistent with the presence of a circulating substance with similar properties to insulin. We conclude that her hypoglycaemia resulted primarily from suppression of endogenous glucose production but also from enhanced glucose utilization. These effects were the result of a circulating growth factor sharing many metabolic effects with insulin, but with a much greater effect on resting energy expenditure and glucose oxidation.

Topics: Adult; Blood Glucose; C-Peptide; Calorimetry; Carbon Dioxide; Female; Hemangiopericytoma; Humans; Hypoglycemia; Insulin; Oxygen Consumption; Peritoneal Neoplasms

In order to evaluate effects of metabolic control on pituitary function in insulin-dependent diabetes exercise, hypoglycaemia (insulin tolerance test), thyrotrophin releasing hormone and gonadotrophin releasing hormone, tests were performed on 25 patients before (Study 1) and after 2 weeks of improved metabolic control (Study 2). Patients were sub-divided into C-peptide negative (CpN, 10 patients with no residual C-peptide secretion) and C-peptide positive (CpP, 15 patients with residual beta-cell function) groups for analysis of results. Exercise induced higher growth hormone responses in CpN patients independent of metabolic control (P less than 0.001). Thyrotrophin releasing hormone induced higher growth hormone responses in CpN patients; this response was threefold greater after improved control (P less than 0.005). Growth hormone and cortisol response to hypoglycaemia and thyroid stimulating hormone and prolactin secretion in response to thyrotrophin releasing hormone were unaffected by residual beta-cell function or metabolic control. Luteinizing hormone response to gonadotrophin releasing hormone in CpN patients was impaired and lower after improved control (P less than 0.002). The results indicate an association between residual pancreatic insulin secretory and hypothalamic/pituitary function, possibly reflecting central neurosecretion of insulin.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Exercise Test; Female; Follicle Stimulating Hormone; Humans; Hypoglycemia; Insulin; Luteinizing Hormone; Male; Pituitary Hormone-Releasing Hormones; Prolactin; Thyrotropin; Thyrotropin-Releasing Hormone

The occurrence of hyperglycaemia following a morning hypoglycaemic episode was studied in nine patients with Type 1 diabetes. Each patient was studied twice, once following induced hypoglycaemia and once in a control study when hypoglycaemia was prevented by glucose infusion. After the initial hypoglycaemic/control period the patients were maintained on their regular insulin regimens and were given standard meals. Hypoglycaemia induced postprandial hyperglycaemia (3.1 +/- 0.8 mmol l-1 above control) which lasted for about 8 h. Maximal growth hormone levels were seen 40 min after glucose nadir (control 7.8 +/- 3.2, hypoglycaemia 74.0 +/- 12.3 mU l-1) and the magnitude of the hyperglycaemia was related to the growth hormone levels following the hypoglycaemia (r = 0.80, p less than 0.01).

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Eating; Epinephrine; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hyperglycemia; Hypoglycemia; Insulin; Male

The insulinoma is the most common pancreas tumour with endocrine activity, with more than 2,000 cases being described in the literature worldwide. The first successful extirpation was performed by Graham in 1928. Clinical appearance is characterized by severe paroxysmal hypoglycaemia together with inadequately increased serum insulin levels. Surgery is indicated in such situations because of limited effectiveness of medicamentous therapy. Surgical approach and long-time results are discussed in this paper, with reference being made to 13 cases of the authors.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Female; Follow-Up Studies; Gastrins; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Neoplasm Recurrence, Local; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Reoperation

Plasma insulin-like growth factor 1 (IGF-1) concentrations were measured in a group of patients with hypoglycaemia due to endogenous hyperinsulinism, and compared with those in a group of patients matched for age and sex with hypoglycaemia and appropriately suppressed insulin levels. Insulin-like growth factor 1 concentrations were significantly higher in the hyperinsulinaemic hypoglycaemic group than in either the hypoinsulinaemic hypoglycaemia group or a group of euglycaemic control subjects. These data provide further evidence that insulin promotes IGF-1 production and release from the liver.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin-Like Growth Factor I; Male; Middle Aged; Somatomedins

Topics: Autoimmune Diseases; C-Peptide; Diabetes Mellitus; Diagnosis, Differential; Glucagon; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Radioimmunoassay; Specimen Handling

The insulin effect (6.5 to 7.5 hours) following hypoglycemia was studied with the euglycemic clamp technique in eight patients with insulin-dependent diabeteses mellitus (IDDM). The results were compared with a control study with the same insulin infusion, but where hypoglycemia was prevented by a glucose infusion. Glucose production (Ra) and utilization (Rd) were evaluated with D-(3-3H) glucose infusion. Hypoglycemia (glucose nadir, 1.5 +/- 0.1 mmol/L) caused a marked increase in cortisol and growth hormone, whereas the release of adrenaline and, in particular, glucagon was low. The plasma free insulin levels were similar in the studies, including during the clamp periods. The glucose infusion rates (GIR) were significantly lower after the hypoglycemia as compared with the control study (control, 2.4 +/- 0.3; hypoglycemia, 1.5 +/- 0.3 mg/kg x min; P less than .05). Thus, hypoglycemia induces prolonged insulin resistance. The posthypoglycemic insulin resistance during a moderate hyperinsulinemic (approximately 30 mU/L) clamp was mainly due to a decreased insulin effect on glucose utilization (control, 2.9 +/- 0.2; hypoglycemia, 2.2 +/- 0.2 mg/kg x min; P less than .02), whereas the insulin effect on glucose production was not significantly different after hypoglycemia.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Epinephrine; Female; Glucagon; Glucose; Glucose Clamp Technique; Glycated Hemoglobin; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin; Insulin Resistance; Male; Random Allocation

Insulin autoimmune syndrome is a syndrome consisting of fasting hypoglycemia, hyperinsulinemia and detectable insulin-binding antibodies in patients who have never been exposed to exogenous insulin. Four cases who developed symptoms of hypoglycemic attack with self-limited duration and spontaneous remission were collected in our hospital from 1984 to 1988. The elevated serum total and free insulin and C-peptide levels, as well as the titer of insulin autoantibodies, decreased gradually; but insulin autoantibodies were still present in the serum for more than six months after the initial episodes of hypoglycemia. Three of four patients had Graves' disease and developed the syndrome after methimazole treatment. The fourth one had a history of hemorrhagic cystitis and denied history of specific drug exposure. The cause or stimulus for insulin autoantibody formation is still unknown, but drugs containing a sulfhydryl group like methimazole may play a role in the development of the syndrome. Extremely high insulin antibodies in patients with fasting hypoglycemia along with elevated serum levels of insulin and C-peptide suggest a diagnosis of insulin autoimmune syndrome and usually exclude the possibility of insulinoma or factitious hypoglycemia.

Topics: Adult; Aged; Autoimmune Diseases; C-Peptide; Female; Humans; Hypoglycemia; Insulin Antibodies; Methimazole

Reactive (or postprandial) hypoglycemia can sometimes represent a severe disorder refractory to conventional therapeutic measures. We present in this first individual trial, to our knowledge, that the administration of a somatostatin analogue (SMS 201-995) may alleviate the severity of complaints and does not appear to be diabetogenic. The effects of the somatostatin analogue were documented in a 5-hour oral glucose tolerance test, where not only the glucose-induced and C-peptide rise was clearly attenuated, but also the blood glucose concentration did not fall low enough to induce hypoglycemic symptoms.

Topics: Blood Glucose; C-Peptide; Food; Glucose Tolerance Test; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin; Male; Middle Aged; Octreotide

Glucose potentiates arginine-induced insulin release. We investigated the dose-response characteristics for both phases of glucose-induced insulin release in normal man, and studied the influence of hyperglycemia on arginine-induced insulin secretion. Dose-response curves of plasma C-peptide increments achieved during 60-minute hyperglycemia clamps (7, 11, 17, 24, and 32 mmol/L) with and without a primed continuous infusion of arginine (infusion rate, 15 mg/kg/min) were analyzed with a modified Michaelis-Menten equation. The ED50 (half-maximally stimulating blood glucose concentration) of first-phase insulin release (determined from plasma C-peptide increments at 5 minutes) was significantly lower than the ED50 for the second phase (60 minutes; 8.4 +/- 0.8 v 14.3 +/- 1.3 mmol/L, respectively, P less than .002). Combined glucose-arginine stimulation significantly increased insulin release. Vmax of both phases of glucose-arginine-stimulated insulin release were positively correlated (r = .75, P less than .05). The ED50 of the influence of glucose on first-phase arginine-induced insulin release was significantly lower than the ED50 for the second phase (9.0 +/- 1.1 v 12.7 +/- 1.0 mmol/L, respectively, P less than .02). For each insulin secretion phase separately, the ED50 for the influence of hyperglycemia on arginine-induced insulin release were not significantly different from the ED50 for glucose-induced insulin secretion (without arginine). When dose-response curves of plasma insulin increments were analyzed with the same equation, the ED50 of second-phase glucose-induced plasma insulin increments was significantly higher than the ED50 assessed from the plasma C-peptide increments (21.6 +/- 2.8 v 14.3 +/- 1.3 mmol/L, respectively, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Arginine; C-Peptide; Dose-Response Relationship, Drug; Glucose; Humans; Hypoglycemia; Insulin; Insulin Secretion; Male

Blood glucose concentrations were measured prospectively in 27 small for dates infants in the first 48 hours after birth: 10 infants became hypoglycaemic. Of these, five had inappropriately raised plasma insulin concentrations. Plasma free fatty acids were lower and carbohydrate intake higher in these five infants, further supporting the diagnosis of hyperinsulinism. The hypoglycaemia recurred in four of the five hyperinsulinaemic infants, but in none of those who were not hyperinsulinaemic. Hyperinsulinism is common in small for dates babies. It is important to recognise this because hypoglycaemia is likely to recur and appropriate treatment is needed to prevent long term sequelae.

Topics: C-Peptide; Dietary Carbohydrates; Fatty Acids, Nonesterified; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Infant, Small for Gestational Age; Prospective Studies

To determine the frequency and outcome of hypoglycemia during diarrhea in childhood, we screened 2003 consecutive patients less than 15 years of age who were admitted to a diarrhea treatment center in Dhaka, Bangladesh. Hypoglycemia, defined as a blood glucose concentration less than 2.2 mmol per liter, was found in 91 patients (4.5 percent), 39 (42.9 percent) of whom died. We also measured the plasma concentrations of glucoregulatory hormones and gluconeogenetic substrates in 46 of the patients with hypoglycemia who were 2 to 15 years old and in 25 normoglycemic patients matched with them for age and weight. The patients with hypoglycemia had had diarrhea for less time than the normoglycemic patients (median, 12 vs. 72 hours; P less than 0.05), and their last feeding had been 18 hours before admission, as compared with 9 hours for the normoglycemic patients (P less than 0.05). The groups were similar in terms of nutritional status, the proportion of patients who had fever, and the types of pathogens recovered from stool samples. The plasma C-peptide concentrations were low (less than 0.30 nmol per liter) in all the hypoglycemic patients. As compared with the normoglycemic patients, the patients with hypoglycemia had elevated median plasma concentrations of glucagon (44 vs. 11 pmol per liter; P = 0.001), epinephrine (3400 vs. 1500 pmol per liter; P = 0.012), norepinephrine (7500 vs. 2900 pmol per liter; P = 0.002), and lactate (3.5 vs. 2.1 mmol per liter; P = 0.020) and similar alanine and beta-hydroxybutyrate concentrations. Eighteen hypoglycemic patients with severe malnutrition had been ill longer than 26 better-nourished patients with hypoglycemia (median duration of illness, 18 vs. 10 hours; P = 0.023) and had lower median plasma concentrations of lactate (1.9 vs. 3.9 mmol per liter; P = 0.021) and alanine (173 vs. 293 micromol per liter; P = 0.040). We conclude that hypoglycemia is a major cause of death in association with diarrhea. Because the glucose counterregulatory hormones were appropriately elevated in the children with diarrhea and hypoglycemia, whereas the gluconeogenetic substrates were inappropriately low, we further conclude that the hypoglycemia observed in such patients is most often due to the failure of gluconeogenesis.

Topics: Adolescent; Alanine; Aspartate Aminotransferases; Bilirubin; Blood Glucose; C-Peptide; Child; Child, Preschool; Diarrhea; Female; Fluid Therapy; Glucagon; Gluconeogenesis; Hormones; Humans; Hydroxybutyrates; Hypoglycemia; Lactates; Male

Investigation of patients with suspected or proven hypoglycemia is often a time-consuming and expensive process. We describe a glucose reduction challenge test which may be useful as an out-patient screening procedure. Insulin is infused for 3 h at 40 mU/kg.h. Plasma glucose was monitored at the bedside during the test, and blood samples were collected for measurement of C-peptide. Responses were examined in 17 normal controls, and 6 patients with insulinomas. In normal subjects, mean plasma glucose fell to a plateau value of 3.2 +/- 0.2 mmol/L (57 +/- 2.6 mg/dL) and remained at that level with few symptoms. In contrast, five of six patients with insulinomas developed severe hypoglycemia, with plasma glucose levels between 1.9 (34 mg/dL) and 2.2 mmol/L (39 mg/dL). Plasma C-peptide concentrations were suppressed to 0.08 pmol/mL or less in normal subjects, but in insulinoma patients remained at 0.32-1.6 pmol/mL i.e. outside the normal range, and diagnostic of nonsuppressible insulin secretion. These data demonstrate that moderate reduction of serum glucose maintained for a prolonged period results in marked suppression of plasma C-peptide, permitting improved discrimination between normal subjects and patients with insulinomas. This glucose reduction challenge can, therefore, be used as a test of glucose-regulating ability, where failure (hypoglycemia) per se represents a measurable abnormality. C-Peptide measurements will determine whether the cause of hypoglycemia is due to hyperinsulinemia.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diagnosis, Differential; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Resistance; Male; Middle Aged

A 42-year-old male began to show frequent hypoglycemic attacks, 25 days after total gastrectomy. By that time, he had received intravenous hyperalimentation therapy with bovine insulin. Incidence of these attacks increased despite the dose of glucose was escalated and insulin administration was interrupted. Serum C-peptide level was 11.4 ng/ml and total immunoreactive insulin (IRI) level was 1170 mu u/ml with 1120 mu u/ml (96%) of gamma-globulin-binding IRI. Since insulin antibody formation was suspected, we decreased the dose of glucose to reduce the endogenous insulin production. Consequently total IRI, binding IRI and C-peptide levels decreased, and hypoglycemic attacks disappeared. These results imply that insulin antibody, once induced by bovine insulin, binds with endogenous insulin. Therefore, it is concluded that heterogenous insulin should not be given during hyperalimentation, especially for patients with good glucose tolerance. When insulin antibody developed, it is effective to reduce the dose of glucose in order to decrease endogenous insulin production.

Topics: Adult; C-Peptide; Gastrectomy; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Male; Parenteral Nutrition, Total; Postoperative Care

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Pancreatic Neoplasms

Recently somatostatin analogues were successfully used to control insulin-induced hypoglycemia in patients with insulinoma. We observed a transient decrease in glucose levels and symptomatic hypoglycemia after administration of the long-acting somatostatin-analogue octreotide (Sandostatin) in two insulinoma patients. We studied the acute effects of octreotide (administered before breakfast) on blood glucose and gluco-regulatory hormones in these patients. In one patient, we studied the effects of glucagon replacement and changing the time of breakfast (relative to octreotide administration) on octreotide-associated changes in blood glucose and glucoregulatory hormones. Compared with control levels, octreotide therapy reduced insulin levels. During hypoglycemia glucagon and growth hormone levels were suppressed, but cortisol levels appropriately increased. The increase in catecholamine levels was normal in one patient, but markedly attenuated in the other. A transient decrease in serum glucose after octreotide was absent after glucagon replacement, but present when breakfast was taken before administration of octreotide. We conclude that in patients with insulinoma, octreotide therapy may be associated with clinically important hypoglycemia, during which counterregulatory hormone secretion may be attenuated.

Topics: Adenoma, Islet Cell; Aged; C-Peptide; Female; Glucagon; Humans; Hypoglycemia; Insulin; Insulinoma; Octreotide; Pancreatic Neoplasms

The effect of the administration of oral glucose with or without a simultaneous intravenous somatostatin infusion on blood glucose, immunoreactive insulin, C-peptide, and glucagon levels in seven patients with idiopathic postprandial hypoglycemia was studied. Oral glucose alone induced an excessive insulin response and hypoglycemia, whereas a slight suppression in glucagon levels without any increase at the hypoglycemic nadir was observed. The simultaneous administration of somatostatin significantly reduced the insulin response and induced a slower rise of blood glucose; no hypoglycemia developed. Only minor variations in glucagon were observed with respect to the basal test. A rebound in insulin, C-peptide, and glucagon levels was observed at the end of the somatostatin infusion. These data show that somatostatin can suppress glucose-induced hypoglycemia in these subjects, thus suggesting that its long-acting analogues might be worth a therapeutic trial in severe idiopathic postprandial hypoglycemia.

Topics: Adult; Blood Glucose; C-Peptide; Female; Food; Glucagon; Glucose; Humans; Hypoglycemia; Insulin; Middle Aged; Somatostatin

To test the hypothesis that growth hormone secretion plays a counterregulatory role in prolonged hypoglycemia in humans, four studies were performed in nine normal subjects. Insulin (15 mU.M-2.min-1) was infused subcutaneously (plasma insulin 27 +/- 2 microU/ml), and plasma glucose decreased from 88 +/- 2 to 53 +/- 1 mg/dl for 12 h. In study 1, plasma glucose, glucose fluxes (D-[3-3H]glucose), substrate, and counterregulatory hormone concentrations were simply monitored. In study 2 (pituitary-adrenal-pancreatic clamp), insulin and counterregulatory hormone secretions (except for catecholamines) were prevented by somatostatin (0.5 mg/h iv) and metyrapone (0.5 g/4 h po), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of growth hormone increase), the pituitary-adrenal-pancreatic clamp was performed with maintenance of plasma growth hormone at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. Isolated lack of a growth hormone response caused a decrease in hepatic glucose production and an increase in glucose utilization that resulted in an approximately 25% greater hypoglycemia despite compensatory increases in plasma catecholamines. Plasma free fatty acid, 3-beta-hydroxybutyrate, and glycerol concentrations were reduced approximately 50%. It is concluded that growth hormone normally plays an important counterregulatory role during hypoglycemia by augmenting glucose production, decreasing glucose utilization, and accelerating lipolysis.

Topics: Adult; Alanine; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Glycerol; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin; Male; Metyrapone; Norepinephrine; Reference Values; Somatostatin

To dissect the mechanisms of the prevention of hypoglycemia during fasting, eight normal humans were studied after overnight and 3-day fasts. Prolonged fasting resulted in the expected decrements in base-line glucose production and plasma glucose, insulin, and C-peptide and increments in plasma glucagon, epinephrine, norepinephrine, growth hormone, and cortisol. After the overnight and 3-day fasts, insulin restoration (0.2 mU.kg-1.min-1) alone resulted in transient decrements in glucose production and only 15 and 19% decrements in plasma glucose, respectively. Selective glucagon deficiency (somatostatin infusion with insulin and growth hormone replacement) resulted in transient decrements in glucose production and additional 24 and 29% decrements in plasma glucose, respectively. Notably, plasma glucose plateaued under both fasting conditions in both instances. Combined alpha- and beta-adrenergic blockade (phentolamine and propranolol infusions) alone had no effect on glycemia under either fasting condition. However, progressive hypoglycemia developed during adrenergic blockade coupled with glucagon deficiency after the overnight fast (85 +/- 2 to 48 +/- 4 mg/dl, P less than 0.001) and after the 3-day fast (65 +/- 2 to 33 +/- 1 mg/dl, P less than 0.001). These were the result of both decrements in glucose production and increments in glucose clearance. Thus we conclude that during fasting 1) the prevention of hypoglycemia is not due solely to decreased insulin secretion. 2) Glucagon plays a primary counterregulatory role. Sympathochromaffin catecholamines are not normally critical but compensate and become critical when glucagon is deficient. Adrenomedullary epinephrine is probably the relevant catecholamine. 3) Other hormones, neurotransmitters, or substrate effects may, or may not, be involved; if they are, they appear to stand low in the hierarchy of glucoregulatory factors.

Topics: Adult; Blood Glucose; C-Peptide; Catecholamines; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin; Lactates; Lactic Acid; Male

Antiinsulin receptor antibodies were detected in the serum of a patient with insulin-resistant diabetes. Fasting hypoglycemia and postprandial hyperglycemia recurred every day. The plasma insulin level was 553 +/- 359 pmol/L [77 +/- 50 microU/mL (mean +/- SD)] in the fasting state and rose above 7500 pmol/L postprandially. The glycemic clamp at 2.8 mmol/L (50 mg/dL) without insulin infusion revealed that the half-life of plasma endogenous insulin was 173 min, indicating severely impaired plasma insulin clearance. During the clamp the glucose infusion rate was almost constant (0.9-1.2 mg/kg.min) despite an exponential decline in the plasma insulin level from 460 pmol/L (65 microU/mL) to 129 pmol/L (18 microU/mL). Intravenous insulin administration did not appreciably accelerate the basal constant decrease in the plasma glucose level during the postabsorptive period. These results indicate the coexistence of marked insulin resistance and constant ability to decrease plasma glucose level. In in vitro experiments, antireceptor immunoglobulin G from this patient increased the fructose 2,6-bisphosphate concentration in the presence of glucagon (less than 0.1 nmol/L) in primary cultured rat hepatocytes. The antireceptor immunoglobulin G stimulated autophosphorylation of rat liver insulin receptor. We conclude that antiinsulin receptor antibodies could impair plasma insulin clearance, resulting in persistent hyperinsulinemia, and that continuous receptor stimulation by the antibodies was responsible for the development of hypoglycemia.

Topics: Animals; Antibodies, Anti-Idiotypic; Blood Glucose; C-Peptide; Cells, Cultured; Eating; Fasting; Fructosediphosphates; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Immunoglobulin G; Insulin; Liver; Male; Middle Aged; Phosphorylation; Rats; Rats, Inbred Strains; Receptor, Insulin

Disopyramide is a group I antiarrhythmic drug which is mainly used for the treatment of ventricular and supraventricular rhythm disturbances. Commonest side effects result from disopyramide's anticholinergic activity. Other side effects such as hypoglycemia have been reported less frequently. We report one observation of disopyramide induced hypoglycemia, and a review of the literature is presented. Including our observation, 14 cases (9 men and 5 women, aged from 41 to 88) have so far been reported. Doses of disopyramide ranged from 200 to 1,200 mg per day, administered from one day to one year. Symptomatology was mainly neurologic (12 patients) and two patients were clinically asymptomatic. The outcome was favorable in all but the 2 patients who died with persistent hypoglycemia after a single dose of 250 mg in one patient and after 400 mg daily during 4 days in the other (without stopping the drug). Renal function was markedly impaired in 9 patients, two of these patients being on a long term dialysis therapy. Blood levels of disopyramide were measured in 7 patients and ranged from 1 to 11.4 ng/ml. In five patients it was in the normal range (1-4 ng/ml). Three patients were rechallenged for disopyramide: hypoglycemia occurred in all, without clinical symptoms in two of them. The main risk factors of disopyramide induced hypoglycemia are a preexisting chronic renal failure, advanced age, and malnutrition. In these patients normally non toxic disopyramide blood levels, as defined in normal subjects, seem to be inappropriately high. We suggest that in patients at risk, disopyramide blood levels should be maintained at the lower range of therapeutic level.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Blood Glucose; C-Peptide; Disopyramide; Humans; Hypoglycemia; Insulin; Kidney Failure, Chronic; Male

Circulating insulin antibodies at birth and the degree of maternal metabolic control were measured in 68 infants of insulin-treated diabetic mothers. Their correlation with neonatal B cell function and with the clinical features of the infants was evaluated in order to better understand their influence on fetal outcome. Maternal metabolic control was assessed on the basis of blood glucose levels, glycosuria and the occurrence of hypoglycemia and/or ketonuria. All infants were clinically evaluated for gestational age, macrosomia, hypoglycemia, hyperbilirubinemia, hypocalcemia, and respiratory distress syndrome. Cord blood plasma glucose, C peptide, and IgG insulin antibodies were also measured. It was shown that poor maternal metabolic control was associated with a higher prevalence of fetal morbidity as well as with signs of B cell hyperfunction. Also the presence of circulating insulin antibodies correlated well with higher C peptide levels and with several neonatal complications. B cell hyperfunction, indicated by high C peptide levels in the infants of diabetic mothers, may possibly play a causal role in the pathogenesis of fetal morbidity. In conclusion, a good fetal outcome in insulin-treated diabetic pregnancies was associated with and may have depended upon: (1) good maternal metabolic control, and (2) absence or low levels of circulating insulin antibodies.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Fetal Blood; Glycated Hemoglobin; Glycosuria; Humans; Hypoglycemia; Immunoglobulin G; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Insulin Antibodies; Islets of Langerhans; Ketone Bodies; Pregnancy; Pregnancy in Diabetics

We previously found that patients with hypoglycemia due to chronic renal and liver disease had anomalous metabolic responses to glucose and glucagon stimulation. In this study we evaluated the use of glucagon (2 mg, iv) tests in the diagnosis of spontaneous hypoglycemia secondary to hepatocellular carcinoma (HCC) and insulinoma. Twenty-one normal subjects, 45 patients with HCC (11 with hypoglycemia), and 14 patients with insulinoma (all with hypoglycemia) were studied. The fasting blood glucose level was low in all patients with hypoglycemia. The fasting plasma insulin and C-peptide concentrations were high in patients with insulinoma and low in patients with HCC and hypoglycemia. The blood glucose responses to glucagon administration were less than normal in patients with HCC and hypoglycemia and within normal limits in patients with insulinoma. The insulinoma patients had increased plasma insulin and C-peptide responses to glucagon despite having low blood glucose levels. Compared with the HCC patients without hypoglycemia, HCC patients with hypoglycemia had impaired plasma insulin and C-peptide responses. The fasting hypoglycemia, hypoinsulinemia, and impaired insulin/C-peptide responses to glucagon in patients with hepatoma and hypoglycemia presumably reflect the production of insulin-like substances by the hepatoma. We conclude that glucagon administration results in characteristic responses in these groups of patients and can be of use in the diagnosis of spontaneous hypoglycemia secondary to hepatoma or insulinoma.

Topics: Adenoma, Islet Cell; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Carcinoma, Hepatocellular; Female; Glucagon; Humans; Hypoglycemia; Insulin; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms

Initially reported in Japan, autoimmune hypoglycemia is related to the presence of insulin-binding antibodies, even in patients who have never been treated with insulin. The authors report a case of spontaneous autoimmune hypoglycemia in a French woman receiving pyritinol. The difference between insulin and C peptide radioimmunoassay levels prompted a search for insulin antibodies. In vitro studies confirmed their presence and showed that they were immunoglobulins G with two binding sites without species specificity. The outcome of autoimmune hypoglycemia is usually favourable, with a rapid decrease of insulin antibodies but steroid therapy is needed when serious clinical manifestations are present. The differential diagnosis with factitious hypoglycemia may be difficult. The reasons for the appearance of the insulin antibodies and the exact mechanisms of hypoglycemia remain hypothetical. However, drugs with a sulfhydril group, such as pyritinol, could play a causative role in this syndrome.

Topics: Aged; Aged, 80 and over; Autoimmune Diseases; Blood Glucose; C-Peptide; Female; Humans; Hypoglycemia; Immunoglobulin G; Insulin; Insulin Antibodies; Pyridines; Pyrithioxin

We measured 14C-alanine conversion to 14C-glucose (an index of gluconeogenesis) and glucose production in six healthy volunteers during low-dose insulin infusion (0.3 mU/kg.min for four hours). Insulin rose from 7 +/- 2 to 20 +/- 2 microU/mL, and plasma glucose fell to a plateau of 65 to 70 mg/dL after 60 minutes. Glucagon and catecholamines increased after 60 minutes, whereas C-peptide decreased immediately. Glucose production decreased transiently by 43% and then returned to baseline after 45 minutes. In contrast, 14C-alanine conversion to 14C-glucose was unchanged for 120 minutes, but then rose twofold above baseline by 240 minutes. Our data suggest that early recovery of glucose production during mild hyperinsulinemia occurs independent of changes in gluconeogenesis. However, gluconeogenesis plays an increasingly more important role in maintaining glucose production when mild hypoglycemia is prolonged.

Topics: Adult; Alanine; Blood Glucose; C-Peptide; Female; Gluconeogenesis; Humans; Hypoglycemia; Insulin; Liver Glycogen; Male; Time Factors

The mechanisms of sc insulin absorption are not understood, and models for interpreting in vivo data cannot be developed without gross simplification. To overcome this difficulty we developed a new approach which makes use of deconvolution analysis and does not require any model of the sc tissue. In five normal subjects and seven insulin-dependent diabetic (IDDM) patients endogenous insulin secretion was suppressed by means of a hypoglycemic glucose clamp procedure (approximately 2.8 mmol/L) sustained by a continuous insulin infusion (approximately 4 pmol/min.kg). A bolus injection of insulin (5.4 nmol) was administered iv, and plasma insulin concentrations were measured frequently for 2 h to assess iv insulin kinetics. Insulin then was injected sc in the abdominal region, and plasma insulin concentrations were measured for 8 h. Each subject was studied twice, with porcine and semisynthetic human insulin (Actrapid, Novo). The rate of insulin absorption was reconstructed by deconvolution from the plasma concentrations and iv insulin kinetic data. Linearity of the iv insulin kinetics, essential for deconvolution analysis, was confirmed by a dose-response study in the range of the measured concentrations (150-1800 pmol/L). In most instances, a two-compartment model was adequate to describe the iv response. The mean plasma insulin clearance rates were 15.5 +/- 1.9 (+/- SD) mL/min.kg (porcine) and 17.2 +/- 6.0 (human) in normal subjects and 20.7 +/- 8.8 (porcine) and 20.9 +/- 9.1 (human) in the IDDM patients. The rate of appearance of human insulin from sc tissue was faster than that of porcine insulin in both normal and IDDM subjects, but no significant differences were found in bioavailability, which was 55 +/- 12% (+/- SD; porcine) and 61 +/- 34% (human) in the normal subjects, and 84 +/- 28% (porcine) and 86 +/- 23% (human) in the IDDM patients. The rate of absorption and bioavailability were higher in the IDDM patients than in the normal subjects, a difference possibly related to increased sc blood flow in the IDDM patients. No differences were found with regard to glucose requirement values, normalized to plasma insulin concentrations, in agreement with the finding that the bioavailability of the two insulin species was similar.

Topics: Adolescent; Adult; Animals; Biological Availability; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemia; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Male; Swine

In this paper the Authors describe a case of factitious hypoglycemia in a 30-year-old nurse who came to the practitioner saying she was drug-addict. A careful history and the clinical examinations showed that the symptoms were due to hypoglycemic episodes. The finding of high plasma insulin levels together with low plasma C-peptide concentrations enabled us to exclude organic causes of hypoglycemia, suggesting the diagnosis of factitious hypoglycemia. After the patient was told we suspected a case of factitious hypoglycemia, the symptoms disappeared.

Topics: Adult; Blood Glucose; C-Peptide; Factitious Disorders; Female; Humans; Hypoglycemia; Insulin; Nursing Assistants

Controversy exists over differences in hormonal counterregulatory (CR) responses to human and porcine insulins with conflicting reports regarding the adrenaline, glucagon, growth hormone, cortisol and prolactin responses to the two species of insulin. It has been suggested that these differences may represent different central nervous system sensitivities to the two types of insulin. The CR responses to an intravenous bolus of 0.1 U/kg of neutral soluble semi-synthetic (SSHI) and biosynthetic (BHI) human insulins, porcine insulin and diluting medium as control were compared in six fasted normal male subjects. The plasma glucose fell similarly with all three insulins reaching a mean nadir of 1.5 +/- 0.2 mmol/l at 25 min. Peak responses to porcine, SSHI and BHI, respectively were: adrenaline--523 +/- 101, 424 +/- 62, 379 +/- 76 pg/ml; glucagon--0.064 +/- 0.01, 0.063 +/- 0.01, 0.078 +/- 0.01 nmol/l; cortisol--507 +/- 42, 539 +/- 65, 507 +/- 42 nmol; growth hormone--76 +/- 10, 76 +/- 5, 64 +/- 15 mU/l; prolactin--507 +/- 72, 608 +/- 103, 523 +/- 118 mU/l. These differences in CR response were not statistically significant. The results do not support the suggestion of a different hormonal counterregulatory response or central nervous system sensitivity to human and porcine insulins when administered by intravenous bolus injections to normal subjects.

Topics: Adult; Blood Glucose; C-Peptide; Epinephrine; Glucagon; Growth Hormone; Hormones; Humans; Hydrocortisone; Hypoglycemia; Insulin; Insulin, Regular, Pork; Male; Prolactin; Reference Values

The role of epinephrine in platelet activation and the effect of an alpha 2-adrenoceptor antagonist, midaglizole, during insulin-induced hypoglycaemia in Type 2 (non-insulin-dependent) diabetes mellitus were examined. The action of midaglizole as a platelet alpha 2-antagonist was confirmed by in vitro studies using platelet-rich plasma and washed platelet suspension. Hypoglycaemia was induced by a bolus injection of short-acting insulin in 24 diabetic patients. They were divided into two groups, a control group (n = 12) and an alpha 2-group (n = 12), and midaglizole was administered orally 60 min before insulin injection in the latter. Blood glucose and plasma C-peptide levels were significantly decreased (p less than 0.005) by insulin injection in both groups. Counter-regulatory hormones, including epinephrine, and arginine vasopressin were similarly increased at the hypoglycaemic nadir compared with the levels at 0 min in both groups. Plasma beta-thromboglobulin was increased at the hypoglycaemic nadir (165.5 +/- 12.6 ng/ml) compared with the level at 0 min (121.0 +/- 11.5, p less than 0.005) in the control group, whereas no significant increase was demonstrated in the alpha 2-group. These results suggest that plasma epinephrine plays an important role in platelet activation during hypoglycaemia in Type 2 diabetes mellitus, and that the platelet activation is prevented by alpha 2-adrenoceptor antagonist.

Topics: Arginine Vasopressin; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Epinephrine; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Imidazoles; In Vitro Techniques; Insulin; Male; Middle Aged; Platelet Aggregation; Reference Values

A direct radioimmunoassay in unextracted plasma is described. The assay has a sensitivity of 4 pmol/l (2 standard deviation from zero). The proinsulin antiserum was immuno-adsorbed against human C-peptide and insulin coupled to glass beads. Cross-reactivity of the antiserum was assessed and shown to be less than 0.01% with both peptides. In normal healthy fasting subjects the plasma proinsulin level was 6.7 +/- 1.7 pmol/l (n = 17) (mean +/- SD). Fasting proinsulin levels in non-insulin dependent diabetics were significantly elevated compared with non diabetics (14.2 +/- 2 pmol/l (n = 11) vs 6.7 +/- 1.7 (n = 17) P less than 0.005). The insulin/proinsulin ratio was 3.4:1 in the non-insulin dependent diabetic compared with 6:1 in non-diabetics. Samples from 21 insulinoma patients were assayed and mean fasting plasma proinsulin level was 255 pmol/l +/- 479 when the patients were hypoglycaemic. The range in pro-insulin levels was large (30-2300 pmol/l). Mean fasting proinsulin level in three hypoglycaemic subjects due to sulphonylurea overdose was 15.7 +/- 2.3 pmol/l. The molar ratio of proinsulin to insulin was 1:6 in healthy subjects, 1:1 in insulinoma patients and 10:1 in sulphonylurea induced hypoglycaemic patients.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin; Radioimmunoassay; Sensitivity and Specificity

Ten patients had factitious hypoglycemia due to surreptitious insulin injections diagnosed and were followed for up to 15 years (median, 5 years; range, 2 months to 15 years). When available, demonstration of anti-insulin antibodies was the most helpful diagnostic test. Decreased plasma C-peptide levels corroborated the diagnosis. Young women (nine of ten) with knowledge of the medical profession or relatives with diabetes mellitus predominated in the sample. Five of the patients had a history of insulin-requiring diabetes mellitus. Two patients eventually committed suicide despite the best efforts at therapy. Only three of ten patients made a successful transition into productive life after the diagnosis of factitious hypoglycemia was established. Factitious hypoglycemia remains a difficult diagnosis to make, and the long-term outcome after the diagnosis is established is unpredictable. All efforts have to be made to confirm the diagnosis before the patients are approached. The confrontation is to be made by an experienced team of health care professionals who have gained the patient's confidence through an understanding but firm manner. Long-term therapy must be planned and initiated before the patient's discharge.

Topics: Adult; C-Peptide; Factitious Disorders; Female; Follow-Up Studies; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Male

Hypoglycaemia (blood glucose 1.3-2.5 mmol/l) was induced in twenty-eight diabetic children by reduction of their morning meal. Fatigue and pallor were the most common signs of hypoglycaemia. Compared to findings during normoglycaemia, plasma concentrations of adrenalin, noradrenalin and cortisol were significantly higher at glucose nadir. Plasma glucagon concentration at glucose nadir was correlated to the fasting C-peptide concentration and inversely to the duration of diabetes. Children who lacked C-peptide also lacked glucagon response to hypoglycaemia. The parents' opinion of the need to give carbohydrates corresponded to the blood glucose level. The presence of adrenergic signs correlated to the plasma adrenalin and the neuroglucopenic signs to blood glucose. The lowest glucose level correlated inversely to the concentration of free insulin. When facilities for glucose infusion are lacking, a rational step in treating the unconscious hypoglycaemic child seems to be the injection of glucagon, considering the blunted or absent glucagon secretion.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Epinephrine; Female; Humans; Hydrocortisone; Hypoglycemia; Insulin; Male; Norepinephrine

The diagnosis of insulinoma on the basis of persistent hypoglycemia requires further confirmation. The insulin suppression test has been used to support this diagnosis prior to surgical intervention. In this study the euglycemic clamp technique was used to compare five control volunteers with four hypoglycemic patients with suspected insulinoma. Insulin was infused over successive two-hour periods at 2, 4, and 8 mU/kg/min. Plasma glucose levels were clamped at 80 mg/dL (4.4 mmol/L) using an artificial pancreas. High insulin levels were measured in all subjects, ranging from 225 +/- 30 microU/mL (1614 +/- 215 pmol/L) to 1018 +/- 239 microU/mL (7304 +/- 1714 pmol/L). Levels of C peptide fell to 0.1 ng/mL (0.028 nmol/L) in control subjects but remained at high levels in the patients. Insulinoma was confirmed on laparotomy in all four patients. In two patients tested after removal of the tumor the results were found to have returned to normal.

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Infusion Systems; Insulinoma; Pancreatic Neoplasms

Exercise-induced hypoglycemia in diabetic patients on sulfonylurea treatment is not uncommon. However, its pathophysiology has not been examined. We studied 9 postabsorptive nondiabetic subjects after oral administration of 1.75 mg glyburide (glibenclamide) (protocol A), during 60 min of leg exercise on a bicycle ergometer at a work load of 80 +/- 10 W (protocol B), and during a combination of these conditions (protocol C). Serum glibenclamide levels rose to similar levels (160 ng/ml) with protocols A and C. Heart rate, blood pressure, and blood lactate levels increased immediately after onset of exercise and were comparable under conditions of protocols B and C. Serum insulin levels fell during protocol B from 6.1 +/- 0.6 to 4.0 +/- 0.3 microU/ml (P less than .001) but increased from 6.5 +/- 0.6 to 12.3 +/- 2.8 microU/ml during protocol A and from 6.6 +/- 0.6 to 12.7 +/- 4.3 microU/ml during protocol C, P less than .001. Maximal levels were reached at 80 min under both conditions. Comparable responses were seen for serum C-peptide concentrations. Blood glucose concentrations did not change during exercise alone. Glycemia decreased markedly after administration of the drug reaching a nadir of 49 +/- 3 mg/dl with protocol A and a nadir of 46 +/- 3 mg/dl under protocol C. However, the nadir was reached 80 min after oral ingestion of the drug when exercise and glyburide were combined, compared to 110 min (P less than .01) after ingestion of the drug alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; C-Peptide; Glucagon; Glyburide; Humans; Hypoglycemia; Insulin; Kinetics; Lactates; Lactic Acid; Male; Physical Exertion

A 43-year-old woman with spontaneous episodes of neuroglycopenic hypoglycemia was found to have immune-mediated thrombocytopenic purpura and primary biliary cirrhosis. Hypoglycemia along with hyperinsulinemia suggested insulinoma. Serum c-peptide levels were disproportionately low, raising the possibility of factitious hypoglycemia. The patient's plasma contained circulating insulin receptor autoantibodies, thought to cause hypoglycemia by their insulin-like actions. With prednisone therapy, her other autoimmune features improved, and the hypoglycemia eventually resolved. Hypoglycemia mediated by insulin receptor autoantibodies should be considered in patients with fasting hypoglycemia and features suggesting an underlying autoimmune disorder before pursuing more invasive procedures. High-dose steroids may be life-saving in this disorder.

Topics: Adult; Autoantibodies; Autoimmune Diseases; C-Peptide; Diagnosis, Differential; Fasting; Female; Humans; Hypoglycemia; Insulin; Liver Cirrhosis, Biliary; Prednisone; Receptor, Insulin; Syndrome; Thrombocytopenia

A soluble-phase proinsulin assay has been developed which does not require solid-phase antibody-binding. A human proinsulin standard curve is prepared in insulin-free and proinsulin-free plasma for comparison with unknown plasma samples. Proinsulin and insulin are bound with excess anti-insulin antiserum, and free C-peptide is removed by charcoal adsorption. The supernatant is then assayed using a routine C-peptide radioimmunoassay which utilises anti-C-peptide antiserum. The sensitivity of the assay (2 standard deviations above zero) is 9 pmol/L using 200 microL plasma sample. The assay is free from insulin cross-reactivity up to 100 mU/L and C-peptide up to 2000 pmol/L. Between-assay CV is 13% at 100 pmol/L. The assay has been used in subjects with hypoglycaemia of various aetiologies and has shown that a raised plasma proinsulin in the presence of hypoglycaemia can occur in sulphonylurea-induced and reactive hypoglycaemia as well as in insulinomas. After hyperglycaemic clamps at 7.5, 10 and 15 mmol/L glucose, type II diabetics both on and off sulphonylurea, were found to have lower proinsulin concentrations compared with normal subjects, commensurate with the diabetics' lower insulin responses.

Topics: Adult; Antibody Specificity; C-Peptide; Diabetes Mellitus; Female; Humans; Hypoglycemia; Immune Sera; Insulin; Male; Proinsulin; Radioimmunoassay; Reference Standards

Surreptitious self-administration of insulin is an important cause of hypoglycemia. A 28-year-old female hospital ward clerk presented with hypoglycemia associated with an elevated plasma insulin level and a low plasma C-peptide concentration. Factitious illness was denied by the patient until it was definitively proven by using a species-specific insulin radioimmunoassay that the type of insulin circulating at the time of hypoglycemia was of animal rather than of human origin. The differential diagnosis of hypoglycemia associated with hyperinsulinemia and the current laboratory methods which may be employed to distinguish between factitious hypoglycemia and endogenous hyperinsulinism are discussed.

Topics: Adult; Animals; Blood Glucose; C-Peptide; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Radioimmunoassay; Species Specificity; Sulfonylurea Compounds

Nineteen normal male volunteers underwent a 10-h glucose clamp study to examine the duration and mechanism of insulin resistance after hypoglycaemia. Dextrose delivery by the Biostator to maintain the target blood glucose level fell below baseline 2 h after induction of hypoglycaemia and remained suppressed for at least 7 h after insulin hypoglycaemia. Insulin secretion as manifested by C-peptide levels remained suppressed for 3-4 h after insulin hypoglycaemia despite return of blood glucose to baseline by 90 min. Glucose kinetic data (3-3H-glucose) performed in six of the subjects indicated that the prolonged insulin resistance was due to significantly increased hepatic glucose production and to suppressed glucose utilisation, persisting for at least 4 h after counterregulatory hormone levels had returned to normal. Post-hypoglycaemic insulin resistance as determined by dextrose delivery was markedly attenuated and the rise in hepatic glucose output totally eliminated in five hypopituitary subjects without growth hormone or cortisol responses to hypoglycaemia. We conclude that post-hypoglycaemic insulin resistance occurs in non-diabetic subjects and persists for at least 7 h following hypoglycaemia. This prolonged insulin resistance is largely related to release of growth hormone and cortisol.

Topics: Adult; C-Peptide; Glucose; Humans; Hypoglycemia; Hypopituitarism; Insulin; Insulin Resistance; Male; Time Factors

To define glycemic thresholds for activation of glucose counterregulatory systems and for symptoms of hypoglycemia, we measured these during stepped reductions in the plasma glucose concentration (in six 10-mg/dl hourly steps) from 90 to 40 mg/dl under hyperinsulinemic clamp conditions, and compared these with the same measurements during euglycemia (90 mg/dl) under the same conditions over 6 h in 10 normal humans. Arterialized venous plasma glucose concentrations were used to calculate glycemic thresholds of 69 +/- 2 mg/dl for epinephrine secretion, 68 +/- 2 mg/dl for glucagon secretion, 66 +/- 2 mg/dl for growth hormone secretion, and 58 +/- 3 mg/dl for cortisol secretion. In contrast, the glycemic threshold for symptoms was 53 +/- 2 mg/dl, significantly lower than the thresholds for epinephrine (P less than 0.001), glucagon (P less than 0.001), and growth hormone (P less than 0.01) secretion. Thus, the glycemic thresholds for activation of glucose counterregulatory systems during decrements in plasma glucose lie within or just below the physiologic plasma glucose concentration range, and are substantially higher than the threshold for hypoglycemic symptoms in normal humans. These findings provide further support for the concept that glucose counterregulatory systems are involved in the prevention, as well as the correction, of hypoglycemia.

Topics: 3-Hydroxybutyric Acid; Adult; Blood Glucose; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hydroxybutyrates; Hypoglycemia; Insulin; Lactates; Lactic Acid; Male; Norepinephrine

This report describes a case of homicide by insulin administration and a study of the effects of storage conditions on insulin in serum. The study revealed insulin to be remarkably stable at refrigerator temperatures. Therefore, for forensic science purposes, insulin immunoassay data are interpretable even when serum is not stored by the standard laboratory method of freezing.

Topics: C-Peptide; Homicide; Humans; Hypoglycemia; Insulin; Male; Middle Aged

To compare glucose counterregulatory mechanisms during short-term hypoglycemia and prolonged hypoglycemia, insulin was infused either intravenously (160 mU X M-2 X min) for 10 min or subcutaneously (15 mU X M-2 X min) for 12 h in normal volunteers. With each type of insulin infusion, hypoglycemia (approximately 50 mg/dl) was either allowed to develop or was prevented (control experiments) by the glucose-clamp technique. During prolonged hypoglycemia, both increased glucose production (1.55 +/- 0.05 versus 0.33 +/- 0.14 mg X kg-1 X min in control experiments at 12 h, P less than 0.01) and suppressed glucose utilization (1.55 +/- 0.06 versus 3.17 +/- 0.15 mg X kg-1 X min in control studies at 12 h, P less than 0.01) were involved in counterregulation. During short-term hypoglycemia, only increased glucose production (3.23 +/- 0.33 versus 0.06 +/- 0.03 mg X kg-1 X min in control experiments at 60 min) was involved, since glucose clearance actually increased (3.99 +/- 0.20 versus 2.88 +/- 0.02 ml X kg-1 X min in control experiments at 60 min, P less than 0.01). Estimated portal venous insulin concentrations decreased 40% (basal 24 +/- 3 versus 14 +/- 1 mU/ml at 60 min, P less than 0.01) in the short-term hypoglycemia experiments but remained at basal levels (basal 25 +/- 1 versus approximately 26 microU/min between 1 and 12 h) during prolonged hypoglycemia. Despite the fact that hypoglycemia was more gradually induced in the prolonged hypoglycemia model, peak counterregulatory hormone responses were at least as great as those during short-term hypoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Alanine; Blood Glucose; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glycerol; Humans; Hypoglycemia; Insulin; Lactates; Lactic Acid; Male; Norepinephrine; Somatostatin

Factitious hypoglycemia is similar in presentation to insulinoma and occurs most commonly in persons with ready access to insulin. Diagnosis previously was based on circumstantial evidence but now can be confirmed by demonstration of high insulin levels and low C-peptide levels in the presence of hypoglycemia. Treatment is primarily psychiatric, and success so far is limited.

Topics: Adult; Blood Glucose; C-Peptide; Factitious Disorders; Female; Humans; Hypoglycemia; Insulin; Middle Aged; Self Administration; Substance-Related Disorders

During mild or moderate nonexhausting exercise, glucose utilization increases sharply but is normally matched by increased glucose production such that hypoglycemia does not occur. To test the hypothesis that redundant glucoregulatory systems including sympathochromaffin activation and changes in pancreatic islet hormone secretion underlie this precise matching, eight young adults exercised at 55-60% of maximal oxygen consumption for 60 min on separate occasions under four conditions: (a) control study (saline infusion); (b) islet clamp study (insulin and glucagon held constant by somatostatin infusion with glucagon and insulin replacement at fixed rates before, during and after exercise with insulin doses determined individually and shown to produce normal and stable plasma glucose concentrations prior to each study); (c) adrenergic blockage study (infusions of the alpha- and beta-adrenergic antagonists phentolamine and propranolol); (d) adrenergic blockade plus islet clamp study. Glucose production matched increased glucose utilization during exercise in the control study and plasma glucose did not fall (92 +/- 1 mg/dl at base line, 90 +/- 2 mg/dl at the end of exercise). Plasma glucose also did not fall during exercise when changes in insulin and glucagon were prevented in the islet clamp study. In the adrenergic blockade study, plasma glucose declined initially during exercise because of a greater initial increase in glucose utilization, then plateaued with an end-exercise value of 74 +/- 3 mg/dl (P less than 0.01 vs. control). In contrast, in the adrenergic blockade plus islet clamp study, exercise was associated with glucose production substantially lower than control and plasma glucose fell progressively to 58 +/- 7 mg/dl (P less than 0.001); end-exercise plasma glucose concentrations ranged from 34 to 72 mg/dl. Thus, we conclude that: (a) redundant glucoregulatory systems are involved in the precise matching of increased glucose utilization and glucose production that normally prevents hypoglycemia during moderate exercise in humans. (b) Sympathochromaffin activation, perhaps sympathetic neural norepinephrine release, plays a primary glucoregulatory role by limiting glucose utilization as well as stimulating glucose production. (c) Changes in pancreatic islet hormone secretion (decrements in insulin, increments in glucagon, or both) are not normally critical but become critical when catecholamine action is deficient. (d) Glucoregulation fails, and

Topics: 3-Hydroxybutyric Acid; Adult; Alanine; Blood Glucose; C-Peptide; Chromaffin System; Epinephrine; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glycerol; Growth Hormone; Homeostasis; Humans; Hydrocortisone; Hydroxybutyrates; Hypoglycemia; Insulin; Islets of Langerhans; Lactates; Lactic Acid; Male; Norepinephrine; Physical Exertion

The clinical usefulness of calcium antagonists was studied in four patients with reactive hypoglycemia including two with alimentary and two with idiopathic. All patients had hyperresponses of plasma insulin (IRI) and C-peptide (CPR) during an oral glucose tolerance test (OGTT). A calcium antagonist (diltiazem 90 mg/d, or nifedipine 30 mg/d, or nicardipine 60 mg/d) was administered orally for about two months. After two months of treatment, plasma IRI and CPR responses during the OGTT were clearly suppressed in all patients and symptomatic reactive hypoglycemia disappeared. One month after the discontinuation of the treatment in two patients, plasma IRI and CPR responses during the OGTT became higher again and symptomatic reactive hypoglycemia recurred. In addition, an intravenous glucose tolerance test was performed before and after two months of the treatment with calcium antagonists in the two patients with reactive hypoglycemia and seven patients with hypertension, who were free from glucose intolerance and were also treated with a calcium antagonist. In these patients, plasma IRI and CPR responses were also reduced after the treatment compared with those before the treatment. These results suggest that calcium antagonists are useful as therapeutic agents for the treatment of reactive hypoglycemia associated with hyperinsulinemia, and that one of the main mechanisms of action of calcium antagonists is a direct action on the pancreatic B-cell to inhibit glucose-induced insulin release.

Topics: Adult; Aged; C-Peptide; Calcium Channel Blockers; Diltiazem; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Male; Middle Aged; Nicardipine; Nifedipine

This study of 74 diabetic pregnant women shows that tight maternal blood glucose control before the 32nd week of gestation significantly reduces the incidence of fetal macrosomia (11%) when compared with that of patients with fair to poor control before the 32nd week of gestation (44%, P less than .05) or with those whose good diabetic control was not achieved until after the 32nd week of gestation (34%, P less than .05). The macrosomic infant produced by a diabetic mother is associated frequently with an elevated amniotic fluid C-peptide level, which shows the evidence of intrauterine fetal hyperinsulinism. The use of tight diabetic control early in pregnancy to reduce the risk of fetal macrosomia and/or neonatal complications is of clinical importance in the management of diabetes in pregnancy.

Topics: Amniotic Fluid; Birth Weight; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Gestational Age; Humans; Hypoglycemia; Infant, Newborn; Infant, Small for Gestational Age; Jaundice, Neonatal; Longitudinal Studies; Pregnancy; Pregnancy in Diabetics; Time Factors

To assess the role of hepatic autoregulation in defense against hypoglycemia, we compared the effects of complete blockade of glucose counterregulation with those of blockade of only neurohumoral counterregulation during moderate (approximately 50 mg/dl) and severe (approximately 30 mg/dl) hypoglycemia induced by physiologic hyperinsulinemia during subcutaneous infusion of insulin in normal volunteers. Compared with observations in control experiments, neurohumoral counterregulatory blockade (somatostatin, propranolol, phentolamine, and metyrapone), during which identical moderate hypoglycemia was achieved using the glucose clamp technique, resulted in suppressed glucose production (0.62 +/- 0.08 vs. 1.56 +/- 0.07 mg/kg per min at 12 h, P less than 0.01) and augmented glucose utilization (2.17 +/- 0.18 vs. 1.57 +/- 0.07 mg/kg per min at 12 h, P less than 0.01). Complete blockade of counterregulation (neurohumoral blockade plus prevention of hypoglycemia) did not further enhance the suppressive effects of insulin on glucose production. However, when severe hypoglycemia was induced during neurohumoral counterregulatory blockade, glucose production was nearly two times greater (1.05 +/- 0.05 mg/kg per min at 9 h) than that observed during complete counterregulatory blockade (0.58 +/- 0.08 mg/kg per min at 9 h, P less than 0.01) and that observed during mere neurohumoral blockade with moderate hypoglycemia (0.59 +/- 0.06 mg/kg per min at 9 h, P less than 0.01). These results demonstrate that glucose counterregulation involves both neurohumoral and hepatic autoregulatory components: neurohumoral factors, which require only moderate hypoglycemia for their activation, augment glucose production and reduce glucose utilization; hepatic autoregulation requires severe hypoglycemia for its activation and may thus serve as an emergency system to protect the brain when other counterregulatory factors fail to prevent threatening hypoglycemia.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Female; Glucose; Homeostasis; Humans; Hypoglycemia; Insulin; Liver; Male; Neurotransmitter Agents

We evaluated the possibility to diagnose the case of insulinoma using the combination of portal blood sampling and gel filtration techniques. The portal blood sampling showed 52 muU/ml of immunoreactive insulin (IRI) level at the closest splenic vein to the tumor, but the level should not be high enough to reasonalize the being of the tumor. The gel filtration pattern of IRI from the blood at the same point was clearly different from the other samples. Therefore, it could be useful for the diagnosis of insulinoma to combine percutaneous transhepatic portal blood sampling and gel filtration in such a case.

Topics: Adenoma, Islet Cell; C-Peptide; Chromatography, Gel; Female; Hepatic Veins; Humans; Hypoglycemia; Insulin; Insulinoma; Middle Aged; Pancreatic Neoplasms; Portal Vein; Splenic Vein

The mean age of the 13 patients studied (9 women, 7 men) was 50.5 +/- 15.7 years. The disease was discovered on account of malaise (3 cases), behavioural disorders (4 cases), coma (3 cases), syncope (1 case) or right hemiparesis (1 case) or in the course of systematic examination (1 case). Eleven patients consulted for evaluation of hypoglycaemia and 2 for behavioural disorders. The history was characteristic, with malaise, loss of consciousness, severe neurological disorders (seizures, hemiparesis, hemiplegia or coma) and psychiatric disorders. These symptoms typically occurred in the morning before breakfast or between meals in 9 patients, and atypically at any point of time or after meals in 4 patients. Their hypoglycaemic nature was demonstrated by blood glucose determination in 11/13 cases and by response to ingestion of sugar in 12/13 cases. The mean period elapsed between the initial symptoms and the final diagnosis was 20.3 +/- 17.3 months. Inappropriate insulin secretion was elicited a.m. before breakfast, during Conn's diet or fasting test, or by calculating the blood insulin/glucose ratio or Turner's coefficient. Prior to surgery, the insulinoma was located by ultrasonography in 3/8 cases, by computerized tomography in 2/6 cases, by selective arteriography in 6/11 cases, and by phlebography with spleno-portal catheterization and staged sampling for insulin and C-peptide assays in 8/9 cases. Histological examination after surgery (11 cases) or necropsy (1 case) showed an adenoma without evidence of malignancy.

Topics: Adenoma, Islet Cell; Adult; Aged; Blood Glucose; C-Peptide; Fasting; Female; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Neurologic Manifestations; Pancreatic Neoplasms; Portography; Tomography, X-Ray Computed; Ultrasonography

Increasing evidence that Type 1 (insulin dependent) diabetes mellitus is an autoimmune disease, together with successful cure/prevention in animal models of this disease (e.g. BB/W rat) has led to several trials of immunotherapy in recent onset Type 1 diabetes of man. In this communication we report our experience with short courses of prednisone and antithymocyte globulin (ATGAM) plus prednisone. Prednisone characteristically suppressed Ia positive T lymphocytes into the normal range, but had no long-lasting effect on T-cell phenotype. ATGAM plus prednisone markedly decreased the ratio of T4/T8 ("helper"/"suppressor-cytotoxic") positive T lymphocytes, and this remained suppressed for months. ATGAM treated patients had lower HbA1c on a lower dose of insulin 100 or more days following immune therapy (with 4 out of 5 patients requiring less than 0.2 U/Kg insulin/day). Two patients in the ATGAM treated group did not require insulin for more than 8 months; during remission they had normal fasting blood glucose values, but with abnormal glucose tolerance on oral glucose tolerance testing. Severe, though transient, thrombocytopenia was observed in 2 patients on ATGAM therapy which outweighed its clinical effects.

Topics: Adolescent; Adult; Antilymphocyte Serum; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Humans; Hypoglycemia; Immunotherapy; Male; Prednisone; T-Lymphocytes; Thrombocytopenia; Time Factors

We have characterized the molecular forms of circulating insulins in patients with hyperinsulinemia of diverse etiology. We have also compared the efficacy of various chromatographic conditions using reversed-phase (RP) HPLC. Using 0.2% trifluoroacetic acid (TFA) and triethylamine (TEA) with acetonitrile as the organic modifier, at an elution rate of 0.17%/min, porcine, bovine, and human insulins could be easily separated as well as abnormal insulins in the plasma of a patient (J.R.) with hyperinsulinemia of unknown etiology. When the reversed-phase C18 column was changed and a gradient of 0.33%/min was used, the abnormal insulin in patient J.R. could not be separated. By changing the solvent system to acetonitrile and isopropanol (vol:vol, 3:1) containing 0.1% TFA, omitting the TEA, and using a gentle gradient of 0.1%/min, various semisynthetic analogues of human insulin could be easily separated and the abnormal insulin could be identified in the plasma of the patient J.R. Abnormal insulin was also found in a patient with MEN-I, but in contrast, the insulins in eight patients with benign sporadic insulinomas appeared to be normal. These results suggest that certain hyperinsulinemic states may be associated with an abnormal insulin and that RP-HPLC is useful for identification of insulin variants in the circulation. However, the conditions of RP-HPLC may be critical if the abnormalities of the insulin are subtle.

Topics: C-Peptide; Chromatography, High Pressure Liquid; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin

In order to investigate whether or not insulin exerts any influence on endogenous insulin secretion, 6 non-obese healthy volunteers were connected to the artificial beta-cell (BIOSTATOR) for 16 hours. After an overnight fast 0.4 U of intermediate acting insulin (Monotard MC/NOVO INDUSTRIES) per kg body weight were injected subcutaneously. The computer program was set to maintain steady-state plasma glucose concentrations at fasting levels by a variable glucose infusion. This approach is able to prevent completely hypoglycemic episodes. Endogenous insulin secretion was evaluated by measuring plasma C-peptide concentrations. Whereas plasma insulin levels increased markedly in response to insulin injection at the same time C-peptide levels declined correspondingly, indicating an inhibition of insulin secretion. Thus, our results provided further support for a negative feedback regulation of insulin secretion by insulin itself.

Topics: Adult; Blood Glucose; C-Peptide; Feedback; Glucose; Humans; Hypoglycemia; Insulin; Insulin Antagonists; Insulin Secretion

Recurrent malaise in a 63 year old woman were found to be due to hypoglycaemic episodes. During a 5 hour oral glucose tolerance test, the "impaired glucose tolerance" type initial hyperglycaemic wave was followed by a post-stimulative hypoglycaemia. Serum C-peptide levels were normal during the test, but the insulin response which was initially normal became excessive, with a consequent decrease of the C-peptide/insulin ratio, similar to that usually observed in hepatic malfunction. An hepatic ultrasonography, a cavography and a selective superior mesenteric arteriography showed an intra-hepatic porto-caval anastomosis, probably congenital in origin. This vascular abnormality accounts for the blood glucose problems: the porto-caval shunt explains the early hyperglycaemia by defective liver uptake of glucose and secondary hyperinsulinism occurs because of the reduced hepatic degradation of the insulin secreted in normal quantity. The late hyperinsulinism then leads to secondary hypoglycaemia.

Topics: Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Liver; Middle Aged; Portal Vein; Venae Cavae

Tumor growth in a 72-year-old male patient with malignant haemangiopericytoma in the left hemithorax could be followed radiologically for 4 years before symptoms of recurrent hypoglycaemia appeared. The endogenous insulin level in serum was maximally and serum IGF-1 and IGF-2 markedly reduced. An intravenous arginine load test showed a normal stimulation capacity of the pancreatic glucagon secretion but not that of insulin. After resection of the tumor, blood sugar metabolism was completely normalised. The insulin level, IGF-1 and IGF-2 in serum returned to normal.

Topics: Aged; Arginine; C-Peptide; Glycated Hemoglobin; Hemangiopericytoma; Humans; Hypoglycemia; Male; Radiography, Thoracic; Thoracic Neoplasms

Glucose counter-regulatory capacity and the hormonal responses to insulin-induced hypoglycemia were studied in eight type 1 diabetics before and after improvement of metabolic control by continuous subcutaneous insulin infusion (CSII). The intensified treatment resulted in a decrease in mean glycosylated hemoglobin from 11.6 +/- 0.5 to 9.3 +/- 0.4% within a mean period of 14 weeks. During a constant rate infusion of insulin (2.4 U/h), steady state levels of glucose appeared in all subjects. The steady state glucose level was identical before and after CSII. The counter-regulatory hormonal responses showed significantly higher epinephrine levels, while glucagon, growth hormone, and cortisol were not influenced. In parallel with the heightened epinephrine response the pulse rate response was significantly enhanced. The restitution of blood glucose after insulin hypoglycemia was not modified. It is concluded that a more vigorous catecholaminergic response to hypoglycemia is achieved after improved metabolic control by CSII.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Heart Rate; Hemoglobin A; Hormones; Humans; Hypoglycemia; Insulin Infusion Systems; Male; Middle Aged

Topics: Adrenergic beta-Antagonists; Adult; Blood Glucose; Blood Pressure; C-Peptide; Carteolol; Glucagon; Growth Hormone; Hemodynamics; Humans; Hydrocortisone; Hypoglycemia; Insulin; Kinetics; Male; Metoprolol; Propranolol; Pulse

Insulin hypoglycaemia test (IHT) for assessment of hypothalamic-pituitary-adrenocortical (HPA) function in patients with pituitary tumours is usually performed by bolus injection of insulin, a procedure which includes the risk of overdosage and/or the need of repeated administration. This study describes that a glucose controlled insulin infusion system (GCIIS) permits to perform the IHT with standardized hypoglycaemia. Ten healthy volunteers and 10 patients with pituitary tumours were studied using the GCIIS (Biostator) on static control (Mode 1:1, BI 35, QI 10, RI 20, FI 300). Insulin administration was discontinued and the GCIIS used only for monitoring of blood glucose (BG), when BG had fallen below 40 mg/dl and initial clinical symptoms for hypoglycaemia were observed. In controls, the GCIIS guided IHT achieved a sufficient degree of hypoglycaemia (BG 27.6 +/- 2.0 mg/dl; mean +/- SEM) and physiological responses for GH (peak 49.4 +/- 6.7 ng/ml), Prl (peak 1766 +/- 614 microU/ml), ACTH (peak 76.0 +/- 8.7 pg/ml) and cortisol (peak 252 +/- 15 ng/ml). The total amount of insulin given was 0.115 +/- 0.012 U/kg. In the patients with pituitary tumours however, the required insulin dose varied markedly from 0.090 (pituitary insufficiency) to 0.340 U/kg (Cushing's syndrome). Minimum BG obtained was 32.5 +/- 1.9 mg/dl. Partial impairment of hypothalamic-pituitary function and, in particular, patients requiring exogenous cortisol supplementation during stress, could be identified. In conclusion, special advantages of the GCIIS-guided IHT are: Optimal insulin dosage with standardized hypoglycaemia due to automatic adjustment to the individual insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenocorticotropic Hormone; Adult; Aged; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Female; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypothalamo-Hypophyseal System; Insulin; Insulin Infusion Systems; Male; Middle Aged; Pituitary Neoplasms; Pituitary-Adrenal System; Prolactin

To elucidate the mechanisms controlling the response of glucagon to hypoglycemia, a vital component of the counterregulatory hormonal response, the role of intraislet insulin was studied in seven normal subjects and five subjects with insulin-dependent diabetes mellitus (IDDM) (of less than 15-mo duration). In the normal subjects, hypoglycemia (arterial plasma glucose [PG] 53 +/- 3 mg/dl) induced by an intravenous insulin infusion (30 mU/m2 X min for 1 h, free immunoreactive insulin [FIRI] 58 +/- 2 microU/ml) elicited a 100% fall in insulin secretion and an integrated rise in glucagon of 7.5 ng/ml per 120 min. When endogenous insulin secretion was suppressed by congruent to 50 or congruent to 85% by a hyperinsulinemic-euglycemic clamp (FIRI 63 +/- 1.5 or 147 +/- 0.3 microU/ml, respectively) before hypoglycemia, the alpha cell responses to hypoglycemia were identical to those of the control study. When the endogenous insulin secretion was stimulated by congruent to 100% (hyperinsulinemic-hyperglycemic clamp, FIRI 145 +/- 1.5 microU/ml, PG 132 +/- 2 mg/dl) before hypoglycemia, the alpha cell responses to the hypoglycemia were also superimposable on those of the control study. Finally, in C-peptide negative diabetic subjects made euglycemic by a continuous overnight intravenous insulin infusion, the alpha cell responses to hypoglycemia were comparable to those of normal subjects despite absent beta cell secretion, and were not affected by antecedent hyperinsulinemia (hyperinsulinemic-euglycemic clamp for 2 h, FIRI 61 +/- 2 microU/ml). These results indicate that the glucagon response to insulin-induced hypoglycemia is independent of the level of both endogenous intraislet and exogenous arterial insulin concentration in normal man, and that this response may be normal in the absence of endogenous insulin secretion, in contrast to earlier reports. Thus, loss of beta cell function is not responsible for alpha cell failure during insulin-induced hypoglycemia in IDDM.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Glucagon; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Islets of Langerhans

Plasma concentrations of proinsulin and C-peptide were measured in five children presenting with severe hypoglycaemia associated with elevated plasma levels of immunoreactive insulin (IRI) in order to determine whether the profile of circulating B-cell products related to the underlying pathophysiology of the pancreas. Results were compared with data from 13 normal infants. Four children, three neonates and a nine year old girl, were subjected to partial or total pancreatectomy. The neonates had nesidioblastosis, nesidioblastosis with a microadenoma, and a functional abnormality without histological derangement respectively; the older child had a localised adenoma. The remaining child, a neonate, had transient hypoglycaemia and elevated IRI levels associated with hyperlactataemia and hyperalaninaemia. All the children had markedly elevated plasma proinsulin concentrations; the highest levels were seen in the child with an isolated adenoma and in the neonate with nesidioblastosis and a microadenoma. Both of these children also had substantially elevated plasma C-peptide concentrations. The remaining three neonates had plasma C-peptide levels, which although in the normal range for normoglycaemia were inappropriately elevated during hypoglycaemia. It is concluded that elevated proinsulin and C-peptide concentrations are seen in children with hypoglycaemia associated with increased plasma IRI levels and that the profile of the concentrations does not provide a reliable marker for the nature of the underlying pancreatic abnormality.

Topics: Alanine; C-Peptide; Child; Female; Humans; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Lactates; Male; Pancreatectomy; Pancreatic Diseases; Pancreatic Neoplasms; Proinsulin

To study glucose counterregulation under conditions approximating those of clinical disorders in which hypoglycemia develops gradually and is reversed over a prolonged period, we injected regular insulin subcutaneously, in a dose (0.15 U/kg) selected to produce two- to threefold increases in plasma insulin, in 11 normal human volunteers and measured plasma glucose, insulin, C-peptide, and counterregulatory hormone concentrations as well as rates of glucose production, glucose utilization, and insulin secretion over 12 h. The data suggest that the mechanisms of gradual recovery from prolonged hypoglycemia may differ from those of rapid recovery from short-term hypoglycemia produced by intravenous injection of insulin in that 1) both stimulation of glucose production and limitation of glucose utilization contribute to recovery from prolonged hypoglycemia; 2) increases in glucagon, epinephrine, growth hormone, and cortisol secretion as well as a decrease in insulin secretion may all participate in glucose counterregulation during prolonged hypoglycemia; 3) epinephrine may play a more important role than glucagon during prolonged hypoglycemia. The latter two conclusions are based primarily on the temporal relationships between changes in the rates of glucose turnover and changes in plasma hormone concentrations and should not be considered proved. However, they provide the basis for testable hypotheses concerning the physiology of gradual recovery from prolonged hypoglycemia that can be expected to be relevant to the pathophysiology of clinical hypoglycemia.

Topics: Adult; Blood Glucose; C-Peptide; Epinephrine; Female; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin; Kinetics; Male; Norepinephrine

In the present study insulin and C-peptide responses to oral glucose as well as C-peptide to insulin ratios and relations were evaluated in 10 nondiabetic obese female subjects with reactive hypoglycemia and in 10 age- and weight-matched controls. Insulin levels and incremental areas did not differ significantly in the two groups, whereas C-peptide concentrations and incremental areas were significantly higher in the obese group with reactive hypoglycemia. C-peptide to insulin molar ratio increments after glucose load as well as relations between incremental areas of the two peptides were significantly higher in obese subjects with reactive hypoglycemia than in controls. Our results suggest that B-cell response to oral glucose as well as insulin uptake by the liver in obese subjects with reactive hypoglycemia are greater than in controls.

Topics: C-Peptide; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Secretion; Liver; Obesity; Time Factors

Hypoglycemia when associated with hyperinsulinemia is usually a consequence of an insulinoma or the administration of either insulin or an insulin secretagogue. This report describes 14 patients with hypoglycemia whose diagnosis was clarified by the use of a species-specific insulin radioimmunoassay. Eleven of the 14 patients had elevated levels of animal insulin due to surreptitious accidental or malicious administration of insulin. Three of the 14 patients had hyperinsulinemia as the result of excessive human insulin release and were found to have either intrinsic pancreatic disease or secretagogue-mediated insulin release.

Topics: Adolescent; Adult; Aged; C-Peptide; Child; Diagnosis, Differential; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Antibodies; Male; Middle Aged; Radioimmunoassay

We describe two children with hypoglycaemia due to pancreatic beta cell hyperactivity. Both had low serum insulin but raised plasma C peptide concentrations when hypoglycaemic. Measurement of C peptide is valuable in the diagnosis of hyperinsulinaemic hypoglycaemia in children.

Topics: C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Infant; Infant, Newborn; Insulin; Islets of Langerhans; Male

An unusual case of factitious hypoglycaemia is described. The distinction between exogenous and endogenous hyperinsulinism is illustrated.

Topics: Adult; C-Peptide; Diabetic Ketoacidosis; Factitious Disorders; Humans; Hypoglycemia; Insulin; Male; Rural Population; South Africa

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemia

The relative hypoglycemic effects of pulsatile versus steadily infused insulin have been examined in six normal subjects in whom pancreatic insulin output was suppressed by somatostatin-14. Soluble insulin was infused continuously overnight on one occasion and on another occasion the same quantity was given in pulses of 2-min duration with a gap of 11 min. The mean plasma glucose concentrations were lower when pulsed insulin was given [mean for the last hour: 4.66 +/- 0.08 mmol/L (+/- SEM) versus 5.53 +/- 0.06 mmol/L (+/- SEM) for steady infusion], diverging significantly (P less than 0.05 paired t test) 7 h after the start of the study. The specific binding of 125I(A14)mono-iodo-insulin to monocytes was greater after pulsed insulin (2.9% with pulsed versus 2.4% with steadily infused insulin at tracer-only point; P less than 0.02 paired t test). Thus, intravenous insulin has greater hypoglycemic effect when pulsed, possibly mediated by greater insulin receptor binding.

Topics: Adult; Blood Glucose; C-Peptide; Drug Administration Schedule; Female; Humans; Hypoglycemia; Infusions, Parenteral; Insulin; Male; Monocytes; Receptor, Insulin; Somatostatin; Time Factors

Using the artificial pancreas, blood glucose levels were maintained at 80 mg/dl in nine hypoglycemic patients (four with histologically proven insulinomas and five with nontumoral hypoglycemia) and in four normal subjects during a 24-h fast. The amount of glucose used, serum insulin levels, and glucose clearance were higher in patients with nontumoral hypoglycemia than in normal subjects and highest in the patients with an insulinoma. Surgical or pharmacological treatment resulted in normalization of all parameters. In contrast to the 72-h fast, the 24-h glucose clamp technique allowed the study of hypoglycemic patients without inducing hazardous hypoglycemia.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Female; Glucose; Humans; Hypoglycemia; Insulin; Insulin Infusion Systems; Insulinoma; Male; Metabolic Clearance Rate; Middle Aged; Pancreatic Neoplasms

To evaluate the roles of counterregulatory hormones and insulin antibodies in the impairment of plasma glucose recovery from hypoglycemia in diabetes mellitus, and to assess the relationship between the glucagon response and duration of the disease, 21 insulin-dependent diabetic patients and 10 nondiabetic subjects were studied. The diabetics consisted of 5 patients with recent onset of diabetes (less than 1 mo); 11 with 2.6 +/- 0.3 (mean +/- SEM) yr duration of diabetes, 5 of whom had insulin antibodies; and 5 patients with long-term diabetes (21 +/- 3 yr), insulin antibodies, and autonomic neuropathy. During insulin-induced hypoglycemia (28 mU/m2 X min for 60 min) in patients with recent-onset diabetes, plasma free insulin, glucose, and counterregulatory hormone concentrations did not differ from those of nondiabetic subjects. In patients with insulin antibodies, the disappearance of insulin after insulin infusion was delayed, and both restitution of normoglycemia and plasma glucagon response were blunted compared with patients without antibodies. When glucagon was infused (80-130 ng/m2 X min) during hypoglycemia in diabetics with impaired glucagon responses in order to simulate normal glucagon responses, plasma glucose recovery was normalized in patients without antibodies but not in those with antibodies. In patients with long-standing diabetes, restitution of normoglycemia was further impaired and this was associated with an absent plasma glucagon response and a diminished plasma epinephrine response. Plasma glucagon responses to hypoglycemia were inversely correlated to the duration of diabetes (r = -0.943; P less than 0.0005). It is concluded that impaired A-cell secretion is the predominant mechanism for the delayed glucose recovery after hypoglycemia in diabetic patients without insulin antibodies and normal epinephrine responses. Slowed disappearance of insulin due to the presence of insulin antibodies further delays the restoration of normoglycemia. Patients with long-standing diabetes and autonomic neuropathy exhibit decreased epinephrine secretion, which leads to an additional retardation of glucose recovery. Since plasma glucagon and epinephrine responses to hypoglycemia were normal at the onset of diabetes but diminished in long-term diabetes, it appears that the impaired glucagon and epinephrine responses to hypoglycemia are acquired defects that develop subsequent to B-cell failure.

Topics: Adolescent; Adult; Antibodies; Blood Glucose; Body Surface Area; Body Weight; C-Peptide; Diabetes Mellitus; Epinephrine; Glucagon; Humans; Hypoglycemia; Insulin; Islets of Langerhans

Topics: Age Factors; C-Peptide; Diabetes Mellitus; Humans; Hypoglycemia; Insulin; Islets of Langerhans

We studied the occurrence, clinical manifestations, and mechanism of hypoglycemia in patients with falciparum malaria in eastern Thailand. Hypoglycemia, which was often severe and recurrent, occurred in 17 patients, including 12 in a series of 151 patients with cerebral malaria. Thirty episodes were investigated. Plasma concentrations of insulin and C peptide were inappropriately high, and lactate and alanine concentrations were significantly higher than in patients with falciparum malaria who were normoglycemic (P less than 0.05). Sixteen patients had received quinine; plasma quinine and insulin concentrations were correlated at the time of hypoglycemia (P = 0.007). In seven healthy fasting volunteers intravenous quinine increased the mean plasma insulin concentration (+/- S.D.) from 8.9 +/- 3.1 to 17.1 +/- 8.4 mU per liter (P = 0.02) and reduced the mean plasma glucose concentration from 88 +/- 20 to 68 +/- 23 mg per deciliter (P = 0.002). Our observations indicate that in falciparum malaria quinine-induced insulin secretion may precipitate hypoglycemia, but other factors, including the large glucose requirements of the malaria parasites may also contribute. This important complication, associated with pregnancy and severe disease, must be excluded in all patients with falciparum malaria who have impaired or deteriorating consciousness.

Topics: 3-Hydroxybutyric Acid; Adolescent; Adult; Alanine; Blood Glucose; Brain Diseases; C-Peptide; Child; Female; Humans; Hydroxybutyrates; Hypoglycemia; Insulin; Lactates; Lactic Acid; Malaria; Male; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Infectious; Quinine

Glucose metabolism was investigated in four infants aged 3-32 months with persistent hypoglycemia and hyperinsulinism of neonatal onset. Fasting hypoglycemia was found to be due both to an insulin-induced decrease in hepatic glucose output to 3.95 +/- 0.30 (SEM) mg/kg X min, a value about two thirds of normal, and to a glucose utilization rate of 4.25 +/- 0.32 mg/kg X min, which exceeded glucose production by about 8%. Simultaneously, and despite hypoglycemia, fasting plasma D-beta-hydroxybutyric acid concentrations were inappropriately low: 406 +/- 146 microM, presumably the result of elevated circulating insulin levels. The infusion of sodium DL-beta-hydroxybutyrate resulted in an increase of plasma glucose (48 +/- 7 vs. 32 +/- 7 mg/dl, P less than 0.01) and lactate (1704 +/- 217 vs. 964 +/- 149 microM, P less than 0.005), without detectable changes in insulin secretion estimated from circulating C-peptide values. Unexpectedly, the increase of plasma glucose was due to the restoration of glucose production up to 6.7 +/- 0.2 mg/kg X min. The individual increments of plasma lactate and glucose production rate were linearly correlated (P less than 0.01). These results together with the known inhibitory effect of ketone bodies on pyruvate dehydrogenation, suggest both increased production of lactate from peripheral recycling of glucose carbon and an increased conversion of this gluconeogenic precursor into glucose.

Topics: 3-Hydroxybutyric Acid; Blood Glucose; C-Peptide; Fasting; Humans; Hydroxybutyrates; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Insulin; Male; Metabolic Clearance Rate

Topics: C-Peptide; Fasting; Humans; Hypoglycemia; Peptides

Two cases of hyperinsulinism from insulin self-administration are described, both patients being admitted to hospital with a diagnosis of insulinoma. In the first case, the diagnosis was clarified after a left pancreatectomy elsewhere, thanks to the discovery of a bottle of insulin. In the second case, the diagnosis was confirmed by the measurement of C-peptide during a hypoglycemic attack. The simultaneous sharp decrease in glucose levels, an exceptional increase in insulinaemia and a reduction or disappearance of serum C-peptide is indicative of this particular type of hyperinsulinism. The two cases described here were remarkably similar. Apart from the most common features, both reported a severe hypoglycemic syndrome of recent onset; negative tolbutamide and calcium tests; a frequent relapse shortly after glucose administration.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Munchausen Syndrome; Pancreatic Neoplasms; Recurrence; Self Administration

In prescribing a diabetic diet more attention has traditionally been paid to the amount of dietary carbohydrate than to its type or structure. We have compared the effect on blood glucose of substituting unrefined, whole foods for refined, processed foods in liberal carbohydrate diets (50-55% of dietary energy) eaten by 10 diabetic children in a randomised crossover study. All measurements were made at home. The unrefined diet used whole foods (including) dried beans) supplying 60 g/day of dietary fibre. The refined diet used processed foods supplying 20 g/day of dietary fibre. Diets were isocaloric for carbohydrate, fat, and protein. Glycaemic control was assessed by daily urine analysis for glucose, home blood glucose measurements, glycosylated haemoglobin, and by a 24-hour profile of blood and urinary glucose carried out at home after 6 weeks on each diet. Glycaemic control was significantly better on the unrefined diet. On profile days mean blood glucose levels on the unrefined and refined diets respectively were: preprandial: 5.5 and 8.4 mmol/l; postprandial 8.5 and 12.2 mmol/l. The mean 24-hour urinary glucose excretion on the unrefined diet was 9.3 g and on the refined diet was 38.0 g. Six months after the study the children were eating appreciably more dietary fibre than before (mean increase 13.6 g/day). Attention to food type and structure can improve blood glucose control in diabetic children and should provide an acceptable and more rational basis for dietary prescription than one based on carbohydrate quantity alone.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Dietary Fiber; Female; Glycosuria; Humans; Hypoglycemia; Insulin; Male; Patient Acceptance of Health Care; Patient Compliance

The authors report on the observation of a woman treated with isoniazide, who presented clinical symptoms of hypoglycemia during treatment (seating, confusion, anxio-depressive syndrome, lipothymia). After the antitubercular treatment was stopped, a moderate hypoglycemia without clinical manifestations accompanied by a marked hyperinsulinemia and normal C-peptide values was detected during a Conn's test. Serum gel filtration on Sephadex G 50 Fine showed that the measured hyperinsulinemia was effectively due to an insulin excess. This excess did not seem caused by surreptitious insulin injection. This seems to be the consequence of a deficiency in insulin catabolism because the C-peptide level was normal. The possible role of isoniazide on carbohydrate metabolism is discussed.

Topics: Adult; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Isoniazid; Peptides

Topics: Adult; C-Peptide; Diagnosis, Differential; Factitious Disorders; Glyburide; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Pancreatic Neoplasms; Peptides

Topics: C-Peptide; Child Abuse; Child, Preschool; Humans; Hypoglycemia; Insulin; Insulin Coma; Male

The increased incidence of severe hypoglycemia reported in young children with diabetes is consistent with a defect in glucagon secretion or a generalized abnormality in islet hormone secretion. To assess pancreatic hormone and gastric inhibitory polypeptide secretion in children with early onset diabetes, 12 children with onset of diabetes prior to the age of 28 months were studied and the data compared to the hormone responses observed in 11 children with LOD, diagnosed after the age of 5 years. Plasma glucose, C-peptide, glucagon, pancreatic polypeptide, and gastric inhibitory peptide concentrations were measured during and following an arginine infusion (500 mg/kg over 60 minutes) and a mixed meal. During arginine infusion, plasma glucose and glucagon increased similarly in both groups and returned to basal concentrations following discontinuation of arginine infusion. In contrast, plasma C-peptide, hPP, and GIP concentrations did not change. Following the mixed meal plasma glucose, hPP, and GIP concentrations increased similarly in the two groups of children, but no change was observed in either plasma glucagon or C-peptide concentrations in either group. These data demonstrate that EOD and LOD are associated with insulin insufficiency alone and that abnormalities in secretion of other pancreatic islet hormone or GIP cannot be implicated in the high incidence of severe hypoglycemia observed in children with EOD.

Topics: Arginine; Blood Glucose; C-Peptide; Child; Child, Preschool; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Gastric Inhibitory Polypeptide; Glucagon; Humans; Hypoglycemia; Infant; Infusions, Parenteral; Insulin; Islets of Langerhans; Male; Pancreatic Polypeptide; Time Factors

Little is currently known about the factors controlling somatostatin secretion. A radioimmunoassay has been developed that is sufficiently specific and sensitive to be used for physiological studies of circulating levels in man. During insulin-induced hypoglycaemia a rise in plasma somatostatin was seen in each of ten subjects studies. Although this paralleled the rise in circulating glucagon and growth hormone, no individual relationships were found either between these variables or to any change in cortisol or insulin C-peptide. In contrast no rise in somatostatin was seen during surgical stress. Thus, contrary to expectation, circulating somatostatin levels can be altered by metabolic stimuli. It seems likely that this peptide may serve an endocrine as well as a paracrine role since its modulating effects may occur not only near to but also at a distance from the site of secretion. It is not yet clear whether the somatostatin measured comes from the hypothalamus, any other part of the central nervous system or the gastrointestinal tract.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Insulin; Male; Middle Aged; Somatostatin; Stress, Physiological; Surgical Procedures, Operative

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Food; Food Deprivation; Glucose Tolerance Test; Humans; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Radioimmunoassay; Tolbutamide

A patient with biopsy-proved biliary cirrhosis and previous gastrojejunostomy and portacaval anastomosis experienced episodes of severe hypoglycemia. She was found to have hyperinsulinemia and hyperglucagonemia. An oral glucose tolerance test showed postgastrectomy hypoglycemia. Results of the intravenous tolbutamide test were diagnostic for insulinoma, but results of the intravenous glucagon test and prolonged fast (96 hours) were not. Failure, on two occasions, to suppress C-peptide normally during insulin-induced hypoglycemia led to a diagnosis of pancreatogenous hyperinsulinemia. The pancreas showed a 10-fold increase in islet volume, with intensely positive staining with anti-insulin and anti-glucagon antiserums in addition to anti-somatostatin and anti-pancreatic polypeptide antiserums. Incidental findings at pancreatic exploration were a mesothelioma, which did not stain with anti-insulin antiserum, and, at autopsy one year later, a hepatoma.

Topics: Blood Chemical Analysis; Blood Glucose; C-Peptide; Female; Glucagon; Glucose Tolerance Test; Humans; Hyperplasia; Hypoglycemia; Insulin; Islets of Langerhans; Middle Aged; Portacaval Shunt, Surgical; Tolbutamide

A radioimmunoassay for C-peptide utilizing synthetic C-peptide as an antigen and tyrosylated synthetic C-peptide for iodination was evaluated for its clinical use. Mean fasting C-peptide levels in 24 normal subjects was 2.6 +/- 0.8 ng/ml. During the oral glucose tolerance test, baseline C-peptide in five normal subjects was 1.5 +/- 0.8 ng/ml, and at 60 min was 5.6 +/- 1.6 ng/ml. For two insulin-dependent diabetic patients, diagnoses of factitious hypoglycemia were documented on the basis of simultaneous free insulin and C-peptide determinations. Sera from 24 insulin-dependent diabetics were analyzed for free and total immunoreactive C-peptide and insulin levels. For 20% of juvenile and 64% of maturity-onset diabetics, the presence of proinsulin-like material bound to insulin antibodies was demonstrated by measurement in unextracted serum. This accounted for 20% to 100% of total C-peptide immunoreactivity in these patients. Simple polyethylene glycol precipitation of immune complexes and the measurement of free immunoreactive C-peptide in the supernatant demonstrated subnormal levels (less than 0.5 ng/ml) in all juvenile diabetics and normal levels (1.8 +/- 1.3 ng/ml) in 70% of maturity-onset diabetics.

Topics: Adolescent; Adult; Antigen-Antibody Complex; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Peptides; Radioimmunoassay

The plasma concentration of C-peptide, insulin (IRI) and glucose was measured in 9 healthy subjects during insulin-induced hypoglycaemia followed by a meal. Identical observations were made in the same subjects after an equivalent period of fasting without hypolycaemia (control study). Endogenous secretion of insulin was suppressed following administration of exogenous insulin and this persisted long after the blood glucose concentration had returned to normal. After the meal the mean blood glucose rose to a peak of 8.4 +/- 0.3 mmol/l (mean +/- SEM) at 60 min and was still raised at 7.5 +/- 0.3 mmol/l at 120 min, compared with a peak value of only 5.1 +/- 0.2 mmol/l at 30 min after the meal in the control study. Following hypoglycaemia the mean plasma IRI rose from 8.3 +/- 1.3 mU/l to a delayed peak of 81.6 +/- 12.7 mU/l at 60 min and was 123.5 +/- 14 mU/l at 120 min post-prandially, compared with a peak of 72.4 +/- 0.5 mU/l at 30 min after the meal in the control study. Acute hypoglycaemia may thus induce in abnormal pattern of insulin secretion in response to a meal, with impaired carbohydrate tolerance in normal subjects.

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Female; Food; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Male

Topics: Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Diagnosis, Differential; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Peptides; Proinsulin

Topics: Adult; B-Lymphocytes; Blood Glucose; C-Peptide; Female; Humans; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Insulin Antibodies; Pregnancy; Pregnancy in Diabetics; Proinsulin

Topics: Adolescent; C-Peptide; Diagnosis, Differential; Female; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Malingering; Pancreatic Neoplasms; Peptides; Self Medication

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Calcium; Humans; Hypoglycemia; Pancreatic Neoplasms; Proinsulin

C peptide is secreted by pancreatic beta cells in amounts equimolar with insulin, and its levels provide a direct indication of endogenous fetal levels of insulin despite the presence of maternal insulin antibodies. To determine the presence of hyperinsulinemia and its relation to the development of complications in infants of diabetic mothers, we measured cord serum levels of C peptide in 79 infants of diabetic mothers and 62 infants of nondiabetic mothers. Infants of diabetic mothers had higher cord levels of C peptide, which were significantly associated with neonatal hypoglycemia and macrosomia (P less than 0.001) but not with hyaline-membrane disease. Cord levels of C peptide in infants of diabetic mothers were elevated at the earliest gestational age studied (less than 34 weeks) and were directly related to the severity of maternal diabetes, as assessed by the White classification. We conclude that hyperinsulinemia is present in infants of diabetic mothers and that it is related to some major complications in such infants.

Topics: Birth Weight; C-Peptide; Female; Fetal Blood; Gestational Age; Humans; Hyaline Membrane Disease; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Peptides; Pregnancy; Pregnancy in Diabetics

Topics: Adult; Blood Glucose; C-Peptide; Glucagon; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Peptides

Topics: Adult; C-Peptide; Diagnosis, Differential; Female; Humans; Hypoglycemia; Insulin

Measurement of serum and urinary C-peptide has been shown to be of value in several conditions other than diabetes mellitus. It is particularly useful because it can distinguish endogenous beta cell secretion from exogenously administered insulin and because circulating insulin-binding antibodies do not interfere with its measurement. Because the liver removes little, if any, C-peptide, peripheral blood values may more accurately reflect beta cell secretion than do peripheral insulin levels. Clinically, serum C-peptide has been most useful in diagnosing hypoglycemic disorders. Diagnosis of insulinomas is facilitated in both diabetic and nondiabetic patients, and surreptitious insulin injection is readily detected. In studies of insulin regulation, circulating C-peptide has been used to demonstrate suppression of endogenous insulin secretion by exogenous insulin. Peripheral insulin and C-peptide levels have been compared in studies of the role of the liver in states of altered insulin homeostasis. Because of its higher urinary clearance, determination of urinary C-peptide is preferable to urinary insulin measurement in situations where frequent blood sampling is impossible or difficult to accomplish.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Humans; Hypoglycemia; Male; Middle Aged; Peptides; Radioimmunoassay

Proinsulin is converted to insulin and C-peptide in the pancreatic in the pancreatic beta cells: the latter two peptides are secreted in equimolar concentrations. Thus, measurements of serum C-peptide provide a means of assessing pancreatic beta cell function in addition to that of insulin. This technique has proved particularly useful in insulin treated diabetic patients in whom the development of circulating insulin antibodies interferes with the radioimmunoassay of the hormone. The C-peptide assay has also been used to facilitate the diagnosis of various hypoglycemic conditions, including islet cell tumors and factitious injection of insulin. The extraction of C-peptide in the urine reflects average serum values over a period of time and urine C-peptide measurements are especially useful in children or individuals in whom repeated blood sampling is difficult.

Topics: Adenoma, Islet Cell; C-Peptide; Diabetes Mellitus; Humans; Hypoglycemia; Insulin Antibodies; Islets of Langerhans; Pancreas; Pancreatic Neoplasms; Peptides; Proinsulin

In seven patients with factitious hypoglycemia due to the surreptitious injection of insulin, we made the diagnosis by measurements of plasma insulin and C-peptide immunoreactivity (in seven patients), facilitated by the finding of circulating insulin-binding antibodies (in two patients). The simultaneous demonstration of low plasma glucose, high immunoreactive insulin and suppressed C-peptide immunoreactivity represents a triad of results pathognomonic of exogenous insulin administration. Determination of plasma free C-peptide and free insulin permitted patients with high titers of insulin antibodies, including those with a history of insulin-treated diabetes, to be studied and diagnosed in a way similar to that in subjects who had no circulating insulin antibodies.

Topics: Adenoma, Islet Cell; Adolescent; Adult; C-Peptide; Child, Preschool; Diabetes Complications; Female; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Male; Pancreatic Neoplasms; Peptides; Self Medication; Substance-Related Disorders

"Essential labile diabetes" is an insulin-dependent diabetes, in the course of which irregular and unpredictable hyperglycemias, frequently with ketosis, and sometimes serious hypoglycemias alternate. In spite of careful treatment with insulin, diet and suitable hygienic measures, this form of diabetes cannot be influenced. Fortunately, it seldom occurs, not more frequently than in 1 to 2% of diabetics. Various attempts have been made to explain the pathogenesis of this form of the disease. The most probable explanation is that there is an almost complete exhaustion of insulin secretion. This hypothesis is based on the extremely low level of the C peptide below 0.60 ng/ml, whereas in non-labile insulin-dependent diabetics the C peptide amounts to more than 2.2 ng/ml

Topics: Activities of Daily Living; Adult; Arginine; C-Peptide; Diabetes Mellitus; Diabetic Ketoacidosis; Diagnosis, Differential; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Secretion; Male; Middle Aged

Topics: C-Peptide; Humans; Hypoglycemia; Insulin; Peptides

The responses of glucagon, growth hormone, and insulin secretion to the oral administration of glucose and to the intravenous infusion of saline, arginine, and insulin were measured in seven patients who had stable diabetes, eight who had unstable diabetes, and seven healthy volunteers. Hyperglycemia suppressed secretion of glucagon in normal subjects but not in diabetics. The oral glucose and arginine infusion tests demonstrated partial preservation of insulin-secretory ability in stable diabetics and its virxual absence in unstable diabetics. Glucagon responses to arginine infusion were similar in all three groups. In response to hypoglycemia induced by insulin infusion, the concentrations of plasma glucagon increased in normal subjects and, to a lesser extent, in stable diabetics but increased in only two of the unstable diabetics. The impairment in glucagon response during hypoglycemia in diabetics correlated positively with the degree of diabetic instability and insulin deficiency during glucose and arginine testing. The severity of the insulin deficiency also correlated with the degree of diabetic instability. These findings support the hypothesis that inherent abnormalities of insulin and glucagon secretion may account for many of the clinical characteristics of unstable and stable diabetic patients.

Topics: Adult; Antigens; Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Glucagon; Glucose; Growth Hormone; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Sodium Chloride

A 21-year-old female patient complaining of frequent hypoglycemic attacks in the presence of a large amount of circulating insulin-binding antibodies without previous known immunization is described. In order to clarify the possible mechanism of the hypoglycemic attacks occurring in this new syndrome, changes in plasma glucose, plasma total and free immunoreactive insulin (IRI), and C peptide immunoreactivity (CPR) levels were investigated in the patient before, during, and after a three-hour glucose infusion. The character of her antibodies were also examined. An abrupt discontinuation of the glucose infusion caused a sharp decline in the plasma glucose level, reaching a nadir of 30 mg./100 nk, at 270 minutes; then she became unconscious. A huge amount of total IRI of 2,834 micron U./ml. was registered at 180 minutes, while the peak value of free IRI of 208 micronU./ml. was observed 45 minutes after the cessation of the glucose infusion. Plasma CPR was increased from high basal level, 19.6 ng./ml., to the maximum level of 29.2 ng./ml. The maximum insulin-binding capacity of IgG in the patient's serum was 6.25 mU./ml. The antibody-combining site was homogeneous, showing one high-affinity site (K: 1.1 X 10(9)M-1). Neither the prolonged fasting nor the administration of tolbutamide induced the hypoglycemic attack in the patient. The hypoglycemia may be explained by an unduly excessive amount of insulin liberated from a large pool of bound insulin irrespective of blood sugar level. The cause of the antibody production is also discussed.

Topics: Adult; Antibodies; Antigens; Autoimmune Diseases; C-Peptide; Chromatography, Gel; Female; Glucose; Humans; Hypoglycemia; Infusions, Parenteral; Insulin; Syndrome

Topics: Adult; C-Peptide; Ethanol; Female; Glucagon; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Peptides