c-peptide and Congenital-Hyperinsulinism

An end-of-fast insulin level ≥ 3 µIU/ml, C-peptide level ≥ 0.6 ng/ml, and proinsulin level ≥ 5 pmol/l with end-of-fast glucose level ≤ 3.0 mmol/l have been established as the criteria for endogenous hyperinsulinemic hypoglycemia. However, all these criteria have been proposed based on patients in Western populations. This study aimed to determine the optimal criteria using a large series of Chinese patients.. This retrospective study comprised 144 patients with surgically proven insulinoma and 40 controls who underwent a 72-h fasting test at the Peking Union Medical College Hospital(PUMCH) from 2000 to 2020. Receiver operating characteristic curves were used for analysis.. In this series of patients, the optimal diagnostic criteria for endogenous hyperinsulinemic hypoglycemia were insulin  ≥ 5.5 μIU/ml, C-peptide ≥ 0.7 ng/ml, and proinsulin ≥ 12 pmol/l with end-of-fast glucose ≤ 2.8 mmol/l; the sensitivity and specificity were 99% and 100% for insulin, 100% and 100% for C-peptide, and 93% and 100% for proinsulin, respectively. The diagnostic efficacy of the criteria based on Western populations was then tested. The sensitivity and specificity of end-of-fast insulin ≥ 3 μIU/ml, C-peptide ≥ 0.6 ng/ml, and proinsulin ≥ 5 pmol/l with end-of-fast glucose ≤ 3.0 mmol/l were 100% and 83%, 100% and 80%, and 97% and 78%, respectively.. New and optimized diagnostic criteria for endogenous hyperinsulinemic hypoglycemia in Chinese populations have been proposed, and these criteria yield satisfactory accuracy.

Topics: C-Peptide; China; Congenital Hyperinsulinism; Fasting; Glucose; Humans; Insulin; Pancreatic Neoplasms; Proinsulin; Retrospective Studies

Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists.. To evaluate an analytic approach to IAS and responses to different treatments.. Observational study in the UK Severe Insulin Resistance Service.. Six patients with hyperinsulinemic hypoglycemia and detectable circulating anti-insulin antibody (IA).. Glycemia, plasma insulin, and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using ELISA and RIA, and IA were further characterized using radioligand binding studies.. All patients were diagnosed with IAS (five IgG, one IgA) based on a high insulin/C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. One patient was managed conservatively, four were treated with diazoxide without sustained benefit, and four were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis.. IAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin/C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response.

Topics: Adult; Aged; Autoimmune Diseases; Biomarkers; Blood Glucose; C-Peptide; Chromatography, Gel; Congenital Hyperinsulinism; Diazoxide; Female; Humans; Immunosuppressive Agents; Insulin; Insulin Antibodies; Insulin Resistance; Male; Middle Aged; Syndrome

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

Congenital hyperinsulinism (CHI) is a rare genetic disorder characterized by excess insulin secretion, which results in hypoglycemia. Mutation of sulfonylurea receptor 1 (SUR1), encoded by the ABCC8 gene, is the main cause of CHI. Here, we captured the phenotype of excess insulin secretion through pancreatic differentiation of ABCC8-deficient stem cells generated by the CRISPR/Cas9 system. ABCC8-deficient insulin-producing cells secreted higher insulin than their wild-type counterparts, and the excess insulin secretion was rescued by nifedipine, octreotide and nicorandil. Further, we tested the role of SUR1 in response to different potassium levels and found that dysfunction of SUR1 decreased the insulin secretion rate in low and high potassium environments. Hence, pancreatic differentiation of ABCC8-deficient cells recapitulated the CHI disease phenotype in vitro, which represents an attractive model to further elucidate the function of SUR1 and to develop and screen for novel therapeutic drugs.

Topics: C-Peptide; Cell Differentiation; Congenital Hyperinsulinism; CRISPR-Cas Systems; Gastrointestinal Agents; Gene Editing; Human Embryonic Stem Cells; Humans; Insulin; Insulin Antagonists; Insulin-Secreting Cells; Models, Biological; Nicorandil; Nifedipine; Octreotide; Phenotype; Potassium Chloride; Sulfonylurea Receptors; Vasodilator Agents

To evaluate thresholds of various biomarkers for defining excess insulin activity to recognize congenital hyperinsulinism.. This was a retrospective chart review of diagnostic fasting tests in children with ketotic hypoglycemia (n = 30) and genetically/pathology confirmed congenital hyperinsulinism (n = 28). Sensitivity and specificity for congenital hyperinsulinism were determined for plasma insulin, β-hydroxybutyrate, free fatty acids (FFA), C-peptide, insulin-like growth factor binding protein-1 (IGFBP-1), and the glycemic response to glucagon (through the glucagon stimulation test [GST]) at the time of hypoglycemia.. Only 23 of the 28 subjects with congenital hyperinsulinism had detectable insulin (median, 6.7 μIU/mL), and insulin was undetectable in all subjects with ketotic hypoglycemia. Compared with ketotic hypoglycemia, subjects with congenital hyperinsulinism had higher GST values (57 vs 13 mg/dL; ΔGST ≥30 mg/dL in 24 of 27 subjects with congenital hyperinsulinism vs 0 of 30 subjects with ketotic hypoglycemia) and C-peptide levels (1.55 vs 0.11 ng/mL), with lower levels of FFA (0.82 vs 2.51 mM) and IGFBP-1 (59.5 vs 634 ng/mL). At the time of hypoglycemia, the upper limits of β-hydroxybutyrate and FFA in subjects with congenital hyperinsulinism were higher than reported previously (β-hydroxybutyrate <1.8 mM and FFA <1.7 mM), providing the best sensitivity for congenital hyperinsulinism vs ketotic hypoglycemia. A C-peptide level ≥0.5 ng/mL was 89% sensitive and 100% specific, and an IGFBP-1 level ≤110 ng/mL was 85% sensitive and 96.6% specific.. Because low or undetectable insulin level during hypoglycemia does not exclude the diagnosis of hyperinsulinism, C-peptide and IGFBP-1 may inform the diagnosis of congenital hyperinsulinism. In this group of children with well-defined congenital hyperinsulinism, thresholds for "suppressed" β-hydroxybutyrate and FFA are higher than previously reported levels.

Topics: Adolescent; Biomarkers; C-Peptide; Child; Child, Preschool; Congenital Hyperinsulinism; Female; Humans; Infant; Infant, Newborn; Insulin; Insulin-Like Growth Factor Binding Protein 1; Male; Retrospective Studies

Ectopic thyroid tissue is most commonly located in a single location, this being the lingual area. Presentation with two ectopic thyroid foci is quite unusual. A girl patient aged 7 years who presented with complaints of two masses in the right anterior neck and submandibular area is reported. Her growth pattern and development were normal. The masses were detected to be dual ectopic thyroid glands by ultrasonography, computed tomography and 99m-technetium pertechnetate thyroid scan. The patient also had subclinical hypothyroidism. She was treated with oral levothyroxine and the masses slightly decreased in size. The repeated thyroid function tests were within the normal limits. Thyroid function tests and imaging studies need to be conducted in all patients with anterior neck masses.

Topics: Blood Glucose; C-Peptide; Calcium Channel Blockers; Choristoma; Codon, Nonsense; Congenital Hyperinsulinism; Diazoxide; Diuretics; Drug Resistance; Female; Humans; Infant, Newborn; Insulin; Nifedipine; Octreotide; Pancreatectomy; Sulfonylurea Receptors; Thyroid Gland; Tongue Diseases

Congenital hyperinsulinism (CHI) is the commonest cause of persistent hypoglycemia in neonates. Diazoxide is the first-line drug in its treatment, but the more severe cases are usually diazoxide-resistant. Recessive ABCC8 and KCNJ11 mutations are responsible for most (82%) of the severe diazoxide-unresponsive CHI. Oral nifedipine has been effective in isolated cases of CHI. Successful treatment of diazoxide-unresponsive CHI with a combination of octreotide and nifedipine has been reported in a single isolated case so far. We report here a case of diazoxide-resistant CHI due to homozygous ABCC8 nonsense mutation. In this case, hypoglycaemia uncontrolled by pancreatectomy and octreotide alone showed a good response to a combination of nifedipine and octreotide. Octreotide was tapered off by one year age and thereafter the child is euglycaemic on oral nifedipine alone. Continuous glucose monitoring sensor was used as an aid to monitor glycaemic control and was found to be a safe and reliable option reducing the number of needle-pricks in small children.

Topics: Blood Glucose; C-Peptide; Calcium Channel Blockers; Codon, Nonsense; Congenital Hyperinsulinism; Diazoxide; Diuretics; Drug Resistance; Female; Humans; Infant, Newborn; Insulin; Nifedipine; Octreotide; Pancreatectomy; Sulfonylurea Receptors

Congenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the β-cell ATP-sensitive K(+) channel (K(ATP) channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K(ATP) mutations have been associated with diazoxide-responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619-629delCCCGAGGACCT, Gln444*, Leu724Pro, Ala847Thr, Trp898*, IVS30-2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598*) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling.

Topics: Asian People; Base Sequence; C-Peptide; Congenital Hyperinsulinism; Diazoxide; Humans; India; Insulin; Molecular Sequence Data; Mutation; Sequence Analysis, DNA; Sulfonylurea Receptors

Persistent hyperinsulinemic hypoglycemia in neonatal period is characterized by insulin hypersecretion. The major feature is severe hypoglycemia, generally unresponsive to routine medical treatment. Subtotal or total pancreatectomy is performed in unresponsive cases. In this case report, we present a newborn with persistent hypoglycemia unresponsive to medical treatment with dysrhythmic left ventricular hypertrophy. The insulin/C-peptide ratio was 58 as a confirmation of diagnosis. Since hypoglycemia persisted after the initial medical treatment, a subtotal pancreatectomy was performed followed by near-total pancreatectomy. A histologic examination revealed diffuse insulin islets. At the 70th post-natal day, death occurred due to heart failure and ventricular dysrhythmia. To our knowledge, severe dysrhythmia and left ventricular hypertrophy in persistent hyperinsulinemic hypoglycemia (PPH) is identified in the patient.

Topics: Arrhythmias, Cardiac; C-Peptide; Congenital Hyperinsulinism; Fatal Outcome; Humans; Hypertrophy, Left Ventricular; Infant, Newborn; Insulin; Male; Pancreas; Pancreatectomy

An infant diagnosed as having hypopituitarism and on adequate hydrocortisone replacement therapy was referred to a tertiary endocrine unit at 5 weeks of age with persistent hypoglycemia that required a high rate of intravenous glucose infusion (up to 18 mg/kg•min⁻¹) to maintain euglycemia.. A controlled hypoglycemia screen was performed to measure levels of plasma glucose, insulin, C-peptide and 3-β-hydroxybutyrate concentrations. The pancreas was analyzed by fluorine-18-L-3,4-dihydroxyphenylalanine ((18)F-DOPA) PET scan. Genetic analyses were performed on the peripheral blood leukocytes, and loss of heterozygosity within the resected focal lesion of the pancreas was investigated by microsatellite analysis. A glucagon stimulation test helped determine pituitary function, and an MRI of the brain and pituitary gland was performed to define the anatomy of the intracranial structures and the pituitary gland.. Focal form of congenital hyperinsulinism localized to the head of the pancreas, septo-optic dysplasia and pituitary hormone deficiencies.. Resection of the focal lesion from the head of the pancreas and hormonal replacement therapy for hypopituitarism.

Topics: 3-Hydroxybutyric Acid; Blood Glucose; C-Peptide; Congenital Hyperinsulinism; Glucagon; Glucose; Humans; Hydrocortisone; Hypopituitarism; Infant; Insulin; Loss of Heterozygosity; Male; Pancreas; Pituitary Hormones; Septo-Optic Dysplasia

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