c-peptide and Diabetic-Nephropathies

People with type 1 diabetes have an increased risk of developing microvascular complications, which have a negative impact on the quality of life and reduce life expectancy. Numerous studies in animals with experimental diabetes show that c-peptide supplementation exerts beneficial effects on diabetes-induced damage in peripheral nerves and kidneys. There is substantial evidence that c-peptide counteracts the detrimental changes caused by hyperglycemia at the cellular level, such as decreased activation of endothelial nitric oxide synthase and sodium potassium ATPase, and increase in formation of pro-inflammatory molecules mediated by nuclear factor kappa-light-chain-enhancer of activated B cells: cytokines, chemokines, cell adhesion molecules, vascular endothelial growth factor, and transforming growth factor beta. However, despite positive results from cell and animal studies, no successful c-peptide replacement therapies have been developed so far. Therefore, it is important to improve our understanding of the impact of c-peptide on the pathophysiology of microvascular complications to develop novel c-peptide-based treatments. This article aims to review current knowledge on the impact of c-peptide on diabetic neuro- and nephropathy and to evaluate its potential therapeutic role.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Humans; Microcirculation; Sodium-Potassium-Exchanging ATPase; Translational Research, Biomedical

C-peptide is a small peptide connecting two chains of proinsulin molecule and is dissociated before the release of insulin. It is secreted in an equimolar amount to insulin from the pancreatic beta-cells into the circulation. Recent evidence demonstrates that it has other physiologic activities beyond its structural function. C-peptide modulates intracellular signaling pathways in various pathophysiologic states and, could potentially be a new therapeutic target for different disorders including diabetic complications. There is growing evidence that c-peptide has modulatory effects on the molecular mechanisms involved in the development of diabetic nephropathy. Although we have little direct evidence, pharmacological properties of c-peptide suggest that it can provide potent renoprotective effects especially, in a c-peptide deficient milieu as in type 1 diabetes mellitus. In this review, we describe possible molecular mechanisms by which c-peptide may improve renal efficiency in a diabetic milieu.

Topics: Animals; C-Peptide; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans

Kidney disease is a serious development in diabetes mellitus and poses an increasing clinical problem. Despite increasing incidence and prevalence of diabetic kidney disease, there have been no new therapies for this condition in the last 20 years. Mounting evidence supports a biological role for C-peptide, and findings from multiple studies now suggest that C-peptide may beneficially affect the disturbed metabolic and pathophysiological pathways leading to the development of diabetic nephropathy. Studies of C-peptide in animal models and in humans with type 1 diabetes all suggest a renoprotective effect for this peptide. In diabetic rodents, C-peptide reduces glomerular hyperfiltration and albuminuria. Cohort studies of diabetic patients with combined islet and kidney transplants suggest that maintained C-peptide secretion is protective of renal graft function. Further, in short-term studies of patients with type 1 diabetes, administration of C-peptide is also associated with a lowered hyperfiltration rate and reduced microalbuminuria. Thus, the available information suggests that type 1 diabetes should be regarded as a dual hormone deficiency disease and that clinical trials of C-peptide in diabetic nephropathy are both justified and urgently required.

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Models, Animal; Humans

Proinsulin C-peptide, released in equimolar amounts with insulin by pancreatic β cells, since its discovery in 1967 has been thought to be devoid of biological functions apart from correct insulin processing and formation of disulfide bonds between A and B chains. However, in the last two decades research has brought a substantial amount of data indicating a crucial role of C-peptide in regulating various processes in different types of cells and organs. C-peptide acts presumably via either G-protein-coupled receptor or directly inside the cell, after being internalized. However, a receptor binding this peptide has not been identified yet. This peptide ameliorates pathological changes induced by type 1 diabetes mellitus, including glomerular hyperfiltration, vessel endothelium inflammation and neuron demyelinization. In diabetic patients and diabetic animal models, C-peptide substitution in physiological doses improves the functional and structural properties of peripheral neurons and protects against hyperglycemia-induced apoptosis, promoting neuronal development, regeneration and cell survival. Moreover, it affects glycogen synthesis in skeletal muscles. In vitro C-peptide promotes disaggregation of insulin oligomers, thus enhancing its bioavailability and effects on metabolism. There are controversies concerning the biological action of C-peptide, particularly with respect to its effect on Na⁺/K⁺-ATPase activity. Surprisingly, the excess of circulating peptide associated with diabetes type 2 contributes to atherosclerosis development. In view of these observations, long-term, large-scale clinical investigations using C-peptide physiological doses need to be conducted in order to determine safety and health outcomes of long-term administration of C-peptide to diabetic patients.

Topics: Animals; Apoptosis; Atherosclerosis; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Disease Models, Animal; Glycogen; Humans; Hyperglycemia; Muscle, Skeletal; Peripheral Nervous System

Topics: Animals; C-Peptide; Cell Membrane; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Endothelium, Vascular; Humans; Inflammation; Nitric Oxide; Regional Blood Flow; Signal Transduction

Insulin is synthesised as a pro-hormone with an interconnecting C-peptide, cleaved during post-translational modification. This review discusses growing evidence which indicates that C-peptide is biologically active, benefiting microvascular complications associated with diabetes.. To explore the renoprotective role of C-peptide in diabetic nephropathy (DN), we reviewed the literature using PubMed for English language articles that contained key words related to C-peptide, kidney and DN.. Numerous studies have demonstrated that C-peptide ameliorates a number of the structural and functional renal disturbances associated with uncontrolled hyperglycaemia in human and animal models of type 1 diabetes mellitus that lead to the development and progression of nephropathy, including abrogation of glomerular hyperfiltration, reduced microalbuminuria, decreased mesangial expansion and increased endothelial nitric oxide synthase levels. The in vitro exposure of kidney proximal tubular cells to physiological concentrations of C-peptide activates extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, protein kinase C, elevates intracellular calcium, and stimulates transcription factors NF-kappaB and peroxisome proliferator-activated receptor-gamma.. Burgeoning studies suggest that C-peptide is more than merely a link between the A and B chains of the proinsulin molecule and represents a future therapeutic tool in reducing complications of DN.

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Fibrosis; Humans; Hyperglycemia; Models, Biological; NF-kappa B; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Protein Kinase C; Sodium-Potassium-Exchanging ATPase

In recent years, accumulating evidence indicates a biological function for proinsulin C-peptide. These results challenge the traditional view that C-peptide is essentially inert and only useful as a surrogate marker of insulin release. Accordingly, it is now clear that C-peptide binds with high affinity to cell membranes, probably to a pertussis-toxin-sensitive G-protein-coupled receptor. Subsequently, multiple signalling pathways are potently and dose-dependently activated in multiple cell types by C-peptide with the resulting activation of gene transcription and altered cell phenotype. In diabetic animals and Type 1 diabetic patients, short-term studies indicate that C-peptide also enhances glucose disposal and metabolic control. Furthermore, results derived from animal models and clinical studies in Type 1 diabetic patients suggest a salutary effect of C-peptide in the prevention and amelioration of diabetic nephropathy and neuropathy. Therefore a picture of Type 1 diabetes as a dual-hormone-deficiency disease is developing, suggesting that the replacement of C-peptide alongside insulin should be considered in its management.

Topics: Animals; Blood Glucose; C-Peptide; Cell Membrane; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Humans; Mice

The C-peptide of proinsulin is important for the biosynthesis of insulin and has for a long time been considered to be biologically inert. Animal studies have shown that some of the renal effects of the C-peptide may in part be explained by its ability to stimulate the Na,K-ATPase activity. Precisely, the C-peptide reduces diabetes-induced glomerular hyperfiltration both in animals and humans, therefore, resulting in regression of fibrosis. The tubular function is also concerned as diabetic animals supplemented with C-peptide exhibit better renal function resulting in reduced urinary sodium waste and protein excretion together with the reduction of the diabetes-induced glomerular hyperfiltration. The tubular effectors of C-peptide were considered to be tubule transporters, but recent studies have shown that biochemical pathways involving cellular kinases and inflammatory pathways may also be important. The matter theory concerning the C-peptide effects is a metabolic one involving the effects of the C-peptide on lipidic metabolic status. This review concentrates on the most convincing data which indicate that the C-peptide is a biologically active hormone for renal physiology.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glomerular Filtration Rate; Humans; Inflammation; Kidney Glomerulus; Kidney Tubules; Lipid Metabolism; Signal Transduction; Sodium-Potassium-Exchanging ATPase

Proinsulin connecting peptide (C-peptide) has been initially regarded as deprived of biological functions other than correct scaffolding of insulin. This was caused by the lack of evident effect of C-peptide administration to healthy subjects or animals. At present, in view of numerous studies concerning its structure, membrane binding and biological functions, C-peptide seems to constitute a crucial role in the pathogenesis of complications in diabetes mellitus type 1 (DM1). Patients who maintain high remnant insulin secretion (and therefore also of C-peptide) develop complications such as nephropathy, neuropathy and later microangiopathy with a milder clinical course. In this article we have covered molecular and cellular aspects of C-peptide functioning, such as: activation of protein kinase C, Na+,K+- ATP-ase, nitric oxide synthase, MAP and ERK 1/2 kinases, improvement of nerve conduction velocity and interactions with exogenous and endogenous insulin. We also outline the clinical consequences of deficiency of this underestimated peptide along with its potential therapeutical possibilities in the primary and secondary prevention of DM1 complications.

Topics: Amino Acid Sequence; Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Humans; Insulin; Proinsulin; Rats; Signal Transduction

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Humans; Neural Conduction; Nitric Oxide Synthase; Randomized Controlled Trials as Topic; Sodium-Potassium-Exchanging ATPase

Topics: C-Peptide; Diabetes Complications; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Humans

Connecting peptide (C-peptide) is a product of proinsulin cleavage. New findings demonstrate, that it may serve to understand the mechanisms involved in the development of long-term complications in type 1 diabetic patients. The present review focuses on: 1. Making a point about C-peptide-induced tubular effects on the basis of clinical and experimental experiments, 2. Precising the molecular mechanisms involved in C-peptide-induced tubular Na,K-ATPase effects.

Topics: Animals; C-Peptide; Calcium; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glomerular Filtration Rate; Humans; Nitric Oxide Synthase; Protein Kinase C; Signal Transduction; Sodium-Potassium-Exchanging ATPase

C-peptide is formed in the biosynthesis of insulin and the two peptides are subsequently released in equimolar amounts to the circulation. C-peptide has long been considered to be without physiologic effects. Recent data now demonstrate that C-peptide in the nanomolar concentration range binds specifically to cell surfaces, probably to G protein-coupled receptors, with subsequent activation of Ca(2+)-dependent intracellular signaling pathways and stimulation of Na+, K(+)-ATPase activities. C-peptide replacement in animal models of type 1 diabetes results in diminished hyperfiltration, improved functional reserve, reduction of urinary albumin excretion, and prevention of glomerular and renal hypertrophy. Administration of C-peptide to physiologic concentrations in patients with type 1 diabetes and incipient nephropathy for periods of 3 hours to 3 months is accompanied by reduced glomerular hyperfiltration and filtration fraction, and diminished urinary albumin excretion. C-peptide replacement together with insulin therapy may be beneficial in type 1 diabetes patients with nephropathy.

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans

Topics: Aged; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Coma; Diabetic Nephropathies; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nutrition Disorders; Patient Selection; Pregnancy; Pregnancy in Diabetics

Topics: Adult; Animals; C-Peptide; Carbohydrate Metabolism; Cattle; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dogs; Graft Survival; Humans; Immunosuppression Therapy; Islets of Langerhans Transplantation; Kidney Transplantation; Middle Aged; Pancreas; Pancreas Transplantation; Pancreatic Ducts; Postoperative Complications; Stomach; Vasculitis

Diabetes mellitus is a heterogeneous disorder. About 80% of the patients with this disease are categorized as having non-insulin-dependent diabetes mellitus, a disorder resulting from varied degrees of insulin resistance and impaired insulin secretion; the causes for these abnormalities are unknown. The remaining 15 to 20% of patients have insulin-dependent diabetes mellitus, a disorder caused by the destruction of insulin-producing endocrine cells within the pancreas and currently considered to be the result of an autoimmune process. During the course of both types of diabetes mellitus, the so-called long-term complications of diabetes invariably occur to some extent in all patients. These complications include retinopathy, nephropathy, neuropathy, and premature atherosclerosis. The molecular basis for these complications is not completely understood, but recent evidence obtained from both experiments in animals and prospective clinical studies indicates that metabolic derangements associated with poor glycemic control are a major determinant of the frequency and severity of these complications. Such evidence is the rationale for current attempts to maintain near-normal glycemia in patients with diabetes mellitus.

Topics: Autoimmune Diseases; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Diagnosis, Differential; Glucagon; Humans; Insulin; Insulin Resistance

The aim of the study was to evaluate circulatory AGE-peptide levels in diabetic nephropathy and to observe the effects of thiamine (vitamin B1) and pyridoxine (vitamin B6) therapy.. Type 2 diabetic patients (N.=57) were divided into two groups as "with nephropathy" (N.=27) and "without nephropathy" (N.=30). Diabetic nephropathy patients were treated with either B6 (N.=12) (250 mg/day) or B1+B6 (N.=15) (250 mg/day, each) for five months. At the beginning and the end of the experimentation period, glucose, HbA1c, triglyceride, cholesterol, insulin, C-peptide, thiamine pyrophosphate, pyridoxal phosphate and AGE- peptides were measured.. AGE-peptides were higher in the diabetic group with nephropathy than without nephropathy (P=0.005). Within five months AGE-peptides increased in the diabetic group without nephropathy (P=0.042) but not in the group with nephropathy treated either with B1+B6 or B6. In B6 treated group a substantial decrease was observed in HbA1c (P=0.033). B1+B6 or B6 treatment both caused an increase in C-peptide (P=0.006, P=0.004).. Among the parameters measured, plasma AGE-peptides was the only parameter found to be higher in type 2 diabetes mellitus patients "with nephropathy" than "without nephropathy". However, patients with nephropathy treated with B1+B6 or B6 did not display any further increase in AGE-peptides within five months. Both of the treatments caused an increase in C-peptide.

Topics: Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Male; Middle Aged; Pyridoxal Phosphate; Pyridoxine; Thiamine; Thiamine Pyrophosphate; Triglycerides; Vitamin B Complex

To evaluate the safety and efficacy of ingested human recombinant interferon-alpha (hrIFN-alpha) for preservation of beta-cell function in young patients with recent-onset type 1 diabetes.. Subjects aged 3-25 years in whom type 1 diabetes was diagnosed within 6 weeks of enrollment were randomly assigned to receive ingested hrIFN-alpha at 5,000 or 30,000 units or placebo once daily for 1 year. The primary outcome was change in C-peptide secretion after a mixed meal.. Individuals in the placebo group (n = 30) lost 56 +/- 29% of their C-peptide secretion from 0 to 12 months, expressed as area under the curve (AUC) in response to a mixed meal. In contrast, children treated with hrIFN-alpha lost 29 +/- 54 and 48 +/- 35% (for 5,000 [n = 27] and 30,000 units [n = 31], respectively, P = 0.028, ANOVA adjusted for age, baseline C-peptide AUC, and study site). Bonferroni post hoc analyses for placebo versus 5,000 units and placebo versus 30,000 units demonstrated that the overall trend was determined by the 5,000-unit treatment group. Adverse events occurred at similar rates in all treatment groups.. Ingested hrIFN-alpha was safe at the doses used. Patients in the 5,000-unit hrIFN-alpha treatment group maintained more beta-cell function 1 year after study enrollment than individuals in the placebo group, whereas this effect was not observed in patients who received 30,000 units hrIFN-alpha. Further studies of low-dose ingested hrIFN-alpha in new-onset type 1 diabetes are needed to confirm this effect.

Topics: Administration, Oral; Adolescent; Adult; Antibodies, Antinuclear; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Eating; Humans; Immunologic Factors; Insulin-Secreting Cells; Interferon-alpha; Placebos; Young Adult

Changes in plasma immunoreactive insulin (IRI) and connecting-peptide immunoreactivity (CPR) concentrations during hemodialysis (HD) were evaluated in diabetic HD patients with 3 different high-flux membranes. The removal properties of the membranes were compared.. In this prospective controlled study, 15 stable diabetic patients on HD were randomly selected for 6 HD sessions with 3 different membranes: polysulfone (PS), cellulose triacetate (CTA), and polymethylmethacrylate (PMMA). Blood samples were obtained from the blood tubing at the arterial (A) site at the beginning and end of the sixth HD session. At 60 minutes after dialysis initiation, blood samples were obtained from both the A and venous (V) sites of the dialyzer to investigate the clearance and removal properties of the membranes.. The plasma IRI and CPR levels decreased significantly at each time point with all 3 membranes. IRI clearance with the PS membrane was significantly higher than that with the CTA and PMMA membranes. No difference was observed in the IRI reduction rate between the 3 membranes. CPR clearance and reduction rate with the PMMA membrane were lower than with the PS and CTA membranes. No significant difference was observed in serum creatinine clearance and reduction rates between the 3 membranes; however, serum urea nitrogen clearance was significantly lower with the PMMA membrane compared with the PS and CTA membranes. A significantly high beta2-microglobulin clearance and reduction rate was achieved in the order PS > CTA > PMMA.. Plasma IRI and CPR are cleared by HD; their clearance rates differ with the dialyzer membranes. Plasma IRI clearance with the PS membrane is higher than that with the CTA and PMMA membranes.

Topics: Blood Glucose; C-Peptide; Cellulose; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Equipment Design; Hemoglobins; Humans; Insulin; Membranes, Artificial; Polymers; Polymethyl Methacrylate; Renal Dialysis; Serum Albumin; Sulfones; Urea; Uremia

A growing body of evidence supports the concept that treatment with the newer angiotensin type-1 receptor blockers (ARBs) improves glucose homeostasis under conditions wherein it is impaired. Controversy exists, however, regarding the ability of losartan, an older ARB, to exert comparable improvement. The present study was undertaken to evaluate the effects of losartan on glucose homeostasis in subjects with type 2 diabetes and nephropathy.. Twenty-seven subjects with type 2 diabetic nephropathy were enrolled in this prospective, randomized, controlled study. Losartan (100 mg daily) or the calcium channel blocker amlodipine (10 mg daily) was administered for a period of 3 months. Fasting blood glucose, serum insulin and C-peptide concentrations were measured at baseline and at the end of the study. Oral glucose tolerance tests were performed to evaluate insulin sensitivity and beta-cell responsiveness. Insulin resistance was measured using the homeostasis model assessment of insulin resistance (HOMA-IR).. Fasting blood glucose, HbA1c, AUC glucose, and urinary protein values were significantly decreased in the losartan group as compared with the amlodipine group (P<0.05). Furthermore, C-peptide concentrations, the insulin sensitivity index, and the insulin-to-glucose ratio were significantly increased after 3 months of therapy with losartan as compared to amlodipine (P<0.05). Reductions of fasting insulin concentrations and HOMA-IR were also observed for the losartan group; however, reductions were not significant when compared with the amlodipine group.. In addition to reducing urinary protein excretion, losartan at 100 mg daily increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetic nephropathy.

Topics: Adult; Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Blood Glucose; C-Peptide; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fasting; Female; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Insulin Resistance; Losartan; Male; Middle Aged; Proteinuria; Time Factors; Treatment Outcome

Antibodies to the smaller isoform of glutamic acid decarboxylase (GAD65Ab) have been linked to the presence of neuropathy in Type 1 diabetes in several small studies. We attempted to confirm this association by measuring GAD65Ab, GAD65Ab epitopes and IA-2Ab in 511 patients who participated in the Diabetes Control and Complications Trial (DCCT). We also tested for correlations between these autoantibodies and C-peptide and glycemic control. We only included patients for whom serum was available from the first 4 years of their illness. The presence or absence of neuropathy was determined by electrophysiological studies, autonomic testing and clinical evaluation at baseline and 5 years into the trial or at close out. Samples from controls (patients without neuropathy at 5 years) were selected for patients who had similar C-peptide responses to a standardized meal at baseline. The GAD65Ab index correlated with HgbA(1c) only in the adult participants and only at baseline. The adults initially in poor control (upper tertile for glycemia) had higher GAD65Ab and lower C-peptides. The GAD65Ab index was not significantly different in patients with confirmed clinical neuropathy at 5 years versus controls matched for C-peptide (.248+/-.03 versus .278+/-.03). Epitope analysis, based on the blocking of conformational epitopes by recombinant Fab, revealed that the binding to multiple epitopes was decreased in the patients with neuropathy.

Topics: Adolescent; Adult; Age Factors; Autoantibodies; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glutamate Decarboxylase; Glycated Hemoglobin; Humans; Insulin-Secreting Cells; Isoenzymes

Pancreas transplant alone can be effective in significantly improving the quality of life of type 1 diabetic patients, and it can also eliminate acute diabetes complications, such as hypoglycemic and/or hyperglycemic episodes. The effects of pancreas transplant alone on long-term complications of diabetes, including nephropathy, are still not settled. We evaluated whether restoration of long-lasting normoglycemia by pancreas transplant alone might have beneficial action on diabetic nephropathy.. A total of 32 type 1 diabetic patients were evaluated before and 1 year after successful pancreas transplant alone, together with 30 matched nontransplanted type 1 diabetic subjects. Several metabolic and kidney function parameters were measured, including plasma glucose, glycohemoglobin (A1C), C-peptide, plasma lipids, blood pressure, creatinine, creatinine clearance, and urinary protein excretion.. Pancreas transplant alone restored sustained normoglycemia, without exogenous insulin administration, and improved plasma lipid levels. Blood pressure decreased significantly. Creatinine concentrations and clearances did not differ before and after transplantation. Urinary protein excretion decreased significantly after pancreas transplant alone, with four microalbuminuric and three macroalbuminuric patients who became normoalbuminuric. None of these changes occurred in the nontransplanted group.. Successful pancreas transplant alone, through restoration of sustained normoglycemia, improves diabetic nephropathy in type 1 diabetic patients.

Topics: Adult; Anticholesteremic Agents; Antihypertensive Agents; Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Male; Pancreas Transplantation; Proteinuria; Time Factors; Triglycerides

Cardiovascular mortality and morbidity are major problems in type 1 diabetic patients with end-stage renal disease (ESRD). The aim of this study was to determine whether islet transplantation can improve cardiovascular function in these patients.. We assessed various markers of cardiac function at baseline and 3 years later in a population of 42 type 1 diabetic patients with ESRD who received a kidney transplant. Seventeen patients then received an islet transplant that had persistent function as defined by long-term C-peptide secretion (kidney-islet group). Twenty-five patients did not receive a functioning islet transplant (kidney-only group).. GHb levels were similar in the two groups, whereas the exogenous insulin requirement was lower in the kidney-islet group with persistent C-peptide secretion. Overall, cardiovascular parameters improved in the kidney-islet group, but not in the kidney-only group, with an improvement of ejection fraction (from 68.2 +/- 3.5% at baseline to 74.9 +/- 2.1% at 3 years posttransplantation, P < 0.05) and peak filling rate in end-diastolic volume (EDV) per second (from 3.87 +/- 0.25 to 4.20 +/- 0.37 EDV/s, P < 0.05). Time to peak filling rate remained stable in the kidney-islet group but worsened in the kidney-only group (P < 0.05). The kidney-islet group also showed a reduction of both QT dispersion (53.5 +/- 4.9 to 44.6 +/- 2.9 ms, P < 0.05) and corrected QT (QTc) dispersion (67.3 +/- 8.3 to 57.2 +/- 4.6 ms, P < 0.05) with higher erythrocytes Na(+)-K(+)-ATPase activity. In the kidney-islet group only, both atrial natriuretic peptide and brain natriuretic peptide levels decreased during the follow-up, with a stabilization of intima-media thickness.. Our study showed that type 1 diabetic ESRD patients receiving a kidney transplant and a functioning islet transplant showed an improvement of cardiovascular function for up to 3 years of follow-up compared with the kidney-only group, who experienced an early failure of the islet graft or did not receive an islet graft.

Topics: Atrial Natriuretic Factor; C-Peptide; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythrocytes; Female; Graft Survival; Humans; Islets of Langerhans Transplantation; Kidney Transplantation; Male; Middle Aged; Natriuretic Peptide, Brain; Postoperative Complications; Sodium-Potassium-Exchanging ATPase

Aim of this study was to investigate whether octreotide, a synthetic somatostatin analogue that inhibits growth hormone, insulin and glucagon secretion and improves glycaemic control in insulin dependent diabetic patients was able to exert similar effects in insulin treated type 2 diabetic patients with chronic renal failure who have high plasma glucagon levels. For this purpose saline or octreotide was randomly administered by continuous subcutaneous infusion (100 mcg/daily) in addition to usual insulin treatment for 5 days to six type 2 insulin treated diabetic patients with chronic renal failure and to six type 2 patients with normal renal function, as a control group. At day 3 of insulin plus saline or insulin plus octreotide treatment, total glucose uptake and hepatic glucose production (HGP) were investigated during an euglycemic clamp; at day 5 GH, glucagon and C-peptide plasma levels were evaluated. Octreotide treatment lowered endogenous insulin secretion (evaluated by C-Peptide levels assay), GH and glucagon in all patients, but caused a significant reduction of daily insulin requirement (32 +/- 14 I.U. vs 41 +/- 19 I.U., P<0.02) only in patients with renal failure. HGP was significantly (P<0.05) lowered in patients with renal failure but glucose uptake remained unchanged. The lowering effect of octreotide on insulin requirement in diabetic patients with renal failure in spite of the contemporaneous inhibition on insulin secretion could be explained on the basis of the greater reduction of glucagon levels which are very elevated in these patients as compared to patients with normal renal function. The lowering of glucagon could decrease HGP and, consequently, insulin requirement.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gluconeogenesis; Glucose Clamp Technique; Human Growth Hormone; Humans; Infusions, Parenteral; Insulin; Insulin Secretion; Kidney Failure, Chronic; Kidney Function Tests; Liver; Male; Middle Aged; Octreotide

To evaluate the long-term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes.. Diet or tablet-treated patients with Type 2 diabetes (n = 256; age 40-75 years, body mass index (BMI) 20-35 kg/m2, HbA1c 4.2-12.8%), without signs of severe microvascular or macrovascular complications, were included in this double-blind, multicentre, parallel-group comparative trial. Patients were randomized at a 2:1 ratio to repaglinide, 1-4 mg at mealtimes, or glipizide, 5-15 mg daily.. Changes in fasting blood glucose (FBG) and HbA1c during the 12 months of treatment showed a significant difference in favour of repaglinide. In oral hypoglycaemic agents (OHA)-naive patients, HbA1c decreased in the repaglinide and glipizide groups by 1.5% and 0.3%, respectively (P < 0.05 between groups). Fasting blood glucose decreased in the repaglinide group by 2.4 mmol/l and increased in the glipizide group by 1.0 mmol/l (P < 0.05 between groups). In the study population as a whole, repaglinide was able to maintain glycaemic control (HbA1c level) during the 1-year study period, whereas control deteriorated significantly with glipizide. Change in HbA1c from baseline was significantly better with repaglinide than with glipizide after 12 months (P < 0.05). In addition, FBG deteriorated significantly in the glipizide group compared with the repaglinide group (P < 0.05). No patients in either group experienced a major hypoglycaemic event; the number of patients experiencing minor hypoglycaemia was similar in the repaglinide and glipizide groups (15% and 19%, respectively).. Repaglinide, given as a prandial glucose regulator, is shown to be an effective and safe treatment of patients with Type 2 diabetes, and is better than glipizide in controlling HbA1c and FBG levels, overall, and in OHA-naive patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Fasting; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines

A randomized study of combined kidney-pancreas transplantation was performed on 30 insulin-dependent diabetic patients with end-stage renal disease to compare the consequences of pancreas transplantation with portal venous (PV) and systemic venous (SV) drainage. Fourteen patients (SV) group) received systemically drained and sixteen (PV group) portally drained pancreas allografts. Enteric drainage was performed in both groups. The routine follow-up included documentation of the clinical course and detailed endocrine studies. At 1 year after transplantation, the patient survival rate was 92% for the SV group and 96% for the PV group; the graft survival rate was 78% and 82%, respectively. Endocrine studies indicated no difference in fasting and stimulated glucose or in glycosylated hemoglobin between the two groups. In addition, no hyperinsulinemia and lipidic abnormalities were evidenced in either group Long-term studies are required to conclude whether PV and SV drainage in pancreas transplantation are equivalent in terms of patient and graft survival as well as metabolic consequences.

Topics: Adult; Anastomosis, Surgical; Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drainage; Female; Glucose Tolerance Test; Humans; Insulin; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Portal Vein; Triglycerides; Veins

Recent studies have indicated that proinsulin C-peptide shows specific binding to cell membrane binding sites and may exert biological effects when administered to patients with Type 1 diabetes mellitus. This study was undertaken to determine if combined treatment with C-peptide and insulin might reduce the level of microalbuminuria in patients with Type 1 diabetes and incipient nephropathy.. Twenty-one normotensive patients with microalbuminuria were studied for 6 months in a double-blind, randomized, cross-over design. The patients received s.c. injections of either human C-peptide (600 nmol/24 h) or placebo plus their regular insulin regimen for 3 months.. Glycaemic control improved slightly during the study and to a similar extent in both treatment groups. Blood pressure was unaltered throughout the study. During the C-peptide treatment period, urinary albumin excretion decreased progressively on average from 58 microg/min (basal) to 34 microg/min (3 months, P < 0.01) and it tended to increase, but not significantly so, during the placebo period. The difference between the two treatment periods was statistically significant (P < 0.01). In the 12 patients with signs of autonomic neuropathy prior to the study, respiratory heart rate variability increased by 21 +/- 9% (P < 0.05) during treatment with C-peptide but was unaltered during placebo. Thermal thresholds were significantly improved during C-peptide treatment in comparison to placebo (n = 6, P < 0.05).. These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.

Topics: Adult; Albuminuria; Autonomic Nervous System Diseases; Blood Glucose; C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Double-Blind Method; Heart Rate; Humans; Insulin; Kidney; Placebos

A homogeneous patient population is necessary to identify genetic factors that regulate complex disease pathogenesis. In this study, we evaluated clinical and biochemical phenotyping criteria for type 2 diabetes in end-stage renal disease (ESRD) probands of families in which nephropathy is clustered. C-peptide concentrations accurately discriminate type 1 from type 2 diabetic patients with normal renal function, but have not been extensively evaluated in ESRD patients. We hypothesized that C-peptide concentrations may not accurately reflect insulin synthesis in ESRD subjects, since the kidney is the major site of C-peptide catabolism and would poorly correlate with accepted clinical criteria used to classify diabetics as types 1 and 2.. Consenting diabetic ESRD patients (N = 341) from northeastern Ohio were enrolled. Clinical history was obtained by questionnaire, and predialysis blood samples were collected for C-peptide levels from subjects with at least one living diabetic sibling (N = 127, 48% males, 59% African Americans).. Using clinical criteria, 79% of the study population were categorized as type 1 (10%) or type 2 diabetics (69%), while 21% of diabetic ESRD patients could not be classified. In contrast, 98% of the patients were classified as type 2 diabetics when stratified by C-peptide concentrations using criteria derived from the Diabetes Control and Complications Trial Research Group (DCCT) and UREMIDIAB studies. Categorization was concordant in only 70% of ESRD probands when C-peptide concentration and clinical classification algorithms were compared. Using clinical phenotyping criteria as the standard for comparison, C-peptide concentrations classified diabetic ESRD patients with 100% sensitivity, but only 5% specificity. The mean C-peptide concentrations were similar in diabetic ESRD patients (3.2 +/- 1.9 nmol/L) and nondiabetic ESRD subjects (3.5 +/- 1.7 nmol/L, N = 30, P = NS), but were 2.5-fold higher compared with diabetic siblings (1.3 +/- 0.7 nmol/L, N = 30, P < 0.05) with normal renal function and were indistinguishable between type 1 and type 2 diabetics. Although 10% of the diabetic ESRD study population was classified as type 1 diabetics using clinical criteria, only 1.5% of these patients had C-peptide levels less than 0.20 nmol/L, the standard cut-off used to discriminate type 1 from type 2 diabetes in patients with normal renal function. However, the criteria of C-peptide concentrations> 0.50 nmol/L and diabetes onset in patients who are more than 38 years old identify type 2 diabetes with a 97% positive predictive value in our ESRD population.. Accepted clinical criteria, used to discriminate type 1 and type 2 diabetes, failed to classify a significant proportion of diabetic ESRD patients. In contrast to previous reports, C-peptide levels were elevated in the majority of type 1 ESRD diabetic patients and did not improve the power of clinical parameters to separate them from type 2 diabetic or nondiabetic ESRD subjects. Accurate classification of diabetic ESRD patients for genetic epidemiological studies requires both clinical and biochemical criteria, which may differ from norms used in diabetic populations with normal renal function.

Topics: Adult; Age of Onset; Algorithms; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Genetic Predisposition to Disease; Humans; Insulin; Insulin Secretion; Kidney Failure, Chronic; Male; Middle Aged; Phenotype; Predictive Value of Tests; Sensitivity and Specificity

Islet allografts in insulin-dependent diabetic (IDDM) patients exhibit variable survival lengths and low rates of insulin-independence despite treatment with anti-T-cell antibodies and maintenance immunosuppression. Use of poorly characterized freshly isolated preparations makes it difficult to determine whether failures are caused by variations in donor tissue. This study assesses survival of standardized beta-cell allografts in C-peptide negative IDDM patients on maintenance immunosuppression following kidney transplantation and without receiving anti-T-cell antibodies or additional immunosuppression. Human islets were isolated from pancreatic segments after maximal 20 h cold-preservation. During culture, preparations were selected according to quality control tests and combined with grafts with standardized cell composition (> or = 50% beta cells), viability (> or = 90%), total beta-cell number (1 to 2 x 10(6)/kg body weight) and insulin-producing capacity (2 to 4 nmol x graft(-1) x h(-1)). Grafts were injected in a liver segment through the repermeabilized umbilical vein. After 2 weeks C-peptide positivity, four out of seven recipients became C-peptide negative; two of them were initially GAD65-antibody positive and exhibited a rise in titre during graft destruction. The other three patients remained C-peptide positive for more than 1 year, two of them becoming insulin-independent with near-normal fasting glycaemia and HbA1c; they remained GAD65- and islet cell antibody negative. The three patients with surviving grafts presented a history of anti-thymocyte globulin therapy at kidney transplantation. Long-term surviving grafts increased C-peptide release following intravenous glucagon or oral glucose but not following intravenous glucose. Thus, cultured human beta-cells can survive for more than 1 year in IDDM patients on maintenance anti-rejection therapy for a prior kidney graft and without the need for an increased immunosuppression at the time of implantation. The use of functionally standardized beta-cell grafts helps to identify recipient and graft factors which influence their survival and metabolic effects. Insulin-independence can be achieved by injection of 1.5 million beta-cells per kg body weight in a liver segment. These beta-cell implants respond well to adenylcyclase activators but poorly to glucose.

Topics: Adolescent; Adult; Autoantibodies; Blood Glucose; C-Peptide; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glucagon; Glutamate Decarboxylase; Glycated Hemoglobin; Histocompatibility Testing; Humans; Islets of Langerhans Transplantation; Kidney Transplantation; Liver; Male; Middle Aged; Tissue Donors; Transplantation, Heterotopic

The characteristic clinical features of diabetes mellitus with mitochondrial DNA (mtDNA) 3243(A-G) mutation are progressive insulin secretory defect, neurosensory deafness and maternal inheritance, referred to as maternally inherited diabetes mellitus and deafness (MIDD). A treatment for MIDD to improve insulin secretory defects and reduce deafness has not been established. The effects of coenzyme Q10 (CoQ10) treatment on insulin secretory response, hearing capacity and clinical symptoms of MIDD were investigated. 28 MIDD patients (CoQ10-DM), 7 mutant subjects with impaired glucose tolerance (IGT), and 15 mutant subjects with normal glucose tolerance (NGT) were treated daily with oral administration of 150 mg of CoQ10 for 3 years. Insulin secretory response, blood lactate after exercise, hearing capacity and other laboratory examinations were investigated every year. In the same way we evaluated 16 MIDD patients (control-DM), 5 mutant IGT and 5 mutant NGT subjects in yearly examinations. The insulin secretory response assessed by glucagon-induced C-peptide secretion and 24 h urinary C-peptide excretion after 3 years in the CoQ10-DM group was significantly higher than that in the control-DM group. CoQ10 therapy prevented progressive hearing loss and improved blood lactate after exercise in the MIDD patients. CoQ10 treatment did not affect the diabetic complications or other clinical symptoms of MIDD patients. CoQ10 treatment did not affect the insulin secretory capacity of the mutant IGT and NGT subjects. There were no side effects during therapy. This is the first report demonstrating the therapeutic usefulness of CoQ10 on MIDD.

Topics: Adult; C-Peptide; Coenzymes; Deafness; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; DNA, Mitochondrial; Family Health; Female; Glucagon; Glucose Intolerance; Glucose Tolerance Test; Hearing; Humans; Lactic Acid; Male; Middle Aged; Mothers; Point Mutation; Time Factors; Treatment Outcome; Ubiquinone

Although some studies have suggested a direct action of troglitazone on vascular cells, its effects on diabetic vascular diseases have not been reported. We therefore investigated the effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy.. A total of 30 patients with type 2 diabetes associated with microalbuminuria (urinary albumin-to-creatinine ratio [ACR] [milligrams per gram creatinine] ranging from 30 to 300 mg/g creatinine) were studied. They were randomly divided into two groups: patients treated with metformin (500 mg/day, n = 13) or with troglitazone (400 mg/day, n = 17) for 12 weeks. ACR, lipid profile, blood pressure, glycated hemoglobin, and plasma glucose during meal-load tests were measured every 4 weeks.. Anthropometric indices (BMI and percent fat), lipid profile, and blood pressure did not change with either treatment. Fasting and postmeal glucose levels decreased similarly in the two groups. Decrements in glycated hemoglobin were greater in the metformin group at 4 and 8 weeks after the initiation of treatment (P < 0.05). Troglitazone reduced ACR (median [25-75th percentiles]) from 70 (49-195) to 40 (31-90) mg/g creatinine at 4 weeks (P = 0.021) and maintained these reduced levels throughout the treatment period (8 weeks: 35 [26-68], P = 0.007; 12 weeks: 43 [26-103], P = 0.047). Metformin did not change ACR throughout the 12 weeks.. Troglitazone ameliorated microalbuminuria in diabetic nephropathy. Furthermore, our findings suggest that troglitazone has some effects on vascular cells other than lowering plasma glucose levels. Troglitazone might be useful for diabetic angiopathy, including nephropathy and coronary artery disease.

Topics: Aged; Albuminuria; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Cholesterol, HDL; Chromans; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Thiazoles; Thiazolidinediones; Triglycerides; Troglitazone

To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, we performed a prospective study of Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with multiple insulin injection treatment. A total of 110 patients with NIDDM was randomly assigned to multiple insulin injection treatment group (MIT group) or to conventional insulin injection treatment group (CIT group). Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary-prevention cohort, and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary-intervention cohort. The appearance and the progression of retinopathy, nephropathy and neuropathy were evaluated every 6 months over a 6-year period. The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages (normoalbuminuria, microalbuminuria and albuminuria) for nephropathy. The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7% for the MIT group and 32.0% for the CIT group in the primary-prevention cohort (P = 0.039), and 19.2% for MIT group and 44.0% for CIT group in the secondary-intervention cohort (P = 0.049). The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7% for the MIT group and 28.0% for the CIT group in the primary-prevention cohort (P = 0.032), and 11.5% and 32.0%, respectively, for the MIT and CIT groups in the secondary-intervention cohort (P = 0.044). In neurological tests after 6 years, MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group, they deteriorated in the CIT group. In conclusion, intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy, nephropathy and neuropathy in Japanese patients with NIDDM. From this study, the glycemic threshold to prevent the onset and the progression of diabetic microangio

Topics: Albuminuria; Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Cholesterol, HDL; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Humans; Insulin; Japan; Male; Middle Aged; Neural Conduction; Prospective Studies; Statistics, Nonparametric; Time Factors; Triglycerides

Topics: Antilymphocyte Serum; Azathioprine; C-Peptide; Cells, Cultured; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Immunosuppression Therapy; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Muromonab-CD3; Postoperative Complications; Prednisone; Tissue Preservation; Transplantation, Heterotopic; Transplantation, Homologous

Topics: Blood Glucose; C-Peptide; Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glycated Hemoglobin; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Pancreas Transplantation; Tacrolimus

To assess individual factors responsible of overall glucose tolerance after successful pancreas transplantation, an i.v. glucose tolerance test, with frequent blood sampling and tolbutamide administration to elicit a second insulin response was used to estimate insulin sensitivity (SI) and glucose effectiveness (SG) with Bergman's minimal model. Insulin secretion was calculated from the combined insulin-C-peptide kinetics method. These parameters were quantified in identically immunosupressed transplants: ISPx, four segmental pancreas recipients with impaired glucose tolerance; TSPx, five segmental pancrease recipients with normal glucose tolerance; WPx, five whole pancreas recipients with normal glucose tolerance; and in two controls groups, Kx, eight nondiabetic kidney recipients, and Ns, eight normal subjects. All participants had normal fasting plasma glucose and normal glycosylated hemoglobin A1C levels. The glucose tolerance KG value was significantly reduced only in ISPx compared with Ns (P < 0.05). SI was reduced by 60% in ISPx, WPx, and Kx compared with normal subjects (P < 0.05), whereas SI was reduced by 30% in TSPx compared with normal controls (P = NS). The reduction in SG was the same in all pancreas transplanted groups, as compared to Kx and Ns (by 33% and 40%, respectively, P < 0.05). The first-phase insulin secretion (0-5 min) was markedly reduced in ISPx and TSPx compared with Ns (by 76% and 50%), to Kx (by 84% and 66%) and to WPx (by 73% and 45%), respectively (P < 0.05), but similar to Ns in WPx. The overall incremental insulin secretion was reduced in ISPx compared with Ns, WPx, and Kx (by 38%, 62%, and 73%, respectively, P < 0.05) and reduced in TSPx compared to WPx and Kx (by 47% and 67%, respectively, P < 0.05) Ns secreted 43% of the total amount of insulin during the first phase the corresponding value was only 13% in ISPx vs. 24% in TSPx, 24% in Kx, and 25% in WPx, respectively (P < 0.05). In conclusion, after pancreas transplantation, the overall glucose tolerance is determined by the net effect of reductions in insulin sensitivity and glucose effectiveness and in the adaptability of the beta-cells to ensure sufficient insulin secretion. beta-cell function was impaired in both the whole pancreas and segmental transplant recipients, and the failure to increase insulin secretion sufficiently leads to glucose intolerance.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Kidney Transplantation; Kinetics; Male; Middle Aged; Pancreas Transplantation; Tolbutamide

We report the long-term metabolic observations made on 37 patients after simultaneous pancreas and kidney transplantation. Plasma C-peptide levels were above the physiological range in all patients and there was no significant difference between patients undergoing delayed duct occlusion (n = 12) or those with drainage of exocrine secretion into the urinary bladder (n = 25). HbA1c was equally at the upper end of the normal range in both subsets of patients. Mean fasting cholesterol (237 mg/dl) and triglycerides (122 mg/dl) were normal, and HDL-cholesterol was above normal with an average concentration of 77 mg/dl. Two patients underwent an oral fat tolerance test and showed extremely low postprandial lipaemia and very high lipoprotein lipase activities. We conclude that patients with a functioning pancreas graft persistently demonstrate normoglycaemia, elevated C-peptide, and a very favourable lipid profile both in the fasting and the postprandial state.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Lipids; Pancreas Transplantation

To investigate the association between Hemoglobin Glycation Index (HGI) and Diabetic Kidney Disease (DKD) in Chinese type 2 diabetic individuals and to construct a risk score based on HGI to predict a person's risk of DKD.. We retrospectively analyzed 1622 patients with type 2 diabetes mellitus (T2DM). HGI was obtained by calculating the fasting plasma glucose (FPG) level into the formula, and they were grouped into low HGI group (L-HGI), medium HGI group (H-HGI) and high HGI group (H-HGI) according to tri-sectional quantile of HGI. The occurrence of DKD was analyzed in patients with different levels of HGI. Multivariate logistics regression analysis was used to analyze the risk factors of DKD in patients with T2DM.. A total of 1622 patients with T2DM were enrolled in the study. Among them, 390 cases were DKD. The prevalence of DKD among the three groups was 16.6%, 24.2% and 31.3%. The difference was statistically significant (P = 0.000). There were significant differences in age (P=0.033), T2DM duration (P=0.005), systolic blood pressure (SBP) (P=0.003), glycosylated hemoglobin (HbA1c) (P=0.000), FPG (P=0.032), 2-hour postprandial plasma glucose (2h-PPG) (P=0.000), fasting C-peptide FCP (P=0.000), 2-hour postprandial C-peptide (2h-CP) (P=0.000), total cholesterol (TC) (P=0.003), low density lipoprotein cholesterol (LDL-C) (P=0.000), serum creatinine (sCr) (P=0.001), estimated glomerular filtration rate (eGFR) (P=0.000) among the three groups. Mantel-Haenszel chi-square test showed that there was a linear relationship between HGI and DKD (x2=177.469, p < 0.001). Pearson correlation analysis showed that with the increase of HGI level the prevalence of DKD was increasing (R= 0.445, P=0.000). It was indicated by univariate logistic regression analysis that individuals in H-HGI was more likely to develop DKD (OR: 2.283, 95% CI: 1.708~ 3.052) when compared with L-HGI. Adjusted to multiple factors, this trend still remained significant (OR: 2.660, 95% CI: 1.935~ 3.657). The combined DKD risk score based on HGI resulted in an area under the receiver operator characteristic curve (AUROC) of 0.702.. High HGI is associated with an increased risk of DKD. DKD risk score may be used as one of the risk predictors of DKD in type 2 diabetic population.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycated Hemoglobin; Humans; Inpatients; Maillard Reaction; Retrospective Studies

The primary objective was to assess beta-cell function of recently-diagnosed young-onset type 2 diabetes mellitus (T2DM) individuals using basal and stimulated C-peptide levels. The secondary objective was to examine the association between C-peptide with metabolic factors and diabetes complications.. A cross-sectional study was conducted for young-onset T2DM individuals aged 18-35 years with a disease duration of not more than 5 years. Plasma C-peptide was measured before and after intravenous glucagon injection. Demographic data, medical history and complications were obtained from medical records and clinical assessment. Continuous data were expressed as median and interquartile range (IQR). Categorical variables were described as frequency or percentage. Multivariable linear regression analysis was used to determine factors associated with C-peptide levels.. 113 participants with young-onset T2DM with a median (IQR) age of 29.0 (9.5) years and 24 (36) months were included in this study. The median (IQR) basal and stimulated C-peptide was 619 (655) pmol/L and 1231 (1024) pmol/L. Adequate beta-cell function was present in 78-86% of the participants based on the basal and stimulated C-peptide levels. We found hypertension, obesity and diabetic kidney disease (DKD) to be independently associated with higher C-peptide levels. In contrast, females, smokers, those on insulin therapy and with longer duration of disease had lower C-peptide levels.. Most recently diagnosed young-onset T2DM have adequate beta-cell function. Elevated C-peptide levels associated with obesity, hypertension and diabetic kidney disease suggest insulin resistance as the key driving factor for complications.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypertension; Obesity

To explore the relationship between C-peptide and glycaemic control rate and diabetic complications (microvascular complication and cerebral infarction) and provide evidence for stratified treatment of type 2 diabetes mellitus (T2DM)-based C-peptide.. This is a cross-sectional real-world observational study. According to the inclusion and exclusion criteria, we studied 1377 patients with T2DM, grouped by fasting C-peptide and HOMA-IR. Blood samples were collected after fasting overnight. Logistic regression was used to analyse the relationship among fasting C-peptide, HOMA-IR, C2/C0 ratio (the ratio of 2 h postprandial C-peptide to fasting C-peptide), glycaemic control rate, and occurrence of diabetic complications. Restricted cubic spline (RCS) curves based on logistic regression were used to evaluate the relationship between C-peptide, glycaemic control rate, and diabetic kidney disease (DKD).. Patients were subdivided according to their fasting C-peptide in 4 groups (Q1,Q2,Q3,Q4). Patients of group Q3 (1.71 ≤ C-peptide < 2.51 ng/ml) showed the lowest incidence of DKD, diabetic retinopathy (DR), and rate of insulin absorption as welll as higher glycaemic control rate. Logistic regression shows that the probability of reaching glycemic control increased with higher levels of C-peptide, compared with group Q1, after adjusting for age, gender, duration of diabetes, body mass index, systolic blood pressure, diastolic blood pressure, creatinine, low-density lipoprotein, triglyceride, total cholesterol, and high-density lipoprotein. RCS curve shows that, when C-peptide is ≤2.68 ng/ml, the incidence of not reaching glycaemic control decreases with increasing C-peptide. The possibility of not reaching glycaemic control decreased with increasing C2/C0, when C-peptide is ≥1.71 ng/ml. RCS curve shows that the relationship between C-peptide and DKD follows a U-style curve. When C-peptide is <2.84 ng/ml, the incidence of DKD decreased with increasing C-peptide. With the increase in the C2/C0 ratio, the incidence of DKD, DR, and fatty liver did not decrease.. When C-peptide is ≥ 1.71 and < 2.51 ng/ml, patients with T2DM had a higher glycemic control rate. Excessive C-peptide plays different roles in DKD and DR; C-peptide may promote the incidence of DKD but protects patients from DR. Higher C2/C0 ratio is important for reaching glycaemic control but cannot reduce the risk of DKD, DR, and fatty liver.

Topics: C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Fatty Liver; Female; Glycemic Control; Humans; Male

The podocyte is one of the main components of the glomerular filtration barrier in the kidney, and its injury may contribute to proteinuria, glomerulosclerosis and eventually kidney failure. C-peptide, a cleavage product of proinsulin, shows therapeutic potential for treating diabetic nephropathy (DN). The aim of this study was to investigate the effect of C-peptide on high glucose-induced podocyte dysfunction. In the present study, we found that the protective effects of islet transplantation were superior to simple insulin therapy for the treatment of DN in streptozotocin (STZ)-treated rats. And such superiority may due to the function of C-peptide secreted at the implanted site. Based on this background, we determined that the application of C-peptide significantly prevented high glucose-induced podocyte injury by increasing the expression of nephrin and synaptopodin. Meanwhile, C-peptide suppressed high glucose-induced epithelial-mesenchymal transition (EMT) and renal fibrosis via decreasing the expression of snail, vimentin, α-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF). Moreover, the Notch and transforming growth factor-β (TGF-β) signaling pathways were activated by high glucose, and treatment with C-peptide down-regulated the expression of the Notch signaling molecules Notch 1 and Jagged 1 and the TGF-β signaling molecule TGF-β1. These findings suggested that C-peptide might serve as a novel treatment method for DN and podocyte dysfunction.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glucose; Hypoglycemic Agents; Insulin; Islets of Langerhans Transplantation; Male; Podocytes; Rats; Rats, Wistar; Receptors, Notch; Sweetening Agents; Transforming Growth Factor beta1

To investigate the association between serum C-peptide level and cardiovascular autonomic neuropathy (CAN) in individuals with type 2 diabetes mellitus (DM) according to estimated glomerular filtration rate (eGFR) METHODS: In a cross-sectional study, we examined 939 individuals with type 2 DM. We measured fasting C-peptide, 2-hour postprandial C-peptide, and ΔC-peptide (postprandial C-peptide minus fasting C-peptide) levels. The individuals were classified into 2 groups based on eGFR: individuals without impaired renal function (eGFR ≥60 ml∙min. Individuals with CAN had lower fasting C-peptide, postprandial C-peptide, and ΔC-peptide levels in patients both with and without impaired renal function. Multivariate logistic regression analyses adjusted for gender, age, and other confounders, including eGFR, showed that serum C-peptide level was significantly associated with CAN (odds ratio [OR] per standard deviation increase in the log-transformed value, 0.67; 95% confidence interval [CI], 0.52-0.87 for fasting C-peptide, P < 0.01; OR, 0.62; 95% CI, 0.47-0.83 for postprandial C-peptide, P < 0.01; OR, 0.71; 95% CI, 0.54-0.93 for ΔC-peptide, P < 0.05).. Serum C-peptide level was negatively associated with CAN in individuals with type 2 DM independent of eGFR.

Topics: Adult; Aged; Autonomic Nervous System; Autonomic Nervous System Diseases; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Risk Factors

Islet transplantation has been proved to be effective in delaying early stage of DN. This study was established to observe the mechanism of islet transplantation on early diabetic nephropathy (DN).. The diabetes mellitus (DM) rat model was established by an injection of a single-dose streptozotocin. According to the treatment, the rats were randomly divided into 4 groups: the untreated DN rats (DN group); the C-peptide treated rats (CP group); the islet transplanted rats (IT group); the normal control rats (NC group). Renal function and structure of glomerular filtration barrier (GFB) were evaluated by urinalysis and histopathological examination, respectively. The renal fibrotic factors, TGF- β1 and CTGF, as well as the anti-renal fibrosis factor HGF were assessed by immunohistochemical staining and western blotting methods.. After C-peptide treatment and islet transplantation, the GFB structure was obviously improved. The blood glucose significantly decreased in the IT group. The 24h urine protein and glomerular basement membrane thickness decreased, the pathological changes of podocytes improved, TGF- β1 and CTGF decreased and HGF increased in the CP group and the IT group compared with that in the DN group (P < 0.05), especially in the IT group.. Islet transplantation could ameliorate the structure of GFB of early DN in a rat model, and the treatment effect was partly attributed to the restoration of C-peptide concentration. Suppressing the fibrosis system can be the potential mechanism of islet transplantation, which is independent of blood glucose control.

Topics: Animals; C-Peptide; Diabetes Mellitus; Diabetic Nephropathies; Disease Models, Animal; Fibrosis; Glomerular Filtration Barrier; Humans; Islets of Langerhans Transplantation; Male; Rats; Rats, Sprague-Dawley; Streptozocin; Transforming Growth Factor beta1; Urinalysis

Type 2 diabetes (T2D) is defined by a single metabolite, glucose, but is increasingly recognized as a highly heterogeneous disease, including individuals with varying clinical characteristics, disease progression, drug response, and risk of complications. Identification of subtypes with differing risk profiles and disease etiologies at diagnosis could open up avenues for personalized medicine and allow clinical resources to be focused to the patients who would be most likely to develop diabetic complications, thereby both improving patient health and reducing costs for the health sector. More homogeneous populations also offer increased power in experimental, genetic, and clinical studies. Clinical parameters are easily available and reflect relevant disease pathways, including the effects of both genetic and environmental exposures. We used six clinical parameters (GAD autoantibodies, age at diabetes onset, HbA

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Insulin Resistance; Male

Cardiovascular and renal complications are the predominant causes of morbidity and mortality amongst patients with diabetes. Development of novel treatments have been hampered by the lack of available animal models recapitulating the human disease. We hypothesized that experimental diabetes in rats combined with a cardiac or renal stressor, would mimic diabetic cardiomyopathy and nephropathy, respectively. Diabetes was surgically induced in male Sprague Dawley rats by 90% pancreatectomy (Px). Isoprenaline (Iso, 1 mg/kg, sc., 10 days) was administered 5 weeks after Px with the aim of inducing cardiomyopathy, and cardiac function and remodeling was assessed by echocardiography 10 weeks after surgery. Left ventricular (LV) fibrosis was quantified by Picro Sirius Red and gene expression analysis. Nephropathy was induced by Px combined with uninephrectomy (Px-UNx). Kidney function was assessed by measurement of glomerular filtration rate (GFR) and urine albumin excretion, and kidney injury was evaluated by histopathology and gene expression analysis. Px resulted in stable hyperglycemia, hypoinsulinemia, decreased C-peptide, and increased glycated hemoglobin (HbA1c) compared with sham-operated controls. Moreover, Px increased heart and LV weights and dimensions and caused a shift from α-myosin heavy chain (MHC) to β-MHC gene expression. Isoprenaline treatment, but not Px, decreased ejection fraction and induced LV fibrosis. There was no apparent interaction between Px and Iso treatment. The superimposition of Px and UNx increased GFR, indicating hyperfiltration. Compared with sham-operated controls, Px-UNx induced albuminuria and increased urine markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and podocalyxin, concomitant with upregulated renal gene expression of NGAL and kidney injury molecule 1 (KIM-1). Whereas Px and isoprenaline separately produced clinical endpoints related to diabetic cardiomyopathy, the combination of the two did not accentuate disease development. Conversely, Px in combination with UNx resulted in several clinical hallmarks of diabetic nephropathy indicative of early disease development.

Topics: Albuminuria; Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diabetic Nephropathies; Disease Models, Animal; Fibrosis; Glomerular Filtration Rate; Heart; Isoproterenol; Kidney; Lipocalin-2; Male; Pancreatectomy; Rats; Rats, Sprague-Dawley; Renal Insufficiency

To explore the clinical features and complications of 545 hospitalized type 1 diabetic patients.
 Methods: All data of 545 patients with typical type 1 diabetes (T1DM) who were hospitalized in the Department of Endocrinology, the Second Xiangya Hospital, Central South University were collected. The data were analyzed retrospectively to explore the clinical features and complications. Clinical and biochemical characteristics were analyzed through comparison between different subgroups according to the onset age (≤13 years old, 14-29 years old, ≥30 years old).
 Results: The median onset age of T1DM patients was 27.0 (15.0, 40.0) years, and the middle-onset was 42.1%. Among the 3 groups, the proportion of female (58.0%) was the highest in the ≤13 years old group, concomitant with the lowest SBP and serum creatinine levels as well as the lowest incidence of all microvascular complications (21.0% of diabetic nephropathy, 23.3% of diabetic retinopathy, 34.1% of diabetic peripheral neuropathy; all P<0.05). Moreover, the fasting C peptide and peak C peptide levels were the lowest in ≥30 years old group compared with the other two groups, and the incidence of ketosis (33.5%) and all macrovascular complications were the highest among the three groups (all P<0.05).
 Conclusion: There are about half of the hospitalized patients with T1DM whose onset ages are ≥30 years. The incidence of ketosis at the onset and the risk for various microvascular and macrovascular complications after onset are higher than those with the onset age <30 years.. 目的：探讨1型糖尿病(type 1 diabetes，T1DM)住院患者的临床特征和并发症情况。方法：回顾性分析545例T1DM住院患者的临床资料，按照不同起病年龄(≤13岁、14~29岁、≥30岁)分析患者的临床特征和并发症情况。结果：545例T1DM患者的中位起病年龄为27.0(15.0，40.0)岁，≥30岁起病者占42.8%。与其他两组比较，≤13岁组女性比例(58.0%)较高，收缩压和血肌酐水平均最低，且所有微血管并发症的发生率(糖尿病肾病21.0%，糖尿病视网膜病变23.3%，糖尿病周围神经病变34.1%)均最低(均P<0.05)；与其他两组比较，≥30岁组空腹C肽及峰值C肽水平均最低，起病时酮症的发生率(33.5%)及大血管并发症的发生率均最高(均P<0.05)。结论：在T1DM住院患者中≥30岁起病者约占一半，起病时酮症的发生率及起病后各种微血管及大血管并发症的风险均较<30岁起病者更高。.

Topics: Adolescent; Adult; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Male; Retrospective Studies; Risk Factors; Young Adult

C-peptide (CP) has demonstrated unique beneficial effects in diabetic nephropathy (DN), but whether and how CP regulates NF-κB and its coactivator, p300, to suppress inducible iNOS and antagonize DN are unknown. iNOS expression, NF-κB nuclear translocation, colocalization and binding of NF-κB to p300, binding of NF-κB to the inos promoter, and the bound NF-κB, p300, and histone 3 lysine 9 acetylation (H3K9ac) at binding sites were measured in high glucose-stimulated mesangial cells. We evaluated pathologic changes, iNOS expression, NF-κB, and p300 contents in diabetic rats. We found that CP inhibited iNOS expression and notably prevented colocalization and binding of NF-κB and p300. CP prevented NF-κB from binding to the inos promoter, especially at the distal site, and reduced bound NF-κB, p300, and H3K9ac. N-terminal plus middle fragment could mostly mimic the antagonizing effects of CP against the pathologic changes of DN and equally suppresses renal iNOS expression as CP. In conclusion, CP prevented NF-κB from recruiting p300 and binding to the inos promoter, and decreased H3K9ac at the binding sites to suppress iNOS expression and antagonize DN, with the effect region identified as N-terminal plus middle fragment.-Li, Y., Li, X., He, K., Li, B., Liu, K., Qi, J., Wang, H., Wang, Y., Luo, W. C-peptide prevents NF-κB from recruiting p300 and binding to the inos promoter in diabetic nephropathy.

Topics: Acetylation; Animals; C-Peptide; Cells, Cultured; Diabetic Nephropathies; Histones; Male; Mesangial Cells; NF-kappa B; Nitric Oxide Synthase Type II; p300-CBP Transcription Factors; Promoter Regions, Genetic; Protein Binding; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley

Diabetic nephropathy one of the major microvascular diabetic complications. Besides hyperglycemia, other factors contribute to the development of diabetic complications as the proinsulin connecting peptide, C-peptide. We described the role of C-peptide replacement therapy on experimentally induced diabetic nephropathy, and its potential mechanisms of action by studying the role of nitric oxide (NO) as a mediator of C-peptide effects by in vivo modulating its production by N

Topics: Angiotensin II; Animals; Biomarkers; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enzyme Inhibitors; Islets of Langerhans; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Proto-Oncogene Proteins c-bcl-2; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Amniotic fluid stem cells (AFSCs) transplantation is a promising therapeutic strategy for diabetic nephropathy. Sirtuin3 (SIRT3) is a novel mitochondrial protective factor. In the present study, we aimed to investigate whether SIRT3 protects against hyperglycemia-induced AFSCs damage and enhances the therapeutic efficiency of AFSCs in diabetic nephropathy.. To establish the diabetic nephropathy model, db/ db mice were used. AFSCs were obtained and transplanted into the kidney tissue of db/ db mice. Gain-of-function assay with SIRT3 overexpression was performed in AFSCs via adenoviral transfections (Ad/SIRT3). Cellular viability and apoptosis were measured via MTT, TUNEL assay and western blotting. Mitochondrial function was assessed via JC1 staining, mPTP opening assay, mitochondrial respiratory function analysis, and immunofluorescence analysis of cyt-c. Mitophagy was assessed via western blotting and immunofluorescence analysis. Renal histopathology and morphometric analysis were conducted via H&E, Masson and PASM staining. Kidney function was detected via ELISA assay, western blotting and qPCR.. SIRT3 was downregulated in AFSCs under high glucose stimulation, where its expression was positively correlated with AFSCs survival and proliferation. Regaining SIRT3 activated mitophagy protecting AFSCs against high glucose-induced apoptosis via preserving mitochondrial function. Transplanting SIRT3-overexpressing AFSCs in db/db mice improved the abnormalities in glucose metabolic parameters, including the levels of glucose, insulin, C-peptide, HbA1c and inflammatory markers. In addition, the engraftment of SIRT3-modified AFSCs also reversed renal function, decreased renal hypertrophy, and ameliorated renal histological changes in db/db mice. Functional studies confirmed that SIRT3-modified AFSCs promoted glomerulus survival and reduced renal fibrosis.. Collectively, our results demonstrate that AFSCs may be a promising therapeutic treatment for ameliorating diabetes and the development of diabetic nephropathy and that the overexpression of SIRT3 in AFSCs may further increase the efficiency of stem cell-based therapy.

Topics: Adenosine Triphosphate; Amniotic Fluid; Animals; Apoptosis; Blood Urea Nitrogen; C-Peptide; Cells, Cultured; Diabetic Nephropathies; Down-Regulation; Genetic Vectors; Glucose; Glycated Hemoglobin; Insulin; Kidney; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria; Mitophagy; Reactive Oxygen Species; Sirtuin 3; Stem Cell Transplantation; Stem Cells

We previously demonstrated that polymorphisms in the carnosinase-1 gene (CNDP1) determine the risk of nephropathy in type 2 diabetic patients. Carnosine, the substrate of the enzyme encoded by this gene, is considered renoprotective and could possibly be used to treat diabetic nephropathy (DN). In this study, we examined the effect of carnosine treatment in vivo in BTBR (Black and Tan, BRachyuric) ob/ob mice, a type 2 diabetes model which develops a phenotype that closely resembles advanced human DN. Treatment of BTBR ob/ob mice with 4 mM carnosine for 18 weeks reduced plasma glucose and HbA1c, concomitant with elevated insulin and C-peptide levels. Also, albuminuria and kidney weights were reduced in carnosine-treated mice, which showed less glomerular hypertrophy due to a decrease in the surface area of Bowman's capsule and space. Carnosine treatment restored the glomerular ultrastructure without affecting podocyte number, resulted in a modified molecular composition of the expanded mesangial matrix and led to the formation of carnosine-acrolein adducts. Our results demonstrate that treatment with carnosine improves glucose metabolism, albuminuria and pathology in BTBR ob/ob mice. Hence, carnosine could be a novel therapeutic strategy to treat patients with DN and/or be used to prevent DN in patients with diabetes.

Topics: Administration, Oral; Albuminuria; Animals; Blood Glucose; C-Peptide; Carnosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidases; Disease Models, Animal; Gene Expression; Glomerular Mesangium; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Kidney Glomerulus; Male; Mice; Mice, Obese; Organ Size

This study aimed to investigate the structural changes in the slit diaphragm, caused by early diabetes, and the nephroprotective effect of C-peptide.. Streptozotocin-induced type 1 diabetic Wistar rats were divided into control, control plus C-peptide, early diabetes, and early diabetes plus C-peptide groups. C-peptide was infused into rats for one day. The slit diaphragm component proteins podocin, CD2AP, and nephrin, were stained immunofluorescently and their distribution quantitatively analyzed by determining the overlapping area ratio. The interfoot process gap length was measured from electron microscopic images.. Diabetic duration correlated best with the area ratio of podocin and CD2AP (r = 0.626), followed by other protein combinations, showing progressive change in the slit diaphragm structure. C-peptide-treatment did not alter area ratios. The interfoot process gap length was wider in diabetic rats (p < 0.05) and did not narrow with C-peptide-treatment in either control or diabetic rats (both p < 0.05).. Diabetes widened the interfoot process gap length and distorted the slit diaphragm structure progressively and heterogeneously in rats with early diabetes; this was not altered by C-peptide-treatment. The nephroprotective effect of C-peptide in decreasing the glomerular filtration rate appears to be functional rather than structural.

Topics: Adaptor Proteins, Signal Transducing; Animals; C-Peptide; Cytoskeletal Proteins; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glomerular Basement Membrane; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Podocytes; Rats; Rats, Wistar

To test the hypothesis that serum C-peptide level would relate to the risk of diabetic retinopathy (DR) in type 2 diabetic patients independently of estimated glomerular filtration rate (eGFR).. A total of 2,062 patients with type 2 diabetes were investigated in this cross-sectional study. Fasting C-peptide, 2-hour postprandial C-peptide, and ΔC-peptide (postprandial C-peptide minus fasting C-peptide) levels were measured. The patients were divided into two groups according to eGFR (ml∙min(-1)1.73m(-2)): patients without renal impairment (eGFR ≥60) and those with renal impairment (eGFR <60).. In subjects both with and without renal impairment, patients with DR showed lower levels of fasting C-peptide, postprandial C-peptide and ΔC-peptide. In multivariate analysis, serum C-peptide levels were significantly associated with DR (odds ratio [OR] of each standard deviation increase in the logarithmic value, 0.85; 95% confidence interval [CI], 0.78-0.92 for fasting C-peptide, P<0.001; OR, 0.87; 95% CI, 0.82-0.92 for postprandial C-peptide, P<0.001; OR, 0.88; 95% CI, 0.82-0.94 for ΔC-peptide, P<0.001) after adjustment for age, gender, and other confounding factors including eGFR.. Serum C-peptide levels are inversely associated with the prevalence of DR in type 2 diabetic patients independently of eGFR.

Topics: Adult; Aged; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prevalence; Renal Insufficiency, Chronic

Type 1 diabetes mellitus (T1DM) is characterized by the deficiencies of insulin and C-peptide. Mounting evidences have proved the beneficial effects of C-peptide on the renal function in T1DM. However, it is still controversial about the roles of C-peptide in T2DM nephropathy since the level of C-peptide fluctuates greatly at different stages of T2DM. In the present study, we found that the serum C-peptide concentration was much lower in GK rats with diabetic nephropathy than that in normal counterparts. A sustained supplementation of C-peptide at a physiological level could ameliorate urinary albumin, independent of blood glucose control. C-peptide treatment improved glomerulosclerosis and podocyte morphology and reduced the thickness of glomerular basement membrane as compared with saline treatment control. Moreover, it decreased fibronectin synthesis in diabetic glomeruli and in cultured rat mesangial cells accompanied by a down-regulation of RAGE and an up-regulation of PKA. Interestingly, H-89, a PKA inhibitor, could reverse the inhibition effect of C-peptide on fibronectin production in cultured mesangial cells. These findings suggest that C-peptide level is low in T2DM rats with nephropathy and a treatment with a physiological dose of C-peptide can prevent renal injury in diabetic GK rats.

Topics: Albuminuria; Animals; C-Peptide; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enzyme Activation; Fibronectins; Kidney; Male; Rats; Receptor for Advanced Glycation End Products; Receptors, Immunologic

To investigate the efficacy of a pegylated C-peptide (Peg-C-peptide) against indices of peripheral neuropathy in a mouse model of type 1 diabetes and to compare efficacy of this C-peptide analogue against that of the native molecule.. C57Bl/6 mice were injected with two consecutive doses of streptozotocin (STZ) to induce type 1 diabetes. Mice were treated twice daily with native C-peptide [0.4-1.3 mg/kg subcutaneously (s.c.)] or twice weekly with Peg-C-peptide (0.1-1.3 mg/kg s.c.) for 20 weeks. Motor and sensory nerve conduction velocities, thermal and tactile responses and rate dependent H-wave depression were assessed after 20 weeks of diabetes. Foot skin intraepidermal fibres and corneal nerves were counted, and sciatic nerve substance P and plasma C-peptide levels were also determined.. After 5 months of STZ-induced diabetes, mice exhibited significant motor and sensory nerve conduction slowing, thermal hypoalgesia, tactile allodynia and attenuation of rate-dependent depression of the H reflex. These functional disorders were accompanied by nerve substance P depletion but not loss of small sensory fibres in the hind paw epidermis or the cornea. The efficacy of twice-daily treatment with native C-peptide in preventing these disorders was matched or exceeded by twice-weekly treatment with Peg-C-peptide. Both native and Peg-C-peptide also increased corneal nerve occupancy in the sub-basal nerve plexus of control rats.. These data identify actions of C-peptide against novel and clinically pertinent aspects of diabetic neuropathy in mice and also establish Peg-C-peptide as a long-acting therapeutic method of potential clinical value.

Topics: Animals; C-Peptide; Cornea; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Administration Schedule; Epidermis; Hindlimb; Mice; Mice, Inbred C57BL; Models, Animal; Neural Conduction; Rats; Sciatic Nerve

Diabetic nephropathy is one of the major microvascular complications of diabetes. We investigated the association between urinary Smad3 (usmad3) levels, glomerular hyperfiltration, and the development of nephropathy in patients with type 2 diabetes mellitus (T2DM).. The usmad3 level was determined by enzyme-linked immunosorbent assay in 245 well-characterised patients with T2DM and 82 healthy control subjects. The associations of the usmad3 level with glomerular hyperfiltration, glucose and lipid profiles, and renal function were evaluated.. The usmad3 level was significantly higher in patients with diabetes than in the control group. The level in the hyperfiltration group was higher than that in the normofiltering group, regardless of whether patients were in the normoalbuminuric or the proteinuria groups. Pearson's correlation analysis suggested that the usmad3 level was significantly correlated with age, systolic blood pressure, fasting plasma glucose, insulin, C-peptide, glycated haemoglobin, and estimated glomerular filtration rate (eGFR). A multiple linear stepwise regression analysis revealed that usmad3 levels in patients with T2DM and an eGFR ≥ 90 ml/min/1.73 m(2) were independently and positively correlated with eGFR, whereas in patients with T2DM and eGFR <90 ml/min/1.73 m(2), the levels were independently and negatively correlated with eGFR.. The usmad3 level was significantly correlated with biphasic changes in the GFR (both glomerular hyperfiltration and reduced eGFR) in patients with T2DM. Usmad3 may serve as a novel marker for hyperfiltration and for screening patients with T2DM for nephropathy.

Topics: Age Factors; Aged; Biomarkers; Blood Glucose; Blood Pressure; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Smad3 Protein

The aim of this study was to assess the relationship between urinary Smad1 and glomerular hyperfiltration (GHF) in type 2 diabetes mellitus (T2DM), and to explore the factors related to the urinary Smad1 in T2DM. The reference value of the estimated glomerular filtration rate (eGFR) was determined in 248 healthy individuals. 30 patients with GHF, 58 patients with norm-GFR T2DM, and 24 healthy patients who served as controls were recruited. Urinary Smad1, fasting plasma glucose (FPG), fasting serum C-Peptide (C-P), hemoglobin A1C (HbA1c), cystatin C, and other chemistry laboratory parameters of T2DM participants and controls were measured. Patients with GHF had higher levels of urinary Smad1 than the control group, and those with norm-GFR. For T2DM patients with body mass index, age, and gender adjustments, urinary Smad1 was positively correlated with FPG, HbA1C, and eGFR, but negatively correlated with fasting serum C-P. Multivariate linear regression analysis demonstrated that eGFR, HbA1C, and fasting serum C-P were independently associated with urinary Smad1. High levels of urinary Smad1 were found in GHF patients with T2DM, which may be another potential mechanism of GHF in relation to diabetic nephropathy.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Case-Control Studies; Cross-Sectional Studies; Cystatin C; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Linear Models; Male; Middle Aged; Reference Values; Smad1 Protein

This study evaluated the association between serum C-peptide levels and chronic vascular complications in Korean patients with type 2 diabetes. Data for 1,410 patients with type 2 diabetes were evaluated cross-sectionally. Fasting and postprandial 2-hour serum C-peptide levels were analyzed with respect to diabetic micro- and macrovascular complications. In the group of patients with lower fasting serum C-peptide quartile, the prevalences of diabetic retinopathy and neuropathy were significantly higher (P = 0.035, P < 0.001, respectively). In the group of patients with lower delta C-peptide (postprandial - fasting C-peptide) quartile, the prevalences of diabetic retinopathy, nephropathy, and neuropathy were significantly higher (P < 0.001 for all). Low delta C-peptide quartile was also associated with increased severity of retinopathy and nephropathy. The age- and sex-adjusted odds ratios (ORs) for retinopathy, neuropathy, and nephropathy in the lowest versus the highest delta C-peptide quartile were 6.45 (95% confidence interval 3.41-12.22), 3.01 (2.16-4.19), and 2.65 (1.71-4.12), respectively. After further adjustment for the duration of diabetes, type of antidiabetic therapy, mean hemoglobin A1c, body mass index, and blood pressure, the ORs were reduced to 2.83 (1.32-6.08), 1.68 (1.12-2.53), and 1.61 (1.05-2.47), respectively, but remained significant. No significant difference was observed in the prevalence of macrovascular complications with respect to fasting or delta C-peptide quartiles. These results suggest that low C-peptide level is associated with diabetic microvascular, but not macrovascular complications in patients with type 2 diabetes mellitus.

Topics: Adult; Aged; Asian People; C-Peptide; Chronic Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Male; Microvessels; Middle Aged; Prevalence; Republic of Korea; Young Adult

The aim of this study was to investigate clinical spectrum of hepatocyte nuclear factor-1β (HNF-1β) mutation in Chinese diabetic patients with renal dysfunction and/or structure abnormalities.. A total of 104 diabetic patients with renal structural abnormalities and/or non-diabetic renal dysfunction were recruited and HNF-1β mutation was screened by direct sequencing.. Three heterozygous missense mutations including c.494G>A (p.R165H), c.662A>T (p.D221V) and c.780G>C (p.E260D) were identified. Progression of diabetes and mild decline of renal function were observed in the mutation carriers during the follow-up. The p.R165H mutation carrier had severe β-cell dysfunction and different extrapancreatic phenotypes. Compared with type 2 diabetes and normoglycemics, the p.R165H mutation carrier had a lower basal C-peptide (0.30, 0.61±0.07 and 0.50±0.04 nmol/L for p.R165H, type 2 diabetes and normoglycemics, respectively) and low values of acute C-peptide response to arginine (0.15, 0.48±0.18 and 0.76±0.08 nmol/L for p.R165H, type 2 diabetes and normoglycemics, respectively).. Patients with the HNF-1β mutation in our population can have different pancreatic and extrapancreatic phenotypes. The exact contributions of mutations to the phenotypes await functional confirmation.

Topics: Adult; Aged; Aged, 80 and over; Asian People; C-Peptide; China; Diabetic Nephropathies; Disease Progression; Female; Hepatocyte Nuclear Factor 1-beta; Heterozygote; Humans; Male; Middle Aged; Mutation, Missense; Pedigree; Phenotype

Over a 23-year period, our center performed 82 renal retransplants in prior simultaneous pancreas-kidney recipients with functioning pancreatic allografts. All patients were insulin-independent at retransplantation. We aimed to quantify the risk of returning to insulin therapy and to identify factors that predispose patients to pancreatic allograft failure after renal retransplantation. Among these 82 patients, pancreatic allograft survival after renal retransplantation was 78%, 49% and 40% at 1, 5 and 10 years. When analyzing risk factors, we unexpectedly found no clear relationship between the cause of primary renal allograft failure, hemoglobin A1c (HbA1c) or fasting C-peptide level at retransplant and subsequent pancreatic allograft failure. An elevated HbA1c in the month after renal retransplant correlated with subsequent pancreatic graft loss and patients experiencing pancreatic graft loss were more likely to subsequently lose their renal retransplant. Although it is difficult to prospectively identify those patients who will return to insulin therapy after repeat renal transplantation, the relatively high frequency of this event mandates that this risk be conveyed to patients. Nonetheless, the survival benefit associated with renal retransplantation justifies pursuing retransplantation in this population.

Topics: Adult; C-Peptide; Diabetic Nephropathies; Female; Follow-Up Studies; Glycated Hemoglobin; Graft Rejection; Graft Survival; Humans; Kidney Transplantation; Male; Pancreas Transplantation; Postoperative Complications; Reoperation; Retrospective Studies; Risk Factors; Survival Rate; Transplantation, Homologous

The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal.. Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio (ΔCP/GCr).. Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to ΔCP/GCr. A negative association to ΔCP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set.. The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.

Topics: Adult; Age Factors; Aged; Blood Glucose; C-Peptide; Cells, Cultured; Cold Ischemia; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Graft Survival; Humans; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney Transplantation; Male; Middle Aged; Models, Biological; Organ Size; Quality Control; Retrospective Studies; Tissue Donors; Transplantation; Treatment Outcome

This study describes the clinical characteristics of childhood- and adolescent-onset type 2 diabetes mellitus (CAT2DM) seen at a diabetes center in southern India.. Between January 1992 and December 2009, 368 CAT2DM patients were registered. Anthropometric measurements were done using standardized techniques. Biochemical investigations included C-peptide measurements and glutamic acid decarboxylase antibody assay wherever feasible. Retinopathy was diagnosed by retinal photography; microalbuminuria, if urinary albumin excretion was between 30 and 299 mg/μg of creatinine; nephropathy, if urinary albumin excretion was ≥300 mg/μg; and neuropathy, if vibration perception threshold on biothesiometry was ≥20 V.. The proportion of CAT2DM patients, expressed as percentage of total patients registered at our center, rose from 0.01% in 1992 to 0.35% in 2009 (P<0.001). Among the 368 cases of CAT2DM, 96 (26%) were diagnosed before the age of 15 years. The mean age at first visit and age at diagnosis of the CAT2DM subjects were 22.2±9.7 and 16.1±2.5 years, respectively. Using World Health Organization growth reference charts, 56% of boys and 50.4% of girls were >85(th) percentile of body mass index for age. Prevalence rates of retinopathy, microalbuminuria, nephropathy, and neuropathy were 26.7%, 14.7%, 8.4%, and 14.2%, respectively. Regression analysis revealed female gender, body mass index >85(th) percentile, parental history of diabetes, serum cholesterol, and blood pressure to be associated with earlier age at onset of CAT2DM.. CAT2DM appears to be increasing in urban India, and the prevalence of microvascular complications is high. Female predominance is seen at younger ages.

Topics: Adolescent; Age Distribution; Age of Onset; Albuminuria; Analysis of Variance; Blood Pressure; Body Mass Index; C-Peptide; Child; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Humans; India; Male; Prevalence; Risk Assessment; Risk Factors; Sex Distribution; Young Adult

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

Type 2 diabetes mellitus and obstructive sleep apnea syndrome (OSAS) are serious comorbidities. Effects of OSAS on diabetic microvascular complications are ongoing research subjects. We evaluated the incidence of OSAS in Type 2 diabetes mellitus patients with nephropathy and with no renal involvement.. A total of 52 people with diabetes were enrolled in this study. Patients body mass indices were calculated and fasting glucose, glycosylated hemoglobin, urea, creatinine, total lipid profile, and urinary albumin excretion were evaluated. Full polysomnography was used to detect sleep disorders.. Baseline characteristics and laboratory results of the patients were similar. Meeting criteria for OSAS was detected in 35 of the 54 patients (67.3%). 25 patients (48%) had mild, six patients (11.5%) had moderate, and four patients (7.7%) had severe sleep disorders. There was no significant relationship between respiratory obstructive parameters and microalbuminuria (R=0.91, p=0.362). Substantial correlation was detected between lower values of serum triglyceride levels and lower respiratory indices (R=0.299, p=0.031).. In type 2 diabetes accompanying OSAS affects glucose regulation but its effect on nephropathy development is currently a subject of research.

Topics: Albuminuria; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Lipids; Male; Middle Aged; Polysomnography; Prospective Studies; Sleep Apnea, Obstructive; Turkey

Many studies have demonstrated an association between hemoglobin levels and cardiovascular disease in diabetic patients. The aim of this study was to determine whether there is an association between hemoglobin concentrations and various clinical parameters, including metabolic factors, plasma C-peptide response after a meal tolerance test, and microvascular complications, in Korean patients with type 2 diabetes.. In total, 337 male patients with type 2 diabetes were recruited. All subjects were subjected to a meal tolerance test and underwent assessment of hemoglobin levels, fasting and postprandial β-cell responsiveness, and microvascular complications.. Patients with lower hemoglobin concentrations had a longer duration of diabetes, a lower body mass index, and lower concentrations of total cholesterol, triglycerides, and low-density lipoprotein cholesterol. They also had lower levels of postprandial C-peptide, Δ C-peptide, and postprandial β-cell responsiveness. They had a higher prevalence of retinopathy and nephropathy. In multivariate analyses, there was a significant association between nephropathy and hemoglobin concentration. Also, hemoglobin concentrations were independently associated with Δ C-peptide levels and postprandial β-cell responsiveness.. Hemoglobin concentrations are associated with postprandial C-peptide responses and diabetic nephropathy in patients with type 2 diabetes.

Topics: Aged; Biomarkers; Blood Glucose; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Hemoglobins; Humans; Insulin-Secreting Cells; Linear Models; Lipids; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Postprandial Period; Prevalence; Republic of Korea; Risk Assessment; Risk Factors

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

Earlier studies reporting outcomes after pancreas transplantation have included a combination of C-peptide cutoffs and clinical criteria to classify type 2 diabetes mellitus (T2DM). However, because the kidney is the major site for C-peptide catabolism, C-peptide is unreliable to discriminate the type of diabetes in patients with kidney disease.. To improve the discriminative power and better classify the type of diabetes, we used a composite definition to identify T2DM: presence of C-peptide, negative glutamic acid decarboxylase antibody, absence of diabetic ketoacidosis, and use of oral hypoglycemics. Additionally among T2DM patients with end-stage renal disease (ESRD), body mass index of <30 kg/m(2) and use of <1 u/kg of insulin per day were selection criteria for suitablity for simultaneous pancreas and kidney transplantation (SPKT). We compared graft and patient survival between T1DM and T2DM after SPKT.. Our study cohort consisted of 80 patients, 10 of whom were assigned as T2DM based on our study criteria. Approximately 15% of patients with T1DM had detectable C-peptide. Cox regression survival analyses found no significant differences in allograft (pancreas and kidney) or patient survival between the 2 groups. The mean creatinine clearance at 1 year estimated by the modification of Diet in Renal Disease (MDRD) equation was not significantly different between the 2 groups. Among those with 1 year of follow-up, all patients with T2DM had glycosylate hemoglobin of <6.0 at 1 year versus 92% of those with T1DM.. SPKT should be considered in the therapeutic armamentarium for renal replacement in selected patients with T2DM and ESRD. Use of C-peptide measurements for ESRD patients can be misleading as the sole criterion to determine the type of diabetes.

Topics: Adult; C-Peptide; Creatinine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Follow-Up Studies; Glycated Hemoglobin; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Retrospective Studies; Survival Analysis; Tissue Donors

The study was undertaken to examine the effects of C-peptide on glomerular volume (V(GLOM)), mesangial matrix synthesis, and degradation in streptozotocin (STZ)-diabetic rats with poor or moderate glycemic control. Series 1 (poor glycemic control) included groups of healthy rats, hyperglycemic rats, diabetic insulin-treated rats and diabetic C-peptide-treated rats. Series 2 (moderate glycemic control) included groups of healthy rats, diabetic insulin-treated rats, diabetic insulin- and C-peptide-treated rats. After 8 weeks, the left kidney was excised for evaluation of V(GLOM) and mesangial matrix area via light microscopy. Mesangial cells were cultured for 48 h and type IV collagen expression and matrix metalloproteinase (MMP)-2 expression were measured by ELISA and RT-PCR. The results indicated that in Series 1, C-peptide administration suppressed the diabetes-induced increase in the V(GLOM) and the mesangial matrix area. In Series 2, C-peptide administration resulted in a similar decrease in the V(GLOM) and a greater decrease in the mesangial matrix area when compared with insulin therapy alone. Moreover, C-peptide (300 nM) completely inhibited the glucose-induced increase of the collagen IV mRNA expression and protein concentration in mesangial cells cultured in 30 mM glucose medium. MMP-2 mRNA expression was not influenced by C-peptide. In conclusion, C-peptide administration to STZ-diabetic rats for 8 weeks results in the inhibition of diabetes-induced expansion of the mesangial matrix. This effect is independent of the level of glycemic control and results from the inhibition of diabetes-induced excessive formation of mesangial type IV collagen.

Topics: Animals; C-Peptide; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Glomerular Mesangium; Matrix Metalloproteinase 2; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Streptozocin; Time Factors

A protective effect of residual beta-cell function on microvascular complications of type 1 diabetes has been suggested. Our aim was to retrospectively evaluate the association of fasting plasma C-peptide values with micro- and macrovascular complications.. We recruited a clinic-based cohort of 471 type 1 diabetic patients born after 1945 and cared for in the period 1994-2004. Centralized measurements and standardized procedures of ascertainment of micro- and macrovascular complications were employed. Individual cumulative averages of A1C up to 2007 were calculated.. Residual beta-cell secretion was detected even many years after diabetes diagnosis. In multivariate linear regression analysis, fasting plasma C-peptide values were positively associated with age at diagnosis (beta = 0.02; P < 0.0001) and triglycerides (beta = 0.20; P = 0.05) and inversely associated with diabetes duration (beta = -0.03; P < 0.0001) and HDL cholesterol (beta = -0.006; P = 0.03). The final model explained 21% of fasting C-peptide variability. With respect to fasting C-peptide values in the lowest tertile (<0.06 nmol/l), higher values were associated with lower prevalence of microvascular complications (odds ratio [OR] 0.59 [95% CI 0.37-0.94]) independently of age, sex, diabetes duration, individual cumulative A1C average during the study period, hypertension, and cardiovascular diseases. No association was evident with macrovascular complications (0.77 [0.38-1.58]).. Our study shows an independent protective effect of residual beta-cell function on the development of microvascular complications in type 1 diabetes, suggesting the potential beneficial effect of treatment that allows the preservation of even modest beta-cell function over time.

Topics: Adult; Age of Onset; Blood Pressure; Body Mass Index; C-Peptide; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Fasting; Female; Humans; Hypertension; Insulin-Secreting Cells; Italy; Male; Multivariate Analysis; Odds Ratio; Regression Analysis

The crucial pathology underlying progressive chronic kidney disease in diabetes is tubulointerstitial fibrosis. Central to this process is epithelial-mesenchymal transformation (EMT) of proximal tubular epithelial cells driven by maladaptive transforming growth factor-beta1 (TGF-beta1) signaling. Novel signaling roles for C-peptide have recently been discovered with evidence emerging that C-peptide may mitigate microvascular complications of diabetes. We studied the potential for C-peptide to interrupt injurious TGF-beta1 signaling pathways and thus block development of EMT in HK2 human kidney proximal tubular cells. Cells were incubated with TGF-beta1 either alone or with C-peptide in low or high glucose. Changes in cell morphology, TGF-beta1 receptor expression, vimentin, E-cadherin, and phosphorylated Smads were assessed. Luciferase reporters were used to assess Smad activity. The cytoskeleton was visualized by TRITC-phalloidin staining. The typical TGF-beta1-stimulated, EMT-associated morphological alterations of proximal tubular cells, including increased vimentin expression, decreased E-cadherin expression, and cytoskeletal rearrangements, were prevented by C-peptide treatment. C-peptide also blocked TGF-beta1-induced upregulation of expression of both type I and type II TGF-beta1 receptors and attenuated TGF-beta1-mediated Smad phosphorylation and Smad transcriptional activity. These effects of C-peptide were inhibited by pertussis toxin. The results demonstrate that C-peptide almost completely reversed the morphological changes in PT cells induced by TGF-beta1 and suggest a role or C-peptide as a renoprotective agent in diabetic nephropathy.

Topics: Biomarkers; C-Peptide; Cadherins; Cell Line; Diabetic Nephropathies; Epithelial Cells; Humans; Kidney Tubules, Proximal; Mesoderm; Phenotype; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1; Up-Regulation; Vimentin

Several intervention studies have convincingly demonstrated the importance of good glycemic control to avoid long-term diabetic complications, but the importance of other risk factors remains controversial. We previously reported a markedly reduced incidence of severe retinopathy and nephropathy during the past decades in an unselected population of type 1 diabetes mellitus diagnosed in childhood. The aim of the present study was to analyze possible risk factors, which could explain the improved prognosis.. In this longitudinal population-based cohort study, we followed all 269 patients in whom type 1 diabetes mellitus was diagnosed in childhood 1961-1985 in a well-defined geographical area in Sweden. The patients were followed until the end of 1990 s. Multivariable regression models were used to analyze the importance of hemoglobin A1c (HbA(1c)), diabetes duration, blood pressure, cardiovascular risk factors and persisting C-peptide secretion for the development of diabetic retinopathy and nephropathy.. Beside longer duration and higher HbA(1c), blood pressure and lipid values were higher and cardiovascular disease and smoking were more common in patients with severe complications. However, multivariable analysis abolished these associations. Diabetes duration and long-term HbA(1c) were the only significant independent risk factors for both retinopathy and nephropathy. The risk of overt nephropathy increased substantially when HbA(1c) was above 9.6% [Diabetes Control and Complications Trial (DCCT) corrected value], while the risk of severe retinopathy increased already when HbA(1c) exceeded 8.6%.. In this unselected population, glycemic control was the only significant risk factor for the development of long-term complications.

Topics: Age of Onset; Albuminuria; Blood Glucose; Blood Pressure; Body Mass Index; C-Peptide; Cardiovascular Diseases; Child; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Glycated Hemoglobin; Homeostasis; Humans; Triglycerides

To compare functional beta-cell mass and insulin sensitivity in insulin-independent pancreas-kidney recipients with that in age- and body mass index-matched nondiabetic kidney recipients and normal controls.. All transplant recipients were on maintenance immunosuppression with mycophenolate mofetil and tacrolimus since more than 2.7 years (2.2-3.8 years). Their C-peptide release was measured during a 170-min hyperglycemic clamp, first in absence and then in presence of glucagon. Data were compared with those after glucose stimulation alone. Insulin sensitivity under basal and stimulated conditions was calculated using homeostasis model assessment of insulin resistance and insulin sensitivity index, respectively.. Functional beta-cell mass in pancreas-kidney recipients with systemic venous drainage was reduced, representing, respectively, 63% and 80% of that in healthy controls and kidney recipients. Pancreas-kidney recipients exhibited lower insulin sensitivity than healthy controls (homeostasis model assessment of insulin resistance was 0.8, 0.7-1.1 vs. 0.4, 0.3-0.8; P=0.02 and insulin sensitivity index was 17, 12-24 mg/kg/min per 100 microU/mL vs. 31, 20-38 mg/kg/min per 100 microU/mL; P=0.04).. Using a hyperglycemic clamp, the functional beta-cell mass in insulin-independent pancreas-kidney recipients was found to be 37% and 20% lower than in healthy controls and nondiabetic kidney recipients.

Topics: Adult; Blood Glucose; C-Peptide; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Insulin; Insulin-Secreting Cells; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Reference Values

The recurrence or persistence of pancreatic autoantibodies after pancreas-kidney transplantation (PKT) is an intriguing finding. We prospectively analyzed 77 PKTs, searching for risk factors for the expression of these autoimmune markers and their impact on pancreas graft function. Among the 77 PKTs, 24.7% had 0 HLA matches, 20.8% displayed delayed graft function, and 14.3% had acute rejection episodes. Immunosuppression included antithymocyte globulin (ATG), tacrolimus, mycophenolate mofetil (MMF), and steroids. Sixty-five patients had both grafts functioning as a follow-up of more than 6 months. In 11 patients anti-glutamic acid decarboxylase (GAD) positivity persists (n = 8) or has recurred (n = 3), 4 of whom show increasing titers. Two patients maintain positive islet cell antibodies (ICA) and anti-GAD antibodies. The 9 patients positive for ICA included 2 who were negative before PKT and 7 who remain positive. The "positive" group (22 patients with positive ICA and/or anti-GAD) did not differ from the global group of 65 functioning PKT in terms of acute rejection episodes, HLA match, and steroid withdrawal. Among the positive patients, there were 2 with borderline glucose levels; however, among the entire "positive" group, the mean fasting glucose, HbA1c, and C-peptide measurements were not significantly different, when compared with the other 65 PKTs. In conclusion, pancreatic autoantibodies may be persistently positive or recur after PKT, despite appropriate immunosuppression. Its impact on long-term pancreas graft survival is unknown. We could not identify risk factors for their expression. An extended follow-up with monitoring and search for other risk factors may be necessary to increase our knowledge in this field.

Topics: Adult; Autoantibodies; Blood Glucose; C-Peptide; Cadaver; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas; Pancreas Transplantation; Reference Values; Retrospective Studies; Tissue Donors; Young Adult

We investigated the relation between C-peptide levels and the prevalence of diabetic complications in patients with type 2 diabetes and the metabolic syndrome.. This study includes all patients with diabetes and treated only with oral hypoglycemic agents who were admitted to our department in 2006. The chronic complications of diabetes (vascular disease, retinopathy, nephropathy, neuropathy) were evaluated.. The 77 patients with type 2 diabetes and treated only with oral hypoglycemic agents were divided in two groups, with and without the metabolic syndrome. The two groups did not differ in glycemic control, blood pressure levels, or duration of diabetes. CRP levels were higher in patients with the metabolic syndrome (p=0.03), and nephropathy was more common (70%, compared with 33%). Similar, C-peptide levels were higher in patients with the metabolic syndrome: 3.12+/-1.36 compared with 1.82+/-1.25 (p<0.001). In patients with the metabolic syndrome, C-peptide levels did not differ in patients with or without diabetic complications (3.01+/-1.16, compared with 3.96+/-2.55; p=0.51). Similarly, C-peptide levels in patients without the metabolic syndrome did not differ according to the presence of complications of diabetes (2.25+/-1.21 versus 1.36+/-1.16; p=0.07). However, C-peptide levels were higher in patients with diabetes and the metabolic syndrome who had either nephropathy or vascular disease, compared with those with those complications but without the metabolic syndrome (p=0.01). CRP levels did not correlate with C-peptide levels in any patient group.. Higher C-peptide levels were associated with metabolic syndrome in patients with type 2 diabetes and in diabetes patients who also had nephropathy and vascular disease.

Topics: Aged; Biomarkers; Blood Glucose; C-Peptide; C-Reactive Protein; Confidence Intervals; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Humans; Hypoglycemic Agents; Male; Metabolic Syndrome; Middle Aged; Prevalence

an increased glomerular filtration rate (GFR) has been postulated as a potential mechanism involved in the progression of diabetic nephropathy. Studies suggest that C-peptide exerts a renoprotective effect on diabetes. The peptide decreases hyperfiltration in patients with type 1 diabetes, as well as in diabetic animal models. In this study, we investigated whether C-peptide causes a change in arteriolar diameter.. C57-Bl mice were made diabetic by means of a single intravenous injection of alloxan 2 wk prior to the experiment. Age-matched normoglycemic mice served as controls. Afferent arterioles, intact with the glomeruli, were dissected and microperfused. The effect of luminal application of C-peptide, compared with scrambled C-peptide or vehicle, was investigated. The effect of the Rho-kinase inhibitor Y-27632 was also investigated.. C-peptide constricted afferent arterioles in diabetic mice by -27% compared with the control value. Normoglycemic arterioles administered C-peptide displayed a delayed and minute response (-4%). Scrambled C-peptide or vehicle administration, whether administered to hyperglycemic or normoglycemic mice, did not induce any effect. Addition of Y-27632 abolished the effect of C-peptide.. C-peptide induces constriction of afferent arterioles in diabetic mice. This can reduce enhanced GFR and may be one of the mechanisms in the renoprotective action of C-peptide in diabetes.

Topics: Amides; Angiotensin II; Animals; Arterioles; C-Peptide; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Kidney Glomerulus; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Norepinephrine; Potassium Chloride; Pyridines; Rho Factor; rho-Associated Kinases; Vasoconstriction; Vasoconstrictor Agents

To analyze outcomes in simultaneous kidney-pancreas transplantation (SKPT) recipients who retain C-peptide production at the time of SKPT.. This retrospective analysis of SKPTs from January 2002 through January 2007 compared outcomes between patients with absent or low C-peptide levels (<2.0 ng/mL, group A) with those having levels > or =2.0 ng/mL (group B).. Among 74 SKPTs, 67 were in group A and seven in group B (mean C-peptide level 5.7 ng/mL). During transplantation, group B subjects were older (mean age 51 vs 41 years, P = .006); showed a later age of onset of diabetes (median 35 vs 13 years, P = .0001); weighed more (median 77 vs 66 kg, P = .24); had a greater proportion of African-Americans (57% vs 13%, P = .004); and had a longer pretransplant duration of dialysis (median 40 vs 14 months, P = .14). With similar median follow-up of 40 months, death-censored kidney (95% group A vs 100% group B, P = NS) and pancreas (87% group A vs 100% group B, P = NS) graft survival rates were similar, but patient survival (94% group A vs 71% group B, P = .03) was greater in group A. At 1-year follow-up, there were no significant differences in rejection episodes, surgical complications, infections, readmissions, hemoglobin A1C or C-peptide levels, serum creatinine, or MDRD GFR levels.. Diabetic patients with measurable C-peptide levels before transplant were older, overweight, more frequently African-American and had a later age of onset of diabetes, longer duration of pretransplant dialysis, and reduced patient survival compared to insulinopenic patients undergoing SKPT. The other outcomes were similar.

Topics: Adult; Age of Onset; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Histocompatibility Testing; Humans; Kidney Transplantation; Middle Aged; Pancreas Transplantation; Predictive Value of Tests; Preoperative Care; Retrospective Studies; Time Factors; Treatment Outcome; Waiting Lists

The present study investigated the relationship between hemoglobin (Hb) levels and autonomic failure using a sensitive marker, coefficient of variation of R-R intervals in electrocardiogram (CVR-R) in order to clarify a cause of normocytic normochromic anemia in type 1 diabetic patients without overt nephropathy. We recruited 46 patients with type 1 diabetes and measured creatinine clearance (Ccr), HbA1c, albuminuria, Hb levels and CVR-R of all patients. In addition, the status of diabetic retinopathy and neuropathy were also evaluated. Serum erythropoietin (EPO), Fe, total iron binding capacity, lactate dehydrogenase, total bilirubin levels and number of reticulocytes and mean corpuscular volume were also measured to distinguish types of anemia. To survey the statistical correlation existing between Hb and body mass index (BMI), Ccr, HbA1c, albuminuria or retinopathy, multiple regression analysis was performed. Serum EPO, Fe, TIBC, LDH and TB levels and number of reticulocytes and MCV were within normal limits. Multiple regression analysis disclosed that HbA1c, nephropathy evaluated by albuminuria and Ccr, and retinopathy has no concern with Hb level. There is only significant relationship between Hb levels and CVR-R. Similar results were obtained even if we analyzed a group of male and female separately. We conclude that CVR-R has the strong relationship on anemia without overt nephropathy in type 1 diabetes, indicating that autonomic failure contributes on the progression of anemia via a poor response of EPO to anemia.

Topics: Adult; Aged; Albuminuria; Anemia; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Electrocardiography; Erythropoietin; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Sensitivity and Specificity

The objective of the study was to analyse levels IL-12 and to relate the findings to the clinical course of type 1 diabetes mellitus (DM1).. We examined a group of 102 children with DM1 and 39 healthy children (as the control). All the children with DM1 had their daily urine albumin excretion, HbA1c, C-peptide measured, 24hrs blood pressure monitoring and ophthalmologic examination. In accordance to the ophthalmologic examination and level IL-12 in the serum the diabetic children were divided into 3 groups: group A: IL-12>0 pg/ml; group B: IL-12=0 pg/ml; group C: IL-12=0 pg/ml and IL12>0 pg/ml. Serum levels of IL-12 and TNFalpha were measured by the immunoenzymatic ELISA method, Quan-tikine High Sensitivity Human by R&D Systems (USA).. Children of group A were characterized by significantly high level of IL-12 and by the absence of TNFalpha as compared with the children of group B, who had undetectable IL-12 along with high TNFalpha level. Additionally, children of group A had significantly lower urine albumin excretion and had only developed retinopathy. However, the children of group B not only had retinopathy, nephropathy but also arterial hypertension. The patients of group A were also analysed against the children of group C, who were characterized by high IL-12 level and some of them had also detectable TNFalpha, but without retinopathy and nephropathy.. The results of our study imply the existence of balance between IL-12 and TNFalpha in type 1 DM children, which seems to warrant the stage of disease without diabetic complications. However, the IL-12 domination tends to prevent or delay nephropathy development but does not protect from retinopathy.

Topics: Adolescent; Albuminuria; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Biomarkers; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Hypertension; Interleukin-12; Male; Neovascularization, Pathologic; Reference Values; Tumor Necrosis Factor-alpha

The purpose of this study was to evaluate whether islet transplantation may stabilize polyneuropathy in uremic type 1 diabetic patients (end-stage renal disease [ESRD] and type 1 diabetes), who received a successful islet-after-kidney transplantation (KI-s).. Eighteen KI-s patients underwent electroneurographic tests of sural, peroneal, ulnar, and median nerves: the nerve conduction velocity (NCV) index and amplitudes of both sensory action potentials (SAPs) and compound motor action potentials (CMAPs) were analyzed longitudinally at 2, 4, and 6 years after islet transplantation. Skin content of advanced glycation end products (AGEs) and expression of their specific receptors (RAGE) were also studied at the 4-year follow-up. Nine patients with ESRD and type 1 diabetes who received kidney transplantation alone (KD) served as control subjects.. The NCV score improved in the KI-s group up to the 4-year time point (P = 0.01 versus baseline) and stabilized 2 years later, whereas the same parameter did not change significantly in the KD group throughout the follow-up period or when a cross-sectional analysis between groups was performed. Either SAP or CMAP amplitudes recovered in the KI-s group, whereas they continued worsening in KD control subjects. AGE and RAGE levels in perineurium and vasa nervorum of skin biopsies were lower in the KI-s than in the KD group (P < 0.01 for RAGE).. Islet transplantation seems to prevent long-term worsening of polyneuropathy in patients with ESRD and type 1 diabetes who receive islets after kidney transplantation. No statistical differences between the two groups were evident on cross-sectional analysis. A reduction in AGE/RAGE expression in the peripheral nervous system was shown in patients receiving islet transplantation.

Topics: Adult; Biomarkers; Biopsy; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Electrophysiology; Humans; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Middle Aged; Peripheral Nerves; Skin

Cell loss by apoptosis occurs in renal injury such as diabetic nephropathy. TNF-alpha is a cytokine that induces apoptosis and has been implicated in the pathogenesis of diabetic nephropathy. The aim was to investigate whether C-peptide or insulin could modulate TNF-alpha-mediated cell death in opossum kidney proximal tubular cells and to examine the mechanism(s) of any effects observed. C-peptide and insulin protect against TNF-alpha-induced proximal tubular cell toxicity and apoptosis. Cell viability was analyzed by methylthiazoletetrazolium assay; cell viability was reduced to 60.8 +/- 2.7% of control after stimulation with 300 ng/ml TNF-alpha. Compromised cell viability was reversed by pretreatment with 5 nM C-peptide or 100 nM insulin. TNF-alpha-induced apoptosis was detected by DNA nick-end labeling and by measuring histone associated DNA fragments using ELISA. By ELISA assay, 300 ng/ml TNF-alpha increased apoptosis by 145.8 +/- 4.9% compared with controls, whereas 5 nM C-peptide and 100 nM insulin reduced apoptosis to 81.6 +/- 4.8 and 77.4 +/- 3.1% of control, respectively. The protective effects of C-peptide and insulin were associated with activation of NF-kappaB. Activation of NF-kappaB by C-peptide was pertussis toxin sensitive and dependent on activation of Galpha(i). Phosphatidylinositol 3-kinase but not extracellular signal regulated mitogen-activated protein kinase mediated C-peptide and insulin activation of NF-kappaB. The cytoprotective effects of both C-peptide and insulin were related to increased expression of TNF receptor-associated factor 2, the product of an NF-kappaB-dependent survival gene. These data suggest that C-peptide and/or insulin activation of NF-kappaB-regulated survival genes protects against TNF-alpha-induced renal tubular injury in diabetes. The data further support the concept of C-peptide as a peptide hormone in its own right and suggest a potential therapeutic role for C-peptide.

Topics: Animals; Apoptosis; C-Peptide; Cell Line; Diabetic Nephropathies; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Insulin; Kidney Tubules, Proximal; Leupeptins; NF-kappa B; Opossums; Signal Transduction; TNF Receptor-Associated Factor 2; Tumor Necrosis Factor-alpha

In response to hyperglycemia, beta-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all beta-cell hormones.. Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, beta-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 +/- 1 kg/m2, 47 +/- 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 +/- 1 kg/m2, 50 +/- 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 +/- 1 kg/m2, 47 +/- 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT).. PKT patients had higher fasting amylin (19 +/- 3 vs. control subjects: 7 +/- 1 pmol/l) and insulin (20 +/- 2 vs. control subjects: 10 +/- 1 microU/ml; each P < 0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P < 0.05). In PKT patients, plasma glucose from 90 to 150 min was 9-31% higher (P < 0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin's plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P < 0.05). OGIS was not significantly different between groups. beta-Cell sensitivity to glucose was reduced in PKT patients (-64%, P < 0.009). Fasting plasma amylin was inversely associated with beta-cell sensitivity to glucose (r = -0.543, P < 0.004).. After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post-glucose load plasma amylin, which appears to be linked to impaired beta-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired beta-cell function in type 1 diabetic patients after PKT.

Topics: Adult; Amyloid; Area Under Curve; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Fatty Acids, Nonesterified; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Islet Amyloid Polypeptide; Islets of Langerhans; Kidney Transplantation; Middle Aged; Pancreas Transplantation

Despite that numerous investigations on the nature of diabetic microangiopathy were carried out, its pathomechanism remains unclear.. The aim of the study was to analyze the relation between early diabetic microangiopathy and the proinflammatory cytokines, NAG and its A and B isoforms in blood and urine in children diagnosed with diabetes mellitus type 1.. The study was carried out on the group of 56 children with diabetes mellitus 1 (age 13.6+/-3.74) and 35 healthy children selected as the controls. All the patients had 24 hrs albuminuria, HbA1c, C-peptide as well as the NAG enzyme and its A and B isoforms serum and urine activities measured. Additionally, all the children had TNF-a and IL6 level in serum measured. Each patient had 24 hrs blood pressure monitored and underwent ophthalmologic examination.. Children with long-standing diabetes mellitus and retinopathy (group 1, n=15) were older and were characterized by a statistically significant longer duration of the disease and higher HbA1c level in comparison with the patients who presented with no sign of diabetic retinopathy (group 2, n=41). In the group 1 statistically significant higher TNF-alpha serum level (p=0.01), NAG (p=0.002) and its isoforms A (p=0.007) and B (p=0.001) urine activities were measured in relation to the group 2. Additionally the level of IL-6 and NAG and its isoforms A and B serum activities were higher in group 1 than in group 2, however the differences were of no statistical significance. Moreover the children from group 2 in comparison with the healthy controls showed statistically significant higher TNF-alpha serum activity (p=0.016) and NAG (p<0.001) and its A (p<0.001) and B (p<0.001) isoforms both serum and urine activities.. The occurrence of the detectable serum TNF-alpha activity in children with diabetes mellitus type 1 showing no sign of diabetic retinopathy and nephropathy and no microalbuminuria with the concomitant increase of NAG and its isoforms serum and urine activities might point toward prompt occurrence of these changes in the eye and the kidneys.

Topics: Adolescent; Albuminuria; Biomarkers; C-Peptide; Child; Comorbidity; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Human Development; Humans; Hypertension; Interleukin-6; Male; Protein C; Risk Factors; Tumor Necrosis Factor-alpha

Although an increasing number of reports suggest that physiological concentrations of C-peptide protect against the development of diabetic nephropathy, possibly through the modulation of Na-K pump activity, the intracellular pathways controlled by C-peptide are still unrecognized. C-peptide and vasopressin share similar intracellular effects including the activation of calcium influx and endothelial nitric oxide synthase. Both hormones stimulate also the activity of Na-K pump activity. Whether the activity of C-peptide is mediated by the recently identified vasopressin-activated calcium-mobilizing receptor (VACM-1) has never been previously investigated.. To clarify this issue, we evaluated the effect of C-peptide on VACM-1 RNA (measured by semiquantitative RT-PCR) and protein expression (measured by immunoblotting) in human skin fibroblasts (where a specific binding of C-peptide was demonstrated) and in human mesangial cells, the cellular target of diabetic nephropathy.. C-peptide-induced activation of VACM-1 was demonstrated in fibroblasts from six healthy individuals (0.51+/-0.1 vs 1.48+/-0.4, arbitrary units+/-s.e., P = 0.025). This finding was paralleled by an increased VACM-1 protein expression (5.64+/-1.0 vs 8.47+/-1.2, arbitrary units+/-s.e., P= 0.043). Similar results were confirmed in three independent cultures of human mesangial cells. VACM-1 activation in fibroblasts was insensitive to phosphatidylinositol-3-kinase inhibitor LY294002, but was inhibited by pertussis toxin, suggesting that activation of VACM-1 could be mediated by a G protein-coupled receptor.. This study demonstrates for the first time that C-peptide activates VACM-1, possibly through a G protein-coupled receptor. Further studies are needed to clarify whether VACM-1 is involved in the protective effect of C-peptide against the development of diabetic nephropathy.

Topics: Antidiuretic Hormone Receptor Antagonists; Blotting, Western; C-Peptide; Cells, Cultured; Chromones; Cullin Proteins; Diabetic Nephropathies; Enzyme Inhibitors; Fibroblasts; Gene Expression Regulation; Glomerular Mesangium; GTP-Binding Proteins; Humans; Morpholines; Pertussis Toxin; Phosphoinositide-3 Kinase Inhibitors; Receptors, Vasopressin; Reverse Transcriptase Polymerase Chain Reaction; RNA; Skin

Topics: C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythrocyte Deformability; Humans; Sodium-Potassium-Exchanging ATPase

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

For selected patients with type 1 diabetes mellitus and end-stage renal failure, simultaneous kidney-pancreas (SKP) or pancreas after kidney (PAK) transplantation is the treatment of choice. However, it is frequently difficult to start a program for fear of serious intraabdominal complications in an immunosuppressed patient. We review our initial experience with these transplantations.. Twenty-three patients (20 SKP, 3 PAK) with type 1 diabetes mellitus received transplants between June 2000 and October 2003. All received immunosuppression therapy with thymoglobulin, prednisone, tacrolimus, and mycophenolate mofetil. The operation included portal venous drainage and exocrine enteric drainage. Rejections were biopsy-proved. Cytomegalovirus prophylaxis with gancyclovir was administered.. The mean follow-up is 13 months (range, 1-30 months) for recipients of mean age 39 +/- 7 years (17 men, 6 women). Mean cold ischemia time for kidney was 10.2 +/- 3.9 hours, and for pancreas was 10.5 +/- 3 hours. The rate of initial graft function was 100%. Graft rejection rate was 8%. The repeat laparotomy rate was 53% (12 patients), with a mean of 0.8 procedures per patient (range, 0 to 5). At the end of follow-up, patient survival was 95%, kidney survival was 85%, and pancreas survival was 83%. Patients with a functioning graft were insulin-free, with a mean fasting glucose concentration of 79 +/- 7 mg/dL, hemoglobin A1C of 4.5% (range, 4% to 4.9%) C-peptide of 5.9 ng/mL (range, 2.1 to 12 ng/mL), and a mean serum creatinine level of 1.6 mg/dL (range, 0.9 to 4.6 mg/dL). There was 1 death, due to posttransplantation lymphoproliferative disease confined to the pancreatic graft and abdominal sepsis at 3 months posttransplantation.. Our results are similar to those of other series of SPK or PAK transplantations: low acute rejection rates, frequent requirement for repeat laparotomy, and good patient and graft survival, permitting an excellent quality of life.

Topics: Adult; C-Peptide; Cytomegalovirus Infections; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hematoma; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Pancreas Transplantation; Postoperative Complications; Reoperation; Time Factors

The vitamin D (VD) receptor (VDR) is extensively expressed in retina. The plasma concentration of 1,25-dihydroxyvitamin D3 has been inversely correlated with the severity of diabetic retinopathy (DR), which raises the possibility that VD, through its antiinflammatory, antioxidant, antiproliferative, and antiangiogenic properties, may protect diabetic retina. The TaqI VDR polymorphism has been associated with severe DR. The FokI VDR polymorphism is a T-to-C substitution in the first codon (f allele), abolishing the first translation initiation site and resulting in a peptide lacking three amino acids (F allele), which increases the transcriptional activity of VDR.. To examine whether FokI polymorphism is involved in severe DR, 254 Caucasians with longstanding C-peptide-negative type 1 diabetes, 128 patients with absent/mild DR (control group), and 126 patients with preproliferative/proliferative DR (study group) were genotyped using PCR-restriction fragment length polymorphism analysis.. The genotype distribution was in Hardy-Weinberg equilibrium and was different between groups (P = 0.046). The frequency of F allele was significantly higher in the control (66.4%) than in the study group (56%, odds ratio = 0.64, 95% confidence interval 0.44-0.92, P = 0.016). In subjects with fewer than 25 yr of diabetes duration (median value, n = 134), this association was strongly increased (P = 0.0008).. In conclusion, we observed, in a cohort of Caucasians with C-peptide-negative type 1 diabetes, a novel association between the functional FokI VDR polymorphism and severe DR, especially among subjects with fewer than 25 yr of diabetes duration.

Topics: Adult; C-Peptide; Case-Control Studies; Codon, Initiator; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Polymorphism, Genetic; Receptors, Calcitriol; Risk Factors; Severity of Illness Index; White People

Diabetes, hypertension, infections, and nephrotoxicity of certain immunosuppressive drugs (i.e., calcineurin inhibitors) can reduce functional survival of the kidney graft. Our aim was to evaluate survival, hypertrophy, and vascular function of the kidney graft in end-stage renal disease (ESRD) type 1 diabetic patients after transplant.. The study population consisted of 234 ESRD type 1 diabetic patients who underwent kidney-pancreas (KP; 166 patients), successful kidney-islet (KI-s; 24 patients), and kidney (KD; 44 patients) transplant. Kidney size, graft survival, vascular function, and microalbuminuria were evaluated prospectively yearly for 6 years. Sixty-eight protocol kidney biopsies were performed routinely between 1993 and 1998 cross-sectionally (3.2 +/- 0.3 years from kidney transplant).. The KP and KI-s groups had better cumulative kidney graft survival at 6 years than did the KD group (KP: 73%; KI-s: 86%; KD: 42%, P < 0.01). The KP group but not the KI-s/KD groups showed a persistent kidney graft hypertrophy up to 6 years of follow-up. A significant increase in creatinine levels from baseline to year 6 was evident in the KD group (1.58 +/- 0.08 to 2.78 +/- 0.44 mg/dl, P < 0.05) but not in the KP/KI-s groups. The KP/KI-s groups only showed a reduction of renal resistance index from baseline to year 6 (KP at baseline: 0.74 +/- 0.01 to 0.68 +/- 0.01%, P < 0.01; KI-s at baseline: 0.72 +/- 0.02 to 0.69 +/- 0.02%, P < 0.05). At year 6, an increase from baseline in urinary albumin excretion was observed only in the KD group (31.4 +/- 9.0 to 82.9 +/- 33.6 mg/l, P < 0.05). Preliminary data suggested that graft nitric oxide (NO) expression was higher in the KP/KI-s groups than in the KD group (data not shown).. In ESRD type 1 diabetic patients, KP and KI-s compared with KD resulted in enhanced kidney graft survival, hypertrophy, and vascular function.

Topics: Adult; Biopsy; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Glycated Hemoglobin; Graft Survival; Humans; Hypertrophy; Immunosuppression Therapy; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Survival Analysis; Time Factors; Treatment Outcome

Even recipients with satisfactory function of transplanted pancreas and kidney may show physical and/or social disability due to diabetic complications. Our aims were to evaluate diabetic complications influencing recipient quality of life and to assess patients' psychosociological status. Nineteen patients with functioning grafts who consented to take part in the study, underwent clinical evaluation and answered questions regarding their quality of life. Results showed excellent endocrine pancreatic function in 17 patients. In most recipients, insulin activity and C-peptide levels were elevated owing to systemic venous drainage. Opthalmological examination revealed blindness in 7 patients (in 4 cases with onset following SPKTx) and retinopathy in 13 patients (in 5 cases it appeared after SPKTx). Assessment of the cardiovascular system revealed satisfactory cardiac function in 16 of 19 patients; 4 patients underwent amputation of a lower limb following SPKTx. All 19 recipients admitted to a great benefit of transplantation; most patients declared ability to organize their life activity and social functions and 4 had regular employment. Conversely, most patients were afraid of graft loss, and half were often sad and even depressed.

Topics: Blindness; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Employment; Humans; Insulin; Insulin Secretion; Kidney Failure, Chronic; Kidney Transplantation; Pancreas Transplantation; Postoperative Complications; Quality of Life

BACKGROUND AND CASE: Simultaneous pancreas and kidney transplantation (SPK) is applied almost exclusively in C-peptide-negative type 1 diabetic patients, although some data on SPK in type 2 diabetes have been published as well. Nothing is known about SPK in the autosomal diabetes form, maturity-onset diabetes of the young (MODY). SPK was performed in a 47-year old man who has MODY3 because of a Arg272His mutation in the hepatocyte nuclear factor-1alphagene. He developed overt diabetes mellitus at 19 years and end-stage diabetic nephropathy 26 years thereafter. Before SPK, the patient had measurable fasting serum C-peptide levels, but lacked beta-cell response to intravenous glucose and glucagon. He was treated with 34 IU of insulin per day. At 2 years post-transplantation, the patient remains normoglycemic and insulin independent. A hyperglycemic clamp test showed a normal beta-cell function.. Identification of MODY3 among all C-peptide-positive patients with advanced diabetic nephropathy might help to select a specific group profiting from SPK.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; DNA-Binding Proteins; Glucose Clamp Technique; Glucose Tolerance Test; Hepatocyte Nuclear Factor 1; Hepatocyte Nuclear Factor 1-alpha; Humans; Kidney Transplantation; Male; Middle Aged; Nuclear Proteins; Pancreas Transplantation; Point Mutation; Transcription Factors

Oxidative stress and neurovascular dysfunction have emerged as contributing factors to the development of experimental diabetic neuropathy (EDN) in streptozotocin-diabetic rodents. Additionally, depletion of C-peptide has been implicated in the pathogenesis of EDN, but the mechanisms of these effects have not been fully characterized. The aims of this study were therefore to explore the effects of diabetes on neurovascular dysfunction and indexes of nerve oxidative stress in type 1 bio-breeding Worcester (BB/Wor) rats and type 2 BB Zucker-derived (ZDR)/Wor rats and to determine the effects of C-peptide replacement in the former. Motor and sensory nerve conduction velocities (NCVs), hindlimb thermal thresholds, endoneurial blood flow, and indicators of oxidative stress were evaluated in nondiabetic control rats, BB/Wor rats, BB/Wor rats with rat II C-peptide replacement (75 nmol C-peptide.kg body wt(-1).day(-1)) for 2 mo, and diabetes duration-matched BBZDR/Wor rats. Endoneurial perfusion was decreased and oxidative stress increased in type 1 BB/Wor rats. C-peptide prevented NCV and neurovascular deficits and attenuated thermal hyperalgesia. Inhibition of nitric oxide (NO) synthase, but not cyclooxygenase, reversed the C-peptide-mediated effects on NCV and nerve blood flow. Indexes of oxidative stress were unaffected by C-peptide. In type 2 BBZDR/Wor rats, neurovascular deficits and increased oxidative stress were unaccompanied by sensory NCV slowing or hyperalgesia. Therefore, nerve oxidative stress is increased and endoneurial perfusion decreased in type 1 BB/Wor and type 2 BBZDR/Wor rats. NO and neurovascular mechanisms, but not oxidative stress, appear to contribute to the effects of C-peptide in type 1 EDN. Sensory nerve deficits are not an inevitable consequence of increased oxidative stress and decreased nerve perfusion in a type 2 diabetic rodent model.

Topics: Animals; Body Weight; C-Peptide; Diabetic Nephropathies; Enzyme Inhibitors; Hindlimb; Hot Temperature; Hyperalgesia; Insulin; Lipid Peroxidation; Male; Motor Neurons; Nerve Tissue; Neural Conduction; Neurons, Afferent; NG-Nitroarginine Methyl Ester; Oxidative Stress; Oxidoreductases; Rats; Rats, Inbred BB; Rats, Zucker; Reaction Time; Regional Blood Flow

The aim of this study was to assess the selection of candidates among 38 dialyzed diabetic patients referred between January 1, 1998 and December 31 2002 for kidney followed by islet transplantation (IAK). The main criteria of eligibility for possible IAK were as follows: (1) plasma C-peptide negative; (2) need for a kidney graft; (3) kidney plus whole pancreas transplantation not desired by the patient; and (4) acceptable results of postkidney graft preislet transplantation evaluation.. Seventeen of 38 patients with positive C-p diabetes received a kidney graft alone. Among the 21 C-p-negative diabetic patients, 3 were not eligible for kidney transplantation mainly for psychological reasons and 4 were eligible for kidney plus pancreas transplantation. The remaining 14 C-p-negative patients underwent kidney transplantation or had previously undergone kidney transplantation. Among them, 1 had moved away, 1 refused IAK, one had slightly positive stimulation tests, 1 was overweight, 1 had breast cancer, and 1 had postkidney graft complications. Among the remaining 8 of 14 C-p-negative, kidney-engrafted patients listed for IAK, 5 have undergone transplantation, 3 with a pre-Edmonton and 2 with the Edmonton protocol.. In conclusion among this series of 38 diabetic patients undergoing dialysis, more than 90% were kidney-grafted. Approximately 50% were ineligible for pancreas transplantation or IAK because of a positive C-p, and 20% were enlisted for IAK. These results highlight the importance of C-p determinations in diabetic dialysis patients to identify eligible patients for pancreas transplantation or IAK.

Topics: Adult; Aged; Biomarkers; C-Peptide; Diabetic Nephropathies; Eligibility Determination; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Patient Selection; Renal Dialysis

Latent autoimmune diabetes in adults (LADA) is subtype of diabetes type 1. It is well know, that 50% patients with new diagnosed diabetes type 2 present late complications. As far we don't know how many patients with new diagnosed diabetes have late complications according to presence of antibodies against islet antigens. The aim of the study was to compare late complications of diabetes: microangiopathy and macroangiopathy in newly diagnosed adult diabetic patients in relation to presence of humoral autoimmune markers.. We evaluated the presence of late complications in group of 41, hospitalized patients base on clinical examination and medical history. Glutaminic acid decarboxylase antibodies (anti-GAD), protein tyrosine phosphatase antibodies (anti-IA-2) and anti-insulin antibodies (IAA) titers were measured by RIA. The C peptide basal and stimulated, HbA1c, glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, urea, creatinine levels and microalbuminuria were evaluated.. The presence of islet cell specific antibodies were shown in 25 subjects. We observed late complications in 13/25 (52%) in group with positive antibodies titers, and in 10/16 (62.5%) in group without antibodies. We diagnosed the nephropathy (16% vs 6.25%), retinopathy (12% vs 0%), polyneuropathy (20% vs 12.5%), hypertension (32% vs 50%), chronic heart disease (8% vs 25%), overweight (32% vs 50%) and hyperlipidemia (12% vs 25%) respectively in subjects with and without antibodies. The concentrations of total cholesterol (185 +/- 47.8 vs 218 +/- 38.7, p < 0.05) and creatinine level (0.8 +/- 0.15 vs 0.95 +/- 24, p < 0.05) were higher in group without antibodies, but fasting glycemia (181 +/- 69.1 vs 132 +/- 32.8, p < 0.05) was higher in the group presenting with autoantibodies. We did not observed the difference between level of glycosylated hemoglobin in the investigated groups.. There is the tendency to higher incidence of microangiopathy in group of patients positive to islet cell antibodies. Conversely the macroangiopathy appears frequently in patients without antibodies.

Topics: Adult; Autoantibodies; Biomarkers; C-Peptide; Chronic Disease; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Female; Glutamate Decarboxylase; Humans; Insulin Antibodies; Islets of Langerhans; Male; Middle Aged; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases

Since the Edmonton protocol, islet transplantation (IT) offers the prospect of adequate glycemic control with no major surgical risk. In our single-center experience of IT, we studied the recruitment of eligible diabetic patients.. Between 1998 and 2002, we screened 79 diabetic patients that were divided into 2 groups according to their renal status: 41 were not receiving dialysis (ND) while 38 were receiving ongoing dialysis (D).. In the ND group, 20 patients initiated the contact with our team, 8 patients were recruited during hospitalization for very poor glycemic imbalance, and 13 were referred by their diabetologist. 14/41 (34%) patients were ineligible for IT either because of very good glycemic balance, detectable C-peptide (C-p), kidney or liver problems, or plans for future pregnancy. 16/41 (39%) did not wish to proceed, 7 of whom were more interested by a pump. 11/41 (27%) were eligible, among which 8 are currently being assessed, 1 is on the waiting list and 2 have been transplanted. In the D group, 17/38 (45%) had a detectable C-p and received a kidney graft alone. Among the remaining 21 C-p negative diabetic patients, 3 were not eligible for kidney transplantation mainly for psychological reasons, and 4 were enlisted for kidney+pancreas transplantation. The remaining 14 C-p negative patients were kidney-transplanted. Among them, 6 were not eligible for IT, mainly for lack of motivation, slightly positive C-p stimulation tests, obesity, cancer, or increased creatininemia. The remaining 8/14 C-p negative kidney-engrafted patients were enlisted for IT. 3 had secondary failure with the pre-Edmonton immunosuppressive (IS) protocol. Five have been transplanted with the Edmonton-like IS regimen.. Twenty-five per cent of the 79 patients for whom islet transplantation was considered underwent pregraft assessment and 12% (10 patients, 8 kidney-transplanted and 2 islet alone) of the 79 have been transplanted. The main eligibility criteria were undetectable Cpeptide, normal kidney function, average weight, glycemic imbalance, hypoglycemia unawareness, and glycemic brittleness.

Topics: Adult; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Male; Middle Aged; Patient Selection; Renal Replacement Therapy; Retrospective Studies; Treatment Outcome

Topics: Adult; Blood Glucose; C-Peptide; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dose-Response Relationship, Drug; Histocompatibility Testing; Humans; Insulin; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Male; Reoperation; Treatment Outcome

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

Our aim was to evaluate the long-term effects of transplanted islets on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients.. A total of 34 type 1 diabetic kidney-transplanted patients underwent islet transplantation and were divided into two groups: successful islet-kidney transplantation (SI-K; 21 patients, fasting C-peptide serum concentration >0.5 ng/ml for >1 year) and unsuccessful islet-kidney transplantation (UI-K; 13 patients, fasting C-peptide serum concentration <0.5 ng/ml). Patients cumulative survival, cardiovascular death rate, and atherosclerosis progression were compared in the two groups. Skin biopsies, endothelial dependent dilation (EDD), nitric oxide (NO) levels, and atherothrombotic risk factors [von Willebrand factor (vWF) and D-dimer fragment (DDF)] were studied cross-sectionally.. The SI-K group showed a significant better patient survival rate (SI-K 100, 100, and 90% vs. UI-K 84, 74, and 51% at 1, 4, and 7 years, respectively, P = 0.04), lower cardiovascular death rate (SI-K 1/21 vs. UI-K 4/13, chi(2) = 3.9, P = 0.04), and lower intima-media thickness progression than the UI-K group (SI-K group: delta1-3 years -13 +/- 30 micro m vs. UI-K group: delta1-3 years 245 +/- 20 micro m, P = 0.03) with decreased signs of endothelial injuring at skin biopsy. Furthermore, the SI-K group showed a higher EDD than the UI-K group (EDD: SI-K 7.8 +/- 4.5% vs. UI-K 0.5 +/- 2.7%, P = 0.02), higher basal NO (SI-K 42.9 +/- 6.5 vs. UI-K 20.2 +/- 6.8 micro mol/l, P = 0.02), and lower levels of vWF (SI-K 138.6 +/- 15.3 vs. UI-K 180.6 +/- 7.0%, P = 0.02) and DDF (SI-K 0.61 +/- 0.22 vs. UI-K 3.07 +/- 0.68 micro g/ml, P < 0.01). C-peptide-to-creatinine ratio correlated positively with EDD and NO and negatively with vWF and DDF.. Successful islet transplantation improves survival, cardiovascular, and endothelial function in type 1 diabetic kidney-transplanted patients.

Topics: Adult; C-Peptide; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Male; Survival Rate; Time Factors; Treatment Failure; Treatment Outcome

Proinsulin C-peptide treatment can partially prevent nerve dysfunction in type 1 diabetic rats and patients. This could be due to a direct action on nerve fibers or via vascular mechanisms as C-peptide stimulates the nitric oxide (NO) system and NO-mediated vasodilation could potentially account for any beneficial C-peptide effects. To assess this further, we examined neurovascular function in streptozotocin-induced diabetic rats. After 6 weeks of diabetes, rats were treated for 2 weeks with C-peptide to restore circulating levels to those of nondiabetic controls. Additional diabetic groups were given C-peptide with NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) co-treatment or scrambled C-peptide. Diabetes caused 20 and 16% reductions in sciatic motor and saphenous sensory nerve conduction velocity, which were 62 and 78% corrected, respectively, by C-peptide. L-NNA abolished C-peptide effects on nerve conduction. Sciatic blood flow and vascular conductance were 52 and 41%, respectively, reduced by diabetes (P < 0.001). C-peptide partially (57-66%) corrected these defects, an effect markedly attenuated by L-NNA co-treatment. Scrambled C-peptide was without effect on nerve conduction or perfusion. Thus, C-peptide replacement improves nerve function in experimental diabetes, and the data are compatible with the notion that this is mediated by a NO-sensitive vascular mechanism.

Topics: Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Male; Motor Neurons; Neural Conduction; Neurons, Afferent; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Sciatic Nerve

The potential effects of islet transplantation on the renal function of 36 patients with type I diabetes mellitus and kidney transplants were studied with 4 yr of follow-up monitoring. Kidney-islet recipients were divided into two groups, i.e., patients with successful islet transplants (SI-K group) (n = 24, fasting C-peptide levels of >0.5 ng/ml for >1 yr) and patients with unsuccessful islet transplants (UI-K group) (n = 12, fasting C-peptide levels of <0.5 ng/ml). Kidney graft survival rates and function, urinary albumin excretion rates, and sodium handling were compared. Na(+)/K(+)-ATPase activity in protocol kidney biopsies and in red blood cells was cross-sectionally analyzed. The SI-K group demonstrated better kidney graft survival rates (100, 83, and 83% at 1, 4, and 7 yr, respectively) than did the UI-K group (83, 72, and 51% at 1, 4, and 7 yr, respectively; P = 0.02). The SI-K group demonstrated reductions in exogenous insulin requirements and higher C-peptide levels, compared with the UI-K group, whereas GFR values were similar. Microalbuminuria (urinary albumin index) increased significantly in the UI-K group only (UI-K, from 92.0 +/- 64.9 to 183.8 +/- 83.8, P = 0.05; SI-K, from 108.5 +/- 53.6 to 85.0 +/- 39.0, NS). In the SI-K group, but not in the UI-K group, natriuresis decreased at 2 and 4 yr (P < 0.01). The SI-K group demonstrated greater Na(+)/K(+)-ATPase immunoreactivity in renal tubular cells (P = 0.05) and higher activity in red blood cells (P = 0.03), compared with the UI-K group. The Na(+)/K(+)-ATPase activity in red blood cells was positively correlated with circulating C-peptide levels but not with glycated hemoglobin levels. Successful islet transplantation was associated with improvements in kidney graft survival rates and function among uremic patients with type I diabetes mellitus and kidney grafts.

Topics: Albumins; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythrocytes; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Renin-Angiotensin System; Sodium; Sodium-Potassium-Exchanging ATPase; Time Factors; Uremia

Topics: Animals; C-Peptide; Clinical Trials as Topic; Diabetes Complications; Diabetic Nephropathies; Fluorocarbons; Graft Survival; Humans; Islets of Langerhans Transplantation

Topics: Aged; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Histocompatibility Testing; Humans; Insulin; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Male; Reoperation; Treatment Outcome

Topics: Antibodies, Monoclonal; Basiliximab; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Glycated Hemoglobin; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Recombinant Fusion Proteins; Reoperation; Retrospective Studies; Time Factors; Transplantation, Homologous

Several studies have demonstrated an association of CTLA4 (IDDM12) alanine-17 with type 1 diabetes, but CTLA4 variants have not yet been investigated in type 2 diabetes. The CTLA4 exon 1 polymorphism (49 A/G) was analyzed in 300 Caucasian patients with type 2 diabetes and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism, and restriction length fragment polymorphism analysis using BBV:I. The distribution of alleles as well as the genotypic and phenotypic frequencies were similar among patients and controls [AA, 42 vs. 39%; AG, 47 vs. 46%; GG, 11 vs. 15%, P = not significant (n.s.); A/G, 65/35% vs. 62/38%, P = n.s.; alanine/threonine 92/58% vs. 85/61%, P = n.s.]. However, detailed analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation (46.8 +/- 0.8 vs. 49.5 +/- 0.8 yr, mean +/- SEM), lower body mass index (21.4 +/- 0.5 vs. 24.4 +/- 0.5 kg/m(2), P = 0.042), and basal C-peptide level (0.33 +/- 0.07 vs. 0.53 +/- 0.07nmol/L), as well as earlier start of insulin treatment (5.8 +/- 1.2 vs. 8.7 +/- 0.6 yr) and higher portion of patients on insulin (71 vs. 61%). Patients with the AA genotype were significantly less likely to develop microangiopathic lesions (P < 0.0005). No differences were found for hypertension or family history of type 2 diabetes. In conclusion, CTLA4 alanine-17 does not represent a major risk factor for type 2 diabetes. Additional studies on larger groups and different ethnic groups are warranted to clarify the association of the GG genotype with faster ss-cell failure and the lower rate of microvascular complications in AA carriers.

Topics: Abatacept; Amino Acid Substitution; Antigens, CD; Antigens, Differentiation; C-Peptide; Codon; CTLA-4 Antigen; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Germany; HLA-DQ alpha-Chains; HLA-DQ Antigens; HLA-DQ beta-Chains; Humans; Immunoconjugates; Immunoglobulin Fc Fragments; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Reference Values; White People

The urinary excretion of insulinotropic glucagon-like peptide 1 (GLP-1) was investigated as an indicator of renal tubular integrity in 10 healthy subjects and in 3 groups of type 2 diabetic patients with different degrees of urinary albumin excretion rate. No significant difference emerged between the groups with respect to age of the patients, known duration of diabetes, metabolic control, BMI, or residual beta-cell pancreatic function. Endogenous creatinine clearance was significantly reduced under conditions of overt diabetic nephropathy, compared with normo and microalbuminuric patients (p < 0.01). Urinary excretion of GLP-1 was significantly higher in normoalbuminuric patients compared to controls (490.4 +/- 211.5 vs. 275.5 +/- 132.1 pg/min; p < 0.05), with further increase under incipient diabetic nephropathy conditions (648.6 +/- 305 pg/min; p < 0.01). No significant difference resulted, in contrast, between macroproteinuric patients and non-diabetic subjects. Taking all patients examined into account, a significant positive relationship emerged between urinary GLP-1 and creatinine clearance (p = 0.004). In conclusion, an early tubular impairment in type 2 diabetes would occur before the onset of glomerular permeability alterations. The tubular dysfunction seems to evolve with the development of persistent microalbuminuria. Finally, the advanced tubular involvement, in terms of urinary GLP1 excretion, under overt diabetic nephropathy conditions would be masked by severe concomitant glomerular damage with the coexistence of both alterations resulting in a peptide excretion similar to control subjects.

Topics: Aged; Albuminuria; Body Mass Index; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Male; Metabolic Clearance Rate; Middle Aged; Peptide Fragments

Our aim was to compare the diurnal blood pressure patterns of people with Type 1 diabetes on continuous ambulatory peritoneal dialysis (CAPD, n=9) or haemodialysis (n=10) to diabetic patients with normo-albuminuria (n=12) or micro-albuminuria (n=15). Blood pressure was measured with an ABPM02 Meditech oscillometric blood pressure monitor. The micro-albuminuric group had significantly higher nocturnal diastolic and mean arterial pressures than the normo-albuminuric group. CAPD and haemodialysis patients had significantly higher day time, nocturnal mean systolic, diastolic and mean arterial blood pressures. Micro-albuminuric and end-stage renal failure patients displayed a loss of the physiological drop of systolic blood pressure, which was only significant in the normo-albuminuric group. Nocturnal drop of blood pressure characterised by diurnal indices were 7.4% in the CAPD, 8.8% in the haemodialysis, 10.0% in the micro-albuminuric and 16.5% in the normo-albuminuric group. These results suggest, that pathological circadian blood pressure variation is common in diabetic patients on dialysis, and ambulatory blood pressure monitoring can be a useful tool both in its the detection and its adequate treatment.

Topics: Adult; Albuminuria; beta 2-Microglobulin; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood Urea Nitrogen; C-Peptide; Cholesterol; Circadian Rhythm; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Triglycerides

Leptin is a protein hormone produced predominantly by adipocytes that affects food intake and energy expenditure. Its serum levels are significantly higher in patients with chronic renal failure compared to healthy subjects. The aim of this study was to compare serum leptin levels in hemodialyzed patients with type II diabetes mellitus (n=26) with body content-matched hemodialyzed patients without diabetes (n=26) and to explore the relationship between parameters of the long term diabetes metabolic control and serum leptin levels. Serum leptin levels in diabetic patients did not significantly differ from those of non-diabetic patients (25.3+/-8.8 vs 25.7+/-8.7 ng/ml). Serum leptin levels in diabetic patients positively correlated with body fat content, body mass index and predialysis serum insulin levels. No significant relationship were observed between serum leptin levels and blood glucose, glycated hemoglobin, glycated protein, serum urea, creatinine, leukocyte count and total hemoglobin respectively. The multiple stepwise regression analysis revealed that body fat content together with body mass index accounted for 77.8% of variations in predialysis serum leptin levels, while insulin levels and the parameters of diabetes metabolic control had only slight prediction value for leptin concentrations. We conclude that serum leptin levels in hemodialysed patients with type III diabetes mellitus do not significantly differ from those of hemodialysed non-diabetic patients. The body fat content and body mass index are the strongest predictors of serum leptin levels, while parameters of long term diabetes metabolic control play probably only minor direct role in its regulation.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Insulin; Kidney Failure, Chronic; Leptin; Male; Reference Values; Regression Analysis; Renal Dialysis; Urea

Topics: C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Pancreas Transplantation; Postoperative Complications; Retrospective Studies; Taiwan; Time Factors

Topics: Adipose Tissue; Age Factors; Age of Onset; Aged; Albuminuria; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Hemoglobin A; Humans; Male; Middle Aged

Although glycemic control has an important impact on the clinical outcomes of patients with diabetes undergoing dialysis, there is a paucity of data on the relationship between glucose metabolism and clinical parameters in these patients. In this study, we compared a cohort of 48 patients with type II diabetes undergoing continuous ambulatory peritoneal dialysis (CAPD) with 84 age- and sex-matched patients with type II diabetes with similar disease duration but normal renal function. Compared with those with normal renal function, patients with type 2 diabetes undergoing CAPD had greater serum angiotensin-converting enzyme activity (median, 57.4 U/L; range, 33.5 to 100.0 U/L v 46.9 U/L; range, 11.6 to 111.2 U/L; P < 0.005), fasting C-peptide (median, 9.1 ng/mL; range, 0.9 to 30.0 ng/mL v 2.2 ng/mL; range, 0.2 to 20.3 ng/mL; P < 0.0001) and triglyceride levels, and lower serum albumin concentrations. Among the patients undergoing CAPD, there was a preponderance of men in the insulin-treated group. Insulin-treated patients also had greater plasma albumin levels and body weights and lower fasting serum C-peptide levels (2.81 +/- 1.77 v 3.12 +/- 2.04 ng/mL; analysis of variance, P = 0.007 adjusted for fasting glucose concentration). Multivariate analysis showed duration of diabetes, hemoglobin A(1c) (HbA(1c)) level, and body weight were independent determinants of insulin requirement in patients undergoing CAPD. The daily insulin dosage required was related to the duration of diabetes (r = 0.5; P = 0.007). In summary, among patients with end-stage renal failure, insulin-treated patients had greater body weights and plasma albumin levels but lower cholesterol levels. Plasma C-peptide concentration and duration of diabetes were the main determinants of insulin requirement, reflecting a decrease in beta-cell reserve, whereas the daily insulin dose correlated mainly with body weight, HbA(1c) level, and duration of diabetes. Kt/V had no effect on insulin resistance or insulin requirement of the patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Insulin Resistance; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Peptidyl-Dipeptidase A; Peritoneal Dialysis, Continuous Ambulatory; Serum Albumin; Treatment Outcome

A sub-study evaluated 698 younger (54.5 +/- 6.9 years) type 2 diabetics of the KID Study participants to establish the prevalence of diabetic complications and associated diseases and their correlation with body mass index (BMI), duration of disease and to C-peptide levels. Only 19.8% of the type 2 diabetics had a normal weight. In all weight subgroups, the average age of diabetes manifestation were around age 45. In 46.6% of all type 2 diabetics we could already demonstrate microangiopathic complications. Strikingly, 15.9% of the patients already had proliferative retinopathies and 12.6% had albuminuria of more than 1000 mg/dl. 74.7% of our type 2 diabetics presented with the well-known risk cluster of the metabolic syndrome: In every other patient, we found hypertension and/or hyperlipoproteinaemia. Accordingly, the prevalence of the macroangiopathic diabetic complications, coronary artery disease and peripheral vascular disease was 17.8%, which is high for a relatively young population with a mean age of 53.9 years and goes conform with recent literature (Lowel et al., 1999). An increase in BMI correlated significantly with deterioration of HbA1, a decrease in HDL cholesterol, an increase in triglycerides and with a higher prevalence of hypertension. The frequency of nephropathy increase significantly up to a BMI of 30-35 kg/m2. Retinopathies and polyneuropathies were associated with BMI but increased significantly with the duration of the diabetic state. In contrast to microangiopathic diabetic complications, there was already a high prevalence of nephropathy after a comparatively short duration of disease. The prevalence of hyperlipoproteinaemia and hypertension did not depend from the duration of diabetes. These concomitant diseases already were frequent early in the disease and did not increase with the duration of disease. However, there was a strong correlation between increasing hyperlipoproteinaemia and hypertension and higher C-peptide levels. We found no coincidence between C-peptide levels and microangiopathic diabetic complications.

Topics: Adult; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Germany; Humans; Male; Middle Aged; Prevalence; Prospective Studies; Randomized Controlled Trials as Topic; Time Factors

Topics: Albuminuria; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Food; Humans

The aim of this study was to determine whether renal functional reserve (RFR) is altered in insulin-dependent diabetic (IDDM) patients according to the stage of diabetic nephropathy. RFR was examined in 33 IDDM patients in similar glycaemic and metabolic control and compared to 12 healthy control subjects, during eight 1 h clearance periods prior to, during and after a 3-h stimulation by amino acid infusion (4.5 mg x kg(-1) x min[-1]). RFR was calculated as the difference between stimulated and baseline glomerular filtration rates (GFR). In 14 early normotensive diabetic patients with normal urinary albumin excretion, mean baseline GFR (133 +/- 3 ml x min(-1) x 1.73 m[-2]) was higher whereas RFR (10 +/- 4 ml x min(-1) x 1.73 m[-2]) was lower (p < 0.05) than in control subjects (113 +/- 4 and 28 +/- 2 ml x min(-1) x 1.73 m(-2), respectively). In 10 normotensive patients who had lived with IDDM for 16 years and who had microalbuminuria, baseline GFR and RFR (109 +/- 7 and 24 +/- 6 ml x min(-1) x 1.73 m(-2), respectively) were similar to those in control subjects. In 9 patients who had suffered IDDM for 23 years and had developed macroalbuminuria and hypertension, baseline GFR (78 +/- 8 ml x min(-1) x 1.73 m[-2]) was lower than in control subjects (p < 0.05) and RFR (8 +/- 4 ml x min(-1) x 1.73 m[-2]) was not significant. In addition, renal vascular resistance decreased significantly during infusion (p < 0.05) in microalbuminuric normotensive patients as well as in control subjects (by 9 +/- 4 and 11 +/- 4 mmHg x l(-1) x min(-1) x 1.73 m(-2), respectively) but not in normoalbuminuric normotensive or macroalbuminuric hypertensive patients. These results indicate that microalbuminuric normotensive patients retain a normal RFR, whereas RFR is reduced or suppressed at two opposite stages of the disease: in normoalbuminuric normotensive patients with a high GFR and in macroalbuminuric hypertensive patients with a decreased GFR. This dissimilar impairment reveals permanent glomerular hyperfiltration in both early IDDM without nephropathy and IDDM with overt diabetic nephropathy, but not in IDDM with incipient nephropathy.

Topics: Adult; Albuminuria; Aldosterone; Amino Acids; Blood Glucose; Blood Pressure; C-Peptide; Creatinine; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Dietary Proteins; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypertension; Kidney; Male; Reference Values; Renal Circulation; Renin; Vascular Resistance

Topics: Albuminuria; Black or African American; Black People; Blood Glucose; Blood Pressure; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Male; Prevalence; Time Factors; Urban Health

Simultaneous pancreas and kidney transplantation (SPK) is capable of achieving normoglycemia, as assessed by oral glucose tolerance tests (OGTT), in the majority of diabetic recipients with end-stage renal disease. Despite its success over the last decade, standard ranges for OGTT after SPK are not available for comparison between studies and techniques. We examined 327 prospectively performed OGTT, undertaken in insulin-free bladder-drained SPK recipients, between 1 month and 10 yr after transplantation. Ranges of values for glucose, insulin and C-peptide were derived and areas under the time concentration curves calculated. The normal range of 2-h glucose values from SPK recipients was comparable to WHO criteria for the diagnosis of diabetes mellitus in a normal population; however, the fasting glucose fell below these levels. Fasting and area-under-the-curve (AUC) glucose were remarkably stable with time after SPK, although insulin fell with time after pancreas transplantation. These ranges may allow clinical evaluation of the endocrine function in individual SPK recipients, provide standards for comparison between different centers and techniques, and provide targets for islet transplantation.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glucose Tolerance Test; Homeostasis; Humans; Insulin; Kidney Transplantation; Male; Pancreas Transplantation; Prospective Studies

To examine the possible association between serum lipoprotein(a) [Lp(a)] concentration and proliferative diabetic retinopathy (PDR) in Korean patients with type 2 diabetes.. A total of 412 Korean outpatients with type 2 diabetes were examined. Diabetic retinopathy was determined by an ophthalmologist using fundoscopic examination. Serum Lp(a) levels were measured by two-site sandwich enzyme-linked immunosorbent assay.. The patients with PDR had higher serum Lp(a) levels than those with no diabetic retinopathy or with nonproliferative diabetic retinopathy (NPDR). Multiple logistic regression analysis showed that high serum Lp(a) levels and the presence of diabetic nephropathy were independent variables having a statistically significant association with PDR.. Korean type 2 diabetic patients with PDR had higher serum Lp(a) levels versus those with no diabetic retinopathy or with NPDR. Although these results suggest that Lp(a) might play a role in the occlusion of retinal capillaries leading to PDR, further prospective studies are required to prove the causal relationship.

Topics: Blood Glucose; Blood Pressure; C-Peptide; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Glycated Hemoglobin; Humans; Korea; Lipoprotein(a); Middle Aged; Prospective Studies; Regression Analysis; Triglycerides

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

To identify the clinical characteristics of early-onset NIDDM patients with severe diabetic complications.. The clinical cases of a large number of diabetic patients who visited a diabetes center within the period 1970-1990 were reviewed. Of a total of 16,842 diabetic patients, 1,065 (6.3%) had early-onset NIDDM (diabetes diagnosed before 30 years of age). These 1,065 patients were divided into two groups, those who developed proliferative retinopathy before the age of 35 (n = 135) and those who did not (n = 930). Development of proliferative retinopathy, nephropathy, renal failure, blindness, and atherosclerotic vascular disease were compared between the two groups.. The subgroup of 135 patients was characterized by poor glycemic control, often requiring insulin therapy and a higher familial prevalence of diabetes, and contained a greater proportion of women than the subgroup of 930 patients. Of the 135 patients, 99 (67%) developed proliferative retinopathy before the first visit. The 135 patients developed severe progressive complications in contrast to the 930 patients. A total of 81 patients (60%) developed diabetic nephropathy at a mean age of 31 years, 31 (23%) developed renal failure requiring dialysis at a mean age of 35 years, 32 (24%) became blind at a mean age of 32 years, and 14 (10%) developed atherosclerotic vascular disease at a mean age of 36 years.. Some Japanese early-onset NIDDM patients develop severe diabetic complications in their youth. Most of them had no symptoms nor regular treatment regarding diabetes until they were noticed to have developed severe diabetic complications. Although the relevant prevalence and the pathogenetic mechanism underlying the rapid onset of the complications remain to be determined, prolonged inadequate treatment of and familial predisposition to diabetes may be contributing factors. Careful diabetes care in the twenties, not only for IDDM but also for NIDDM patients, is warranted.

Topics: Adult; Age Factors; Age of Onset; Arteriosclerosis; Blindness; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Kidney Failure, Chronic; Male; Middle Aged; Retrospective Studies

Topics: C-Peptide; Cholecystectomy, Laparoscopic; Cholelithiasis; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged

Topics: Adult; Bone Marrow Transplantation; C-Peptide; Cadaver; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Male; Time Factors; Tissue Donors; Transplantation Chimera

Topics: C-Peptide; Cell Separation; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Retrospective Studies; Time Factors; Transplantation, Homologous; Treatment Failure; Treatment Outcome

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Kidney Transplantation; Pancreas Transplantation; Prospective Studies; Quality of Life; Time Factors

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Florida; Follow-Up Studies; Glycated Hemoglobin; Hispanic or Latino; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Retrospective Studies

Topics: C-Peptide; Diabetic Angiopathies; Diabetic Nephropathies

The intraportal injection of human pancreatic islets has been indicated as a possible alternative to the pancreas transplant in insulin-dependent diabetic patients. Aim of the present work was to study the effect of intraportal injection of purified human islets on: (a) the basal hepatic glucose production; (b) the whole body glucose homeostasis and insulin action; and (c) the regulation of insulin secretion in insulin-dependent diabetes mellitus patients bearing a kidney transplant. 15 recipients of purified islets from cadaver donors (intraportal injection) were studied by means of the infusion of labeled glucose to quantify the hepatic glucose production. Islet transplanted patients were subdivided in two groups based on graft function and underwent: (a) a 120-min euglycemic insulin infusion (1 mU/kg/min) to assess insulin action; (b) a 120-min glucose infusion (+75 mg/di) to study the pattern of insulin secretion. Seven patients with chronic uveitis on the same immunosuppressive therapy as grafted patients, twelve healthy volunteers, and seven insulin-dependent diabetic patients with combined pancreas and kidney transplantation were also studied as control groups. Islet transplanted patients have: (a) a higher basal hepatic glucose production (HGP: 5.1 +/- 1.4 mg/kg/ min; P < 0.05 with respect to all other groups) if without graft function, and a normal HGP (2.4 +/- 0.2 mg/kg/min) with a functioning graft; (b) a defective tissue glucose disposal (3.9 +/- 0.5 mg/kg/min in patients without islet function and 5.3 +/- 0.4 mg/kg/min in patients with islet function) with respect to normals (P < 0.01 for both comparisons); (c) a blunted first phase insulin peak and a similar second phase secretion with respect to controls. In conclusion, in spite of the persistence of an abnormal pattern of insulin secretion, successful intraportal islet graft normalizes the basal HGP and improves total tissue glucose disposal in insulin-dependent diabetes mellitus.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glucagon; Glucose; Glucose Clamp Technique; Homeostasis; Humans; Infusions, Intravenous; Insulin; Islets of Langerhans Transplantation; Kidney Transplantation; Liver; Liver Transplantation; Male; Middle Aged; Uveitis

The majority of islet transplant recipients remain insulin-requiring, although many have near-normal connecting peptide (CP) levels. Insulin resistance may be one possible cause of the continuing need for exogenous insulin in islet transplant recipients. To assess this, we have studied the insulin sensitivity index (S1) in one patient with near-normal CP levels after islet transplant who remained insulin-requiring.. The islet transplant recipient is a 36-year-old woman with no residual CP who received a kidney transplant, followed 7 days later by an islet transplant. The islets were infused into the liver via the umbilical vein. Induction immunosuppression consisted of OKT3, prednisone, cyclosporin A, and azathioprine, with maintenance on the latter three.. Maximum CP levels after a standardized Sustacal meal were 2.09, 1.18, 0.85, and 0.81 nmol/l at 1,6,18, and 24 months posttransplant, respectively. Insulin requirements at the same times were 0.27, 0.45, 0.49, and 0.62 U.kg(-1).d(-1), while S1 was 36.3, 53.3, and 13.2 min (-1).nmol(-1).ml at 6,18, and 24 months, respectively. This compares with S1 values of 43.3+/- 10.0 min (-1).nmol(-1).ml for normal subjects.. This patient had near-normal S1 and CP levels, but she was unable to discontinue insulin therapy, suggesting that other factors are critical. Despite this, she maintained normal or near-normal glycated hemoglobins, indicating metabolic benefit from the islet transplant.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Insulin; Islets of Langerhans Transplantation; Kidney Transplantation

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Liver Failure; Liver Transplantation; Middle Aged; Pancreas Transplantation; Patient Selection; Retrospective Studies; Transplantation, Autologous; Transplantation, Homologous

After successful pancreas transplantation, insulin-dependent diabetic patients are characterized by a normal or at worst impaired oral glucose tolerance (World Health Organisation criteria). It is not known which pathophysiological mechanisms cause the difference between normal and impaired oral glucose tolerance. Therefore, we studied 41 patients after successful combined pancreas-kidney transplantation using stimulation in the fasting state with oral glucose (75 g), intravenous glucose (0.33 g/kg) and glucagon bolus injection (1 mg i.v.). Glucose (glucose oxidase), insulin and C-peptide (immunoassay) were measured. Repeated-measures analysis of variance and multiple regression analysis were used to analyse the results which showed: 28 patients had a normal, and 13 patients had an impaired oral glucose tolerance. Impaired oral glucose tolerance was associated with a greatly reduced early phase insulin secretory response (insulin p < 0.0001; C-peptide p = 0.037). Age (p = 0.65), body mass index (p = 0.94), immunosuppressive therapy (cyclosporin A p = 0.84; predniso(lo)ne p = 0.91; azathioprine p = 0.60) and additional clinical parameters were not different. Reduced insulin secretory responses in patients with impaired oral glucose tolerance were also found with intravenous glucose or glucagon stimulations. Exocrine secretion (alpha-amylase in 24-h urine collections) also demonstrated reduced pancreatic function in these patients (-46%; p = 0.04). Multiple regression analysis showed a significant correlation of 120-min glucose with ischaemia time (p = 0.003) and the number of HLA-DR mismatches (p = 0.026), but not with HLA-AB-mismatches (p = 0.084). In conclusion, the pathophysiological basis of impaired oral glucose tolerance after pancreas transplantation is a reduced insulin secretory capacity. Transplant damage is most likely caused by perioperative influences (ischaemia) and by the extent of rejection damage related, for example, to DR-mis-matches.

Topics: Adult; alpha-Amylases; Analysis of Variance; Biomarkers; Blood Glucose; Blood Group Incompatibility; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Glucagon; Glucose Intolerance; Glucose Tolerance Test; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Insulin; Insulin Secretion; Kidney Transplantation; Male; Pancreas Transplantation; Reference Values; Regression Analysis; Time Factors

Seven type I insulin-dependent diabetic patients on continuous ambulatory peritoneal dialysis treatment were selected for this study. Each patient participated in three different 6-hour 'single-dwell' studies on 3 consecutive days. A mean dose of 33 +/- 1.3 U Insulin Actrapid Human was given intraperitoneally each day. The procedures for intraperitoneal insulin administration were: (1) with 1,000 ml Ringer lactate; (2) with 1,000 ml 3.86% glucose-containing dialysate, and (3) into an empty peritoneal cavity. The calculation of the intraperitoneal volume was done with a single injection indicator dilution technique in which 100 kBq radioiodinated serum albumin (RISA) was added into the fluid prior to instillation. Free insulin and glucose were analyzed at 16 time intervals in blood and in dialysate during each dwell. After drainage the peritoneal cavity was rinsed with 1,000 ml Ringer lactate followed by two consecutive 5-hour exchanges with 2,000 ml glucose-containing dialysate. Recovery of insulin and RISA was measured in rinsing fluid and in sampled dialysate during the 6-hour dwell. The kinetic calculations made for insulin were disappearance rate (mU/min) from the peritoneal cavity, and appearance rate in circulating blood. After drainage and rinsing, 66.0 +/- 10 and 71.8 +/- 9.8% of the insulin instilled had disappeared after 6 h from the glucose fluid and from the Ringer solution respectively and did not differ significantly. However, the estimated disappearance rate from the peritoneal cavity was significantly higher in Ringer than in glucose from the time interval 120 to 360 min. A high and peak-shaped insulin concentration in the plasma was found following insulin injection into an empty peritoneal cavity, and was significantly higher than when insulin was dissolved in a 1,000-ml fluid volume. However, a higher blood concentration was also found when Ringer was instilled than when a hyperosmolal glucose solution was instilled. A high first-pass elimination in the liver is suggested. In conclusion, fluid volume and also the osmolality of the solution in the peritoneal cavity decreases the transport rate, but not the bioavailability of insulin given intraperitoneally. Both a high peak shape and a continuous insulin appearance in blood can be achieved. It is suggested that there is a high first-pass elimination of insulin during absorption from the peritoneal cavity. However, the values are uncertain and extended investigations must be done.

Topics: Adult; Aged; Blood Proteins; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Half-Life; Humans; Infusions, Parenteral; Insulin; Insulin Antibodies; Insulin, Regular, Pork; Iodine Radioisotopes; Male; Metabolic Clearance Rate; Middle Aged; Peritoneal Cavity; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

Topics: Adult; Blood Glucose; C-Peptide; Cell Separation; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glycated Hemoglobin; Graft Rejection; Humans; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Care; Transplantation, Homologous; Treatment Outcome

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Duodenum; Female; Follow-Up Studies; Glucose; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Kidney Failure, Chronic; Kidney Transplantation; Male; Pancreas Transplantation; Time Factors

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Time Factors

Topics: Adult; Antilymphocyte Serum; Blood Glucose; C-Peptide; Cell Separation; Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Humans; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney Transplantation; Male; Middle Aged; T-Lymphocytes

Topics: Adult; Blood Glucose; C-Peptide; Cryopreservation; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Insulin; Islets of Langerhans Transplantation; Kidney Transplantation; Male; Tissue Donors

Topics: Adult; Amylases; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fasting; Female; Follow-Up Studies; Glucose Clamp Technique; Glycated Hemoglobin; Graft Rejection; Humans; Insulin; Insulin Antibodies; Kidney Transplantation; Pancreas Transplantation; Proinsulin; Time Factors

To investigate risk factors for distal symmetric (sensory) neuropathy among prevalent cases of non-insulin-dependent diabetes mellitus (NIDDM) in a population-based study in southern Colorado.. Prevalent neuropathy was identified in 77 of 277 people with NIDDM by a standardized history and neurologic examination. Fifteen known or suspected risk factors for neuropathy were determined without knowledge of neuropathy status.. Older age at examination, longer duration of diabetes, higher glycohemoglobin percentage, lower fasting C-peptide, insulin use, and presence of retinopathy and nephropathy (microalbumin > or = 200 micrograms/ml) were all significantly associated with neuropathy. Sex, ethnicity (Hispanic versus non-Hispanic white), height, systolic blood pressure, peripheral vascular disease, cigarette and alcohol use, and serum lipid levels were not significantly associated with neuropathy. In a multivariate logistic model, increasing age (odds ratio [OR] = 1.3, 95% confidence interval [CI] = 1.1-1.6), longer duration of diabetes (OR = 1.3, CI = 1.0-1.6), increased glycohemoglobin percentage (OR = 1.5, CI = 1.1-2.1), and insulin use (OR = 2.8, CI = 1.3-6.1) were associated with neuropathy. Retinopathy (OR = 3.0, CI = 1.2-7.7), but not nephropathy, was important when added to this model.. Worse glycemic control and insulin use were independently associated with neuropathy in people with NIDDM. Whether insulin use represents another marker for severity of the metabolic disturbance or is an independent risk factor for neuropathy requires further study. We could not confirm associations of neuropathy with height, with nephropathy, or with retinopathy, independent of duration of diabetes.

Topics: Adult; Age Factors; Aged; C-Peptide; Confidence Intervals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Insulin; Logistic Models; Male; Middle Aged; Odds Ratio; Risk Factors; Time Factors

Topics: Adult; Apolipoproteins A; Apolipoproteins B; Blood Glucose; C-Peptide; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Eating; Fasting; Fatty Acids, Nonesterified; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Insulin; Kidney Transplantation; Lipase; Lipids; Lipoprotein Lipase; Male; Pancreas Transplantation; Time Factors; Triglycerides

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Islets of Langerhans Transplantation; Kidney Failure, Chronic; Kidney Transplantation; Parenteral Nutrition, Total; Prednisolone; Time Factors; Transplantation, Homologous

Topics: C-Peptide; Cell Separation; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Glycated Hemoglobin; Guanidines; Humans; Immunosuppressive Agents; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Time Factors

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Eating; Fasting; Glucagon; Glycated Hemoglobin; Humans; Islets of Langerhans; Kidney Transplantation; Middle Aged; Pancreas Transplantation; Reference Values; Tolbutamide

Topics: Adult; Blood Glucose; C-Peptide; Cryopreservation; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Kidney Transplantation; Portal Vein; Retrospective Studies; Time Factors; Transplantation, Homologous; Treatment Failure

Because of the previous controversial findings in diabetic patients with older methodologies, we assessed bone mineral density (BMD) in 78 patients (38 males and 40 females) with non-insulin-dependent diabetes mellitus using dual energy x-ray absorptiometry (DEXA). BMD was measured in lumbar vertebrae (L2-4). The BMD of each patient was calculated as the percentage of the mean value (%BMD) obtained from a healthy control group matched for sex and age. The %BMD of the patients with diabetes was about 100% for females and 96% for males, as compared with BMD of normal controls. The %BMD of the patients with diabetes was significantly correlated with body mass index and urinary C peptide level, and inversely correlated with age and duration of diabetes within 20 years. No relationships were found between %BMD and serum calcium, phosphorus, or glycosylated hemoglobin A1C levels. These observations suggest that metabolic abnormalities associated with diabetes mellitus alter the BMD, and that such factors as duration of the disease and deficit in insulin secretion are risk factors for decreased BMD.

Topics: Absorptiometry, Photon; Adult; Aged; Aged, 80 and over; Bone Density; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis

In this study, pancreas transplantation is used as a clinical model of pancreas denervation in humans. To assess the role of innervation on the feedback autoinhibition of insulin secretion, we studied four groups of subjects--group 1: 16 patients with combined pancreas and kidney transplantation (plasma glucose = 5.1 mM, HbA1c = 6.4%, creatinine = 86 mM); group 2: 8 patients with chronic uveitis on the same immunosuppressive therapy as transplanted patients (12 mg/day prednisone, 5 mg.kg-1.day-1 CsA); group 3: 4 uremic, nondiabetic patients in chronic hemodialysis; group 4: 7 normal, nondiabetic control subjects. The following means were used to study the groups: 1) a two-step hyperinsulinemic euglycemic clamp (insulin infusion rate = 1 mU and 5 mU.kg-1.min-1); and 2) a 0.3 mU.kg-1.min-1 hypoglycemic clamp (steady-state plasma glucose = 3.1 mM). Basal plasma-free IRI (84 +/- 6, 42 +/- 12, 72 +/- 12, and 30 +/- 6 pM in groups 1, 2, 3, and 4, respectively), basal C-peptide (0.79 +/- 0.05, 0.66 +/- 0.05, 3.04 +/- 0.20, and 0.59 +/- 0.06 nM in groups 1, 2, 3, and 4, respectively), and glucagon (105 +/- 13, 69 +/- 4, 171 +/- 10, and 71 +/- 5 pg/ml in groups 1, 2, 3, and 4, respectively) were increased in groups 1 and 3 with respect to groups 2 and 4 (P < 0.01). During euglycemic hyperinsulinemia, plasma C-peptide decreased by 45, 20, and 44% in groups 2, 3, and 4, respectively, but showed no significant change from the basal in patients with transplanted pancreases.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Hydroxybutyric Acid; Adult; Analysis of Variance; Blood Glucose; C-Peptide; Denervation; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Epinephrine; Fatty Acids, Nonesterified; Feedback; Follow-Up Studies; Glucagon; Glucose Clamp Technique; Glycated Hemoglobin; Hormones; Humans; Hydroxybutyrates; Insulin; Insulin Secretion; Kidney Transplantation; Lactates; Pancreas; Pancreas Transplantation; Pancreatic Polypeptide; Somatostatin; Uremia

An epidemiologic study of end-stage diabetic nephropathy in France (Uremidiab) was performed, aiming to establish the prevalence of both types of diabetes in dialysis patients. Because discrimination between type I and type II diabetes remains mostly clinical, our aim was to evaluate what the most fitted clinical criteria were. We studied 494 hemodialyzed diabetic patients. A first classification (Cn) was offered by the nephrologist. Clinical data of 472 patients (22 patients of the 494 have been excluded) were then collected with a standardized questionnaire, allowing one diabetologist of us to establish the diagnosis of type of diabetes (classification Cd). Plasma C-peptide at this stage of the disease was expected to be very discriminative, measured in 88 patients and defined classification Ccp (< or = 0.6 ng/ml = "negative C-peptide" = type I, > 0.6 ng/ml = "positive C-peptide" = type II). Classification Cd observed 98 type I and 374 type II diabetes. Cn overestimated type I diabetes, 37% of type II diabetes being misclassified because insulin-treated. Classification Ccp observed 74 positive C-peptide patients, classified as type II, among whom 45 were insulin-treated. Only 3 patients were discordant for classification Cd and Ccp. Predictive value of "negative C-peptide" and "positive C-peptide" were 100% and 96% respectively. Multiple regression analysis of the Ccp classification was performed with the clinical criteria and showed very significant correlation with: age at the time of diagnosis of diabetes (AGE), maximal body mass index ever reached (BMI MAX) and delay between diagnosis and consistent insulin use (DI).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; C-Peptide; Diabetes Mellitus; Diabetic Nephropathies; Fasting; Female; France; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Reproducibility of Results; Retrospective Studies

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Fetal Tissue Transplantation; Fluorescein Angiography; Follow-Up Studies; Glycated Hemoglobin; Graft Survival; Humans; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation

Topics: Abdominal Neoplasms; Adolescent; Adult; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glycated Hemoglobin; Graft Rejection; Graft Survival; Humans; Insulin; Islets of Langerhans Transplantation; Kidney Transplantation; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Pancreatectomy; Transplantation, Autologous; Transplantation, Heterotopic

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Glucose Tolerance Test; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Insulin Secretion; Kidney Transplantation; Pancreas Transplantation; Uremia

Topics: Adult; Animals; Antibodies, Heterophile; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Fetal Tissue Transplantation; Glycated Hemoglobin; Humans; Immunoglobulin M; Immunosuppressive Agents; Kidney Transplantation; Lymphocytes; Pancreas Transplantation; Swine; Transplantation, Heterologous

We have previously shown that the loss of acute first phase insulin secretion precedes pancreas allograft rejection and development of glucose intolerance in Type 1 diabetic patients. In order to examine whether there is a progressive loss of phases of insulin secretion and beta-cell function in technically successful pancreas transplants during the first year, we measured glucose, insulin, and C-peptide responses to physiological (mixed meal) and pharmacological (IV glucose and IV glucagon) stimulation in 27 glucose-tolerant, insulin-independent allograft recipients at 3, 6, and 12 months. Mean +/- SE fasting serum glucose levels were normalized throughout the study period. Postprandial serum glucose profiles tended to increase by 12 months compared to 3 and 6 months, although peak glucose levels were not statistically different. Following pancreas transplantation, basal serum insulin levels were high at 3 months (163 +/- 17 pM), 6 months (165 +/- 22 pM), and 12 months (248 +/- 54 pM, p = NS) in the Type 1 diabetic pancreas allograft recipients when compared to normal (25 +/- 3 pM). We observed slight elevations in postprandial insulin and C-peptide profiles at 12 months compared to 3 and 6 months. Following IV glucose and glucagon stimulation, serum insulin and C-peptide levels as well as phases of insulin release did not differ over the 12-month study period. Similarly, the glucose decay constant (KG) was nearly identical at 3, 6, and 12 months. In summary, 1 year following successful whole cadaveric, heterotopic pancreas transplantation in Type 1 diabetic recipients, fasting serum glucose remains normalized, while postprandial glucose tends to rise.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Analysis of Variance; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Eating; Female; Follow-Up Studies; Glucagon; Glucose Tolerance Test; Humans; Insulin; Kidney Transplantation; Male; Pancreas Transplantation; Regression Analysis; Transplantation, Homologous

The variation of urinary C-peptide clearance in relation to hyperglycemia and renal damage was evaluated in 57 patients with non-insulin-dependent diabetes mellitus (NIDDM) with and without overt proteinuria, 14 nondiabetic patients with renal disease (RD) and 18 healthy control subjects. Urinary C-peptide clearance expressed as the ratio of urinary C-peptide to creatinine clearance (CCP/CCR) in the fasting state did not differ in control subjects and RD patients, and was higher equally in NIDDM patients with and without proteinuria. In NIDDM patients without overt proteinuria, urinary levels of C-peptide, beta 2-microglobulin (B2M), N-acetyl-beta-D-glucosaminidase (NAG) and albumin as well as CCP/CCR ratio all decreased significantly with short-term glycemic control (P less than 0.05). Despite a wide range of CCP/CCR ratio (0.07-0.73), a weak but significant correlation (r = 0.56, P less than 0.005) was found between fasting serum and urinary C-peptide levels in NIDDM patients. These results suggest that urinary C-peptide may easily be affected by hyperglycemia per se rather than renal damage, while urinary B2M, NAG and albumin may be affected by both hyperglycemia and renal damage. When the urinary C-peptide level is interpreted, the influence of hyperglycemia on it must be taken into consideration.

Topics: Acetylglucosaminidase; beta 2-Microglobulin; Biomarkers; C-Peptide; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hyperglycemia; Kidney Diseases; Male; Middle Aged; Proteinuria; Reference Values

Metabolic glucose control was followed in 36 patients at 12-month intervals for up to 5 years after a successful combined kidney and segmental duct-occluded pancreas transplantation. All recipients had normal blood glucose levels at each examination. HbA1 values, intravenous glucose tolerance test, C-peptide levels and C-peptide responses to glucagon stimulation were also, on average, within the normal range. Several individual patients had, however, abnormal values for these parameters. At most 46% had abnormal values for HbA1 and intravenous glucose tolerance test, up to 13% showed low C-peptide values and up to 46% of the stimulated C-peptide responses were inadequate at the different intervals. These parameters did not deteriorate with time. This was true both for the whole group of patients as well as for the 6 patients with a 5-year observation time evaluated separately. Despite these abnormalities in glucose metabolism, all patients remained normoglycaemic without need for exogenous insulin up to 5 years after transplantation. The long-term ability of duct-occluded segmental pancreatic grafts to preserve euglycaemia therefore seems to remain intact at least for 5 years.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Glucagon; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Kidney Transplantation; Pancreas Transplantation; Reference Values; Uremia

Insulin action and insulin specific binding to erythrocytes were examined in ten recipients of a pancreatic segment and renal graft (Group 1), in nine non-diabetic kidney recipients (Group 2) and in ten age- and weight-matched healthy control subjects (Group 3). All transplant recipients were normoglycaemic without need of insulin, received the same immunosuppression and had good renal graft function at 11-18 months post-transplantation, when the investigation was performed. Using the insulin clamp technique, insulin action was expressed as the metabolic clearance rate of glucose at insulin infusion rates of 1.0 (MCRsubmax) and 10.0 (MCRmax) mU.kg-1.min-1. In comparison with the healthy control subjects, fasting free insulin and C-peptide levels were significantly higher in Groups 1 and 2, but no differences between Groups 1 and 2 were found (p greater than 0.05). Mean values +/- SEM of MCRsubmax in Groups 1, 2 and 3 were 6.30 +/- 0.55, 6.09 +/- 0.69 and 10.52 +/- 1.10 ml.kg-1.min-1 respectively, and of MCRmax 12.65 +/- 0.78, 13.14 +/- 0.92 and 19.28 +/- 1.42 ml.kg-1.min-1 respectively. Insulin action was significantly decreased in Groups 1 and 2 at the low as well as the high insulin infusion rates but there was no difference between the two groups of recipients (p greater than 0.05). No differences in binding data (specific binding, number of binding sites per cell) were found. It is concluded that insulin resistance is common to all immunosuppressed organ recipient and is not related to the pancreas graft. The decrease maximal response to insulin and normal insulin binding to erythrocytes tend to suggest a post-receptor defect in insulin action.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythrocytes; Female; Humans; Insulin; Kidney Transplantation; Kinetics; Male; Pancreas Transplantation; Receptor, Insulin; Reference Values

Topics: Adult; Blood Glucose; C-Peptide; Cell Separation; Centrifugation, Density Gradient; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Immunosuppression Therapy; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney Transplantation

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Islets of Langerhans Transplantation; Kidney Transplantation; Models, Theoretical; Portal System; Transplantation, Homologous

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Histocompatibility Testing; Humans; Insulin; Kidney Transplantation; Male; Pancreas Transplantation; Uremia

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Kidney Failure, Chronic; Kidney Transplantation; Octreotide; Pancreas Transplantation

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glucagon; Graft Rejection; Humans; Kidney Transplantation; Male; Pancreas Transplantation

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Glucagon; Glucose Tolerance Test; Glycated Hemoglobin; Graft Survival; Humans; Immunosuppression Therapy; Kidney Transplantation; Pancreas Transplantation; Pancreatic Ducts; Postoperative Complications

The effect of residual C-peptide secretion in longer standing IDDM on glycaemic control and the prevalence and evolution of complications over 2 years was evaluated. Thirty-one subjects with IDDM of 15.4 (1.5) years duration (mean SEM)) and residual C-peptide secretion, were matched for age, duration of diabetes and body mass index with 31 subjects without detectable C-peptide secretion. At trial entry and over 2 years, levels of HbA1, fructosamine and mean blood glucose were essentially similar in both groups. Levels of glycated albumin (GSA) were significantly higher in the C-peptide negative group after 3 and 9 months (P less than 0.05). An increased prevalence of proliferative retinopathy in the C-peptide negative group and of peripheral vascular disease in the C-peptide secretor group was apparent at entry to the study (both P less than 0.05), although no significant differences were observed after 1 or 2 years. There was no difference in the prevalence of peripheral or autonomic neuropathy, hypertension, nephropathy or ischaemic heart disease. Subjects with C-peptide concentrations greater than 0.100 pmol/ml at entry to this study had lower daily insulin requirements after 1 and 2 years, but behaved like the larger group with any detectable C-peptide secretion in all other respects. Residual C-peptide secretion was lost after 1 year in 7 patients, in whom glycaemic control during the year had been particularly poor. Insulin antibody titres were no different in the 2 groups at any time point. This study suggests that residual C-peptide secretion in longer standing IDDM confers the potential for limited improvements in glycaemic control. This effect appears to be insufficient to prevent the evolution of microvascular complications over a 2-year period. Residual C-peptide secretion and relative hyperinsulinaemia may be associated with an excess of peripheral vascular disease.

Topics: Adult; Albuminuria; Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Blood Pressure; C-Peptide; Coronary Disease; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Follow-Up Studies; Fructosamine; Glycated Hemoglobin; Hexosamines; Humans; Hypertension; Middle Aged

To assess the long-term effect of islet transplantation on metabolic abnormalities and chronic complications of diabetic recipients, the long-term follow-up data of 36 type 1 diabetic subjects with functioning islet grafts for more than 1 year were analysed in this article. 36 type 1 diabetics, with mean age of 34.30 +/- 12.05 yr and mean duration of 11.53 +/- 5.29 yr, were followed up for a mean period of 29.39 +/- 9.50 mo after successfully transplanting with short-term cultured islet tissue of human fetal pancreases. The effect of islet transplants was identified as excellent in 13 subjects, good in 12 and fair in 11. The comparative studies were carried out of the mean levels of serum C-peptide, plasma glucose, GHb and GPP, serum lipids, and mean excretion of urine sugar, and the diabetic retinopathy, nephropathy as well as the autonomic neuropathy before transplantation in comparison with those of the present. The results of the study demonstrated that islet transplants could improve the function of islet B cells and the glucose metabolism, and might delay the development of diabetic retinopathy, nephropathy and autonomic neuropathy in successfully transplanted diabetic recipients, but not exert any influences on those of patients in fair group.

Topics: Adolescent; Adult; C-Peptide; Carbohydrate Metabolism; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Follow-Up Studies; Humans; Islets of Langerhans Transplantation; Lipids; Male; Middle Aged

To study the role of hormonal and neural factors in the control of the entero-insular axis the insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) responses to oral and intravenous glucose were investigated in 5 patients who had received a combined kidney and paratopic pancreas transplant, with physiological portal venous drainage. The incremental areas under the insulin and C-peptide responses to oral glucose were significantly greater than the responses to intravenous glucose (insulin: patients 7983 +/- 1937 (+/- SE) vs 3513 +/- 2188 mU l-1 min, p less than 0.002, control subjects 5505 +/- 1035 vs 1066 +/- 484 mU l-1 min, p less than 0.004; C peptide: patients 440 +/- 80 vs 144 +/- 61 nmol l-1 min, p less than 0.01, control subjects 200 +/- 38 vs 63 +/- 16 nmol l-1 min, P less than 0.01). The incretin effects for insulin (patients 4.4 +/- 1.4, control subjects 7.7 +/- 1.8) and C-peptide (patients 4.4 +/- 0.9, control subjects 3.7 +/- 0.9) and the GIP responses to oral and intravenous glucose were not significantly different between transplant patients and control subjects. As the incretin effect was preserved, despite a denervated pancreas, hormonal rather than neural factors may be more important in mediating increased insulin secretion after oral carbohydrate. The normal GIP response is compatible with its proposed role as an insulinotropic hormone.

Topics: Adult; Blood Glucose; C-Peptide; Diabetic Nephropathies; Diabetic Neuropathies; Female; Gastric Inhibitory Polypeptide; Glucose; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney Transplantation; Male; Middle Aged; Nervous System; Pancreas Transplantation; Portal Vein; Reference Values

Topics: Adult; Blood Glucose; C-Peptide; Diabetic Nephropathies; Follow-Up Studies; Graft Survival; Humans; Kidney Transplantation; Middle Aged; Pancreas; Pancreas Transplantation; Pancreatic Ducts

Topics: Antibodies, Monoclonal; Blood Glucose; C-Peptide; Cyclosporins; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glucose Tolerance Test; Humans; Insulin; Kidney Transplantation; Pancreas Transplantation

The aim of the present study was to evaluate the role of residual insulin production in long-term Type 1 (insulin-dependent) diabetes mellitus. Ninety-seven patients with a disease duration of 9-16 years and onset before the age of 30 years were studied. C-peptide excretion in 24-h urine samples was measured as an indicator of residual insulin production. Thirty-five patients (36%) excreted C-peptide (greater than or equal to 0.2 nmol); as many as possible of them were carefully matched with a non-excretor patient with regard to age at onset of diabetes and disease duration. Twenty-nine pairs were obtained, and 22 of them agreed to participate in further investigations of glycaemic control and microangiopathic lesions. The patients who excreted C-peptide had significantly lower HbA1c than the non-excretor group, 6.9 +/- 0.3% vs 7.9 +/- 0.3%, (p less than 0.025). Moderate-to-advanced background retinopathy was found in 2 patients in the excretor group and in 7 patients in the non-excretor group. Microalbuminuria [ratio of albumin: creatinine (mg/l:mmol/l) greater than or equal to 5] was found in 1 and in 5 patients, respectively, while proteinuria [ratio of protein: creatinine (mg/l:mmol/l X 10) greater than or equal to 136] was found in 0 and in 4 patients, respectively. Microalbuminuria and/or proteinuria was found in 7 of the non-excretor group as compared to 1 in the excretor group (p = 0.046).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Albuminuria; beta 2-Microglobulin; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Male; Proteinuria

The content of insulin and C-peptide-like immunoreactivity (CPR) were determined in the tail of pancreas from 35 autopsied diabetic and 21 non-diabetic subjects. In the 28 diabetics who had been followed for more than 6 months, the relation between the amount of insulin or CPR in the pancreas and the stability of fasting serum glucose during diabetic life before death was analyzed together with the relation between the serum CPR response to the breakfast tolerance test before death and insulin content at autopsy. As an index of the instability of the blood sugar level, the standard deviation of the mean of 15 successive determinations of fasting serum glucose was used. Both insulin and CPR content in the pancreas were significantly decreased in diabetics as compared with non-diabetics. SD of the mean fasting serum glucose and insulin or CPR content in the tail of pancreas showed a significant inverse correlation on a logarithmic scale (P less than 0.01, r = -0.704 and P less than 0.01, gamma = -0.757, respectively). Serum CPR value during the breakfast tolerance test correlated significantly with the insulin content in the pancreas of diabetic subjects. These findings suggest that one of the causes of the instability of fasting serum glucose levels is the devastation of pancreatic beta-cells and that the pancreatic insulin content is logarithmically and inversely related to fluctuations in fasting serum glucose.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fasting; Female; Food; Humans; Insulin; Liver Cirrhosis; Male; Middle Aged; Pancreas

To define risk factors and markers associated with proliferative retinopathy (PR), we compared 44 insulin-dependent diabetic patients with PR with 45 matched patients without advanced retinopathy (NR). Glycemic control assessed by HbA1 measurements from 5 yr preceding diagnosis of PR was significantly worse than in NR patients. The NR patients had more frequently been treated with multiple daily insulin injections than the PR patients. About half of the PR patients had Albustix-positive proteinuria, and these patients were further characterized by an abnormal lipid profile in plasma and increased frequency of cardiovascular disease. In contrast, PR patients without proteinuria did not differ from NR patients in these variables. Sensorimotor and autonomic neuropathy were twice as frequent in the PR than in the NR group. There was no correlation between anti-insulin antibody titer, immune complexes, and the presence of PR, but T-lymphocyte response to different stimuli was slightly reduced in the PR patients. The anti-insulin-antibody titer correlated with duration of diabetes in the NR but not the PR group. The frequency of HLA-DRw8 was slightly higher in the PR group than in the NR group (16 vs. 0%, NS), but we could not confirm the previously suggested association between HLA-DR4 and PR. Serum C4 levels were low in the diabetics but did not differ between PR patients without proteinuria and NR patients. In conclusion, poor glycemic control was clearly associated with PR in this study, and attempts to prevent this hazardous complication should include means to improve insulin therapy. We did not find support for the view that susceptibility to PR is associated with any known HLA antigen(s).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; HLA Antigens; Humans; Male; Middle Aged; Risk

In an 11-year study of experimental insulin-deficient diabetes (IDDM) induced in rhesus monkeys by streptozotocin or total pancreatectomy, the authors have found that pathophysiologic changes occur in eye and kidney, which closely resemble the early stages of human insulin deficient diabetes mellitus (IDDM). In addition, morphologic changes of thickening of glomerular capillary basement membrane and expansion of mesangial matrix (by light microscopy) appear within 3 years of onset of hyperglycemia. However, progression to irreversible complications of advanced diabetic nephropathy or proliferative retinopathy, have not occurred. This animal model resembles human disease in that the animals tend to become ketotic unless maintained with exogenous insulin; C-peptide production is low to absent, and large amounts of glycosylated hemoglobin develop within a month of onset. The monkeys differ from humans in the absence of hypertension and hyperlipidemia. The authors suggest that the abnormalities in basement membrane form and function caused by hyperglycemia form the necessary background upon which other factors, such as hypertension and hyperlipidemia, then act to cause irreversible complications. The role of pancreatic transplantation is in prevention of these background changes.

Topics: Animals; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Eye; Glycated Hemoglobin; Hypertrophy; Kidney; Macaca mulatta; Pancreas Transplantation; Proteinuria

Clinical pancreas transplantation at the University of Minnesota began in 1966. An initial series of 14 whole pancreas grafts was reported in part to the American Surgical Association in 1970. Only one patient survived for more than 1 year with a functioning graft. Twenty attempts at islet allotransplantation in the mid-1970s were unsuccessful. In 1978 we resumed performing pancreas transplants by the segmental technique, allowing the use of related donors. The current series (July 25, 1978 to December 20, 1983) includes 86 pancreas transplants (51 cadaver, 35 related) in 75 patients (41 with and 34 without previous kidney grafts). Variations in management of the pancreatic duct include three ligated, 15 duct-open, 39 duct-injected, and 29 pancreaticojejunostomies. The latter technique is currently preferred. Currently (April 1984) 61 patients are alive (81%), 24 have functioning grafts (32%), and 21 are insulin-independent (28%), three with open-duct grafts for 4.4 to 5.7 years, seven with silicone-injected grafts from 10 to 39 months, and 14 with pancreaticojejunostomies for 3 to 31 months; 15 of the grafts have functioned for greater than 1 year. Twenty-two of the grafts (25%) failed for technical reasons (thrombosis, infection, or ascites); 35 grafts functioned for 1 to 13 months before totally failing from either rejection, fibrosis, or recurrent disease; five patients died with functioning grafts. The graft survival rate has been higher for pancreases from related (15/35, 43% functioning) than from cadaver (9/51, 18% functioning) donors. The success rate has increased, e.g., 11/22 recipients of pancreas transplants in 1983 currently have functioning grafts (50%). Metabolic studies show most patients with functioning grafts to be euglycemic; however, three of 24 have chronic hyperglycemia unless supplemented with insulin, but they are no longer ketosis-prone. Glucose tolerance test results are normal or nearly normal in 12 and abnormal in 12 of the recipients with currently functioning grafts. Regression of diabetic nephropathy has been documented in two long-term recipients. Pancreas transplantation is currently applicable as treatment for selected diabetics who have demonstrated their propensity to develop serious secondary complications.

Topics: Adult; C-Peptide; Cadaver; Diabetes Mellitus; Diabetic Nephropathies; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Insulin; Jejunum; Kidney Transplantation; Male; Middle Aged; Organ Preservation; Pancreas; Pancreas Transplantation; Pancreatic Ducts; Postoperative Care; Tissue Donors; Uremia

Topics: C-Peptide; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Hemoglobins; Humans

Recently, the radioimmunological determination of C-peptide came into interest because of the jugdement of the remaining function of the islet apparatus in insulin-dependent diabetics. As the degradation of C-peptide preferably takes place in the kidney we performed an intravenous glucose load in 32 patients with kidney diseases. The following results were obtained: 1. In patients with a healthy carbohydrate metabolism a clear correlation exists between the concentration of creatinine on the one hand, the creatinine-clearance and the fasting C-peptide concentration respectively the measured amount of C-peptide on the other hand. 2. The more advanced the renal insufficiency the better is the correlation between the parameter of the kidney function and the C-peptide concentration. 3. In diabetic patients there shows to be no clear correlation between the C-peptide levels and the kidney function. --In insulin-dependent diabetics the amount of C-peptide is only of diagnostic use if the renal function is well known.

Topics: Adult; Aged; C-Peptide; Creatinine; Diabetic Nephropathies; Female; Glucose Tolerance Test; Humans; Islets of Langerhans; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Peptides