Fasting C-peptide Concentrations Research Articles

Detection of glycemic abnormalities in adolescents with beta thalassemia using continuous glucose monitoring and oral glucose tolerance in adolescents and young adults with β-thalassemia major: Pilot study

Background:Both insulin deficiency and resistance are reported in patients with β-thalassemia major (BTM). The use of continuous blood glucose monitoring (CGM), among the different methods for early detection of glycemic abnormalities, has not been studied thoroughly in these adolescents.Materials and Methods:To assess the oralglucose tolerance (OGT) and 72-h continuous glucose concentration by the continuous glucose monitoring system (CGMS) and calculate homeostatic model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI) was conducted in 16 adolescents with BTM who were receiving regular blood transfusions every 2-4 weeks and iron-chelation therapy since early childhood.Results:Sixteen adolescents with BTM (age: 19.75 ± 3 years) were investigated. Using OGTT, (25%) had impaired fasting blood (plasma) glucose concentration (BG) (>5.6 mmol/L). 2-h after the glucose load, one of them had BG = 16.2 mmol/L (diabetic) and two had impaired glucose tolerance (IGT) (BG > 7.8 and <11.1 mmol/L). Monitoring the maximum (postprandial) BG using CGMS,4 adolescents were diagnosed with diabetes (25%) (BG >11.1 mmol/L) and 9 with IGT (56%). HOMA and QUICKI revealed levels <2.6 (1.6 ± 0.8) and >0.33 (0.36 ± 0.03), respectively, ruling out significant insulin resistance in these adolescents. There was a significant negative correlation between the β-cell function (B%) on one hand and the fasting and the 2-h BG (r=−0.6, and − 0.48, P < 0.01, respectively) on the other hand. Neither fasting serum insulin nor c-peptide concentrations were correlated with fasting BG or ferritin levels. The average and maximum blood glucose levels during CGM were significantly correlated with the fasting BG (r = 0.68 and 0.39, respectively, with P < 0.01) and with the BG at 2-hour after oral glucose intake (r = 0.87 and 0.86 respectively, with P < 0.001). Ferritin concentrations were correlated with the fasting BG and the 2-h blood glucose levels in the OGTT (r = 0.52, and r = 0.43, respectively, P < 0.01) as well as with the average BG recorded by CGM (r = 0.75, P < 0.01).Conclusion:CGM has proven to be superior to OGTT for the diagnosis of glycemic abnormalities in adolescents with BTM. Defective β-cell function rather than insulin resistance appeared to be the cause for these abnormalities.

Predicting the Glycemic Response to Gastric Bypass Surgery in Patients With Type 2 Diabetes

OBJECTIVETo find clinically meaningful preoperative predictors of diabetes remission and conversely inadequate glycemic control after gastric bypass surgery. Predicting the improvement in glycemic control in those with type 2 diabetes after bariatric surgery may help in patient selection.RESEARCH DESIGN AND METHODSPreoperative details of 154 ethnic Chinese subjects with type 2 diabetes were examined for their influence on glycemic outcomes at 1 year after gastric bypass. Remission was defined as HbA1c ≤6%. Analysis involved binary logistic regression to identify predictors and provide regression equations and receiver operating characteristic curves to determine clinically useful cutoff values.RESULTSRemission was achieved in 107 subjects (69.5%) at 12 months. Diabetes duration <4 years, body mass >35 kg/m2, and fasting C-peptide concentration >2.9 ng/mL provided three independent preoperative predictors and three clinically useful cutoffs. The regression equation classification plot derived from continuous data correctly assigned 84% of participants. A combination of two or three of these predictors allows a sensitivity of 82% and specificity of 87% for remission. Duration of diabetes (with different cutoff points) and C-peptide also predicted those cases in which HbA1c ≤7% was not attained. Percentage weight loss after surgery was also predictive of remission and of less satisfactory outcomes.CONCLUSIONSThe glycemic response to gastric bypass is related to BMI, duration of diabetes, fasting C-peptide (influenced by insulin resistance and residual β-cell function), and weight loss. These data support and refine previous findings in non-Asian populations. Specific ethnic and procedural regression equations and cutoff points may vary.

Predicting the glycemic response to gastric bypass surgery in patients with type 2 diabetes

OBJECTIVE To find clinically meaningful preoperative predictors of diabetes remission and conversely inadequate glycemic control after gastric bypass surgery. Predicting the improvement in glycemic control in those with type 2 diabetes after bariatric surgery may help in patient selection. RESEARCH DESIGN AND METHODS Preoperative details of 154 ethnic Chinese subjects with type 2 diabetes were examined for their influence on glycemic outcomes at 1 year after gastric bypass. Remission was defined as HbA 1c ≤6%. Analysis involved binary logistic regression to identify predictors and provide regression equations and receiver operating characteristic curves to determine clinically useful cutoff values. RESULTS Remission was achieved in 107 subjects (69.5%) at 12 months. Diabetes duration 35 kg/m 2 , and fasting C-peptide concentration >2.9 ng/mL provided three independent preoperative predictors and three clinically useful cutoffs. The regression equation classification plot derived from continuous data correctly assigned 84% of participants. A combination of two or three of these predictors allows a sensitivity of 82% and specificity of 87% for remission. Duration of diabetes (with different cutoff points) and C-peptide also predicted those cases in which HbA 1c ≤7% was not attained. Percentage weight loss after surgery was also predictive of remission and of less satisfactory outcomes. CONCLUSIONS The glycemic response to gastric bypass is related to BMI, duration of diabetes, fasting C-peptide (influenced by insulin resistance and residual β-cell function), and weight loss. These data support and refine previous findings in non-Asian populations. Specific ethnic and procedural regression equations and cutoff points may vary.

Clinical analysis of fulminant type 1 diabetes in China and comparison with a nationwide survey in Japan

ObjectivesTo report 26 cases of fulminant type 1 diabetes found in Guangdong Medical College Futian Hospital and Central South University Second Xiangya Hospital in China and to study the difference between Chinese and Japanese patients. MethodsThe clinical and biochemical characteristics of 26 patients who had been diagnosed with fulminant type 1 diabetes mellitus in China were analyzed retrospectively and then compared with those characteristics of 161 patients from a nationwide survey in Japan at the time of diagnosis and follow-up 6 months. ResultsThe mean values of the characteristics from these two data sets, including fasting and postprandial serum C-peptide concentration, serum sodium and potassium level, positive for GADAb were significantly different (P=0.003, P=0.005, P=0.035, P=0.030, P<0.001, respectively). ConclusionsThe clinical and biochemical characteristics of Chinese patients did not largely differ from those of Japanese patients. Further studies are needed for some unique characteristics found in our group.

A dietary pattern that is associated with C-peptide and risk of colorectal cancer in women

Higher serum C-peptide concentrations have shown to be associated with an increased risk of colorectal cancer (CRC). Therefore, we used diet information to identify food groups that correlated with fasting serum concentrations of C-peptide and assess the association of this dietary pattern and CRC risk. Major food contributors to fasting C-peptide concentrations were identified with stepwise linear regression in a subsample (n=833) of women from a large cohort. We then summed the consumption frequency of the major food contributors to form a C-peptide dietary pattern for the entire cohort (n=66,714). Risk for CRC was computed using Cox proportional hazard model with the C-peptide dietary pattern score as the predictor. In up to 20years of follow-up, we ascertained 985 cases of CRC and 758 colon cancer. After adjusting for confounders, the C-peptide dietary pattern, characterized by higher meat, fish, and sweetened beverage intake, but lower coffee, high fat dairy, and whole grains intake, showed direct association with CRC risk (RR comparing extreme quintiles=1.29, 95% CI=1.05-1.58, p trend=0.048). The same comparison was slightly stronger for colon cancer (RR=1.35, 95% CI=1.07-1.70, p trend=0.009). In stratified analysis, there was no association between the C-peptide dietary pattern and colon cancer among lean and active women. However, for overweight or sedentary women, RR for the same comparison was 1.58 (95% CI=1.20-2.07, p trend=0.002) (p for interaction=0.007). We derived a dietary pattern that correlated with C-peptide concentrations. This pattern was associated with an increase in colon cancer, especially among women who were overweight or sedentary.

Detection of Glycemic Abnormalities in Young Adult Patients with Beta Thalassemia Major Using Continuous Glucose Monitoring System (CGMS) and Oral Glucose Tolerance Test (OGTT)

Abstract▪2158▪This icon denotes a clinically relevant abstract Introduction:Both insulin deficiency and insulin resistance are reported in patients with β thalassemia major (BTM). The use of continuous blood glucose monitoring system (CGMS) among the different methods for early detection of glycaemic abnormalities has not been studied thoroughly in these patients. Aims:The aims of this study were: 1. to detect glycaemic abnormalities, if any, in young adults with BTM using fasting blood glucose (FBG), oral glucose tolerance test (OGTT), 72-h continuous glucose concentration by CGMS system, and serum insulin and C-peptide concentrations 2. To compare the results of these two methods in detecting glycaemic abnormalities in these patients and 3. To calculate homeostatic model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI) in these patients. In order to evaluate whether glycaemic abnormalities are due to insulin deficiency and/or resistance. Materials and methods:Randomly selected young adults (n = 14) with BTM were the subjects of this study. All patients were investigated using a standard oral glucose tolerance test (OGTT) (using 75 gram of glucose) and 72-h continuous glucose concentration by CGM system (Medtronic system). Fasting serum insulin and C-peptide concentrations were measured and HOMA-B, HOMA-IR were calculated accordingly. Results:Using OGTT, 5 patients had impaired fasting glucose (IFG) (Fasting BG from 5.6 to 6.9 mmol/L). Two of them had impaired glucose tolerance IGT (BG from 7.8 and < 11.1 mmol/L) and one had BG = 16.2 mmol/L after 2-hrs (diabetic). Using CGMS in addition to the glucose data measured by glucometer (3–5 times/ day), 6 patients had IFG. The maximum (postprandial) BG recorded exceeded 11.1 mmol/L in 4 patients (28.5%) (Diabetics) and was > 7.8 but < 11.1 mmol/L in 8 patients (57%) (IGT).The mean values of HOMA and QUICKI in patients with BTM were < 2.6 (1.6± 0.8) and > 0.33 (0.36±0.03) respectively ruling out significant insulin resistance in these adolescents. There was a significant negative correlation between the β-cell function (B %) on the one hand and the fasting and the 2-h BG (r= −0.6, and − 0.48, P< 0.01 respectively) on the other hand. Serum insulin concentrations were not correlated with fasting BG or ferritin levels. The average and maximum BG levels recorded by CGMS were significantly correlated with the fasting BG (r= 0.69 and 0.6 respectively with P < 0.01) and with the BG at 2-hour after oral glucose intake (r= 0.87and 0.86 respectively with P < 0.01). Ferritin concentrations were positively correlated with the fasting BG and the 2-h BG levels in the OGTT (r= 0.69, 0.43 respectively, P < 0.001) as well as with the average and the maximum BG recorded by CGM (r =0.75, and 0.64 respectively with P < 0.01). Ferritin concentrations were negatively correlated with the β-cell function (r= −0.41, P< 0.01). Conclusion:CGMS has proved to be superior to OGTT for the diagnosis of glycaemic abnormalities in young adult patients with BTM. In our patients, defective β-cell function rather than insulin resistance appeared to be the cause for these abnormalities. The significant correlations between serum ferritin concentrations and the beta cell functions suggested the importance of adequate chelation to prevent β-cell dysfunction Disclosures:No relevant conflicts of interest to declare.

The effect of vitamin D supplementation on peripheral regulatory T cells and β cell function in healthy humans: a randomized controlled trial

Increasing evidence supports the role of vitamin D (vitD) in modifying the risk to develop type 1 diabetes (T1D) and other autoimmune diseases. VitD3 might stimulate regulatory T cells (Tregs), a central player in the maintenance of self-tolerance. In addition, direct effects of vitD on β-cell function are postulated. The aim of our study was to evaluate the effect of a high dose vitD supplementation on Tregs frequency (%Tregs) and β-cell function assessed by a mixed meal tolerance test (MMTT) in healthy humans. A double-blind, placebo controlled trial was performed in 59 healthy adult subjects (49% females). Subjects received oral vitD3 (140,000 IU monthly) or placebo for 3 months. %Tregs within 20,000 CD4+ T cells of peripheral blood was determined by multi-parametric FACS-analysis. A liquid MMTT was carried out before and after treatment. %Tregs increased significantly in the vitD group, but remained unchanged in the placebo group. Fasting C-peptide concentrations did not change significantly in either group. Similarly, the mean AUC for C-peptide after 3 months and the change in mean values from baseline to the end of the treatment were comparable in both groups. A short time high dose vitD3 supplementation significantly increased the frequency of Tregs, but did not further improve β-cell function in apparently healthy subjects. The immunomodulatory potential of vitD might be an important mechanistic link for the association of vitD and T1D.

Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss–induced decrease in liver fat in humans

The rs738409 C→G single nucleotide polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin) leads to a missense mutation (I148M), which is associated with increased liver fat but not insulin resistance. The I148M mutation impedes triglyceride hydrolysis in vitro, and its carriers have an increased risk of developing severe liver disease. We explored whether the rs738409 PNPLA3 G allele influences the ability of weight loss to decrease liver fat or change insulin sensitivity. We recruited 8 subjects who were homozygous for the rs738409 PNPLA3 G allele (PNPLA3-148MM) and 10 who were homozygous for the rs738409 PNPLA3 C allele (PNPLA3-148II). To allow comparison of changes in liver fat, the groups were matched with respect to baseline age, sex, body mass index, and liver fat. The subjects were placed on a hypocaloric low-carbohydrate diet for 6 d. Liver fat content (proton magnetic resonance spectroscopy), whole-body insulin sensitivity of glucose metabolism (euglycemic clamp technique), and lipolysis ([(2)H(5)]glycerol infusion) were measured before and after the diet. At baseline, fasting serum insulin and C-peptide concentrations were significantly lower in the PNPLA3-148MM group than in the PNPLA3-148II group, as predicted by study design. Weight loss was not significantly different between groups (PNPLA3-148MM: -3.1 ± 0.5 kg; PNPLA3-148II: -3.1 ± 0.4 kg). Liver fat decreased by 45% in the PNPLA3-148MM group (P < 0.001) and by 18% in the PNPLA3-148II group (P < 0.01). Weight loss is effective in decreasing liver fat in subjects who are homozygous for the rs738409 PNPLA3 G or C allele. This trial was registered at www.hus.fi as 233775.

Clinical characteristics of fulminant type 1 diabetes associated with pregnancy in China

To report 12 cases of pregnancy-associated fulminant type 1 diabetes mellitus (PF) found in China from 2003 to 2010. The clinical and biochemical characteristics of these cases with PF were compared with a group of cases of child-bearing age with fulminant type 1 diabetes that was not associated with pregnancy (NPF). The clinical and biochemical characteristics of 12 PF cases were analyzed retrospectively and then compared with those characteristics of 20 NPF cases in China. The difference between Chinese and Japanese PF cases was investigated. The mean values of the characteristics from PF and NPF cases in China, including postprandial serum C-peptide concentration, plasma glucose concentration, and serum chloride were different. Compared to the 22 PF cases in Japan, the mean age of these 12 PF cases was much younger. The mean fasting and postprandial serum C-peptide concentration level were lower, and the mean HbA1c levels was higher in 12 PF cases in China. Eight of 12 PF cases in China developed the disease during pregnancy. Other four PF case developed the disease within 2weeks after delivery. 12 PF cases in China showed more severe beta-cell destruction, the prognosis of their fetuses was extremely poor.

Comparison of MRI-assessed body fat content between lean women with polycystic ovary syndrome (PCOS) and matched controls: less visceral fat with PCOS

BACKGROUND Polycystic ovary syndrome (PCOS) is a heterogeneous disorder. However, PCOS has a strong resemblance to the metabolic syndrome, including preponderance of visceral fat deposition. The aim of this study is to compare fat distribution between lean women with PCOS and controls matched for body composition but with regular menstrual cycles and proven fertility. METHODS In this prospective cross-sectional study in a fertility outpatient clinic, 10 Caucasian women with PCOS and 10 controls, all with a BMI between 19 and 25 kg/m(2), were included. Fasting glucose, insulin and C-peptide concentrations, homeostasis model assessment (HOMA), hormonal levels and bioelectrical impedance analysis (BIA) variables were assessed and fat content and ovarian volume determinations were obtained with magnetic resonance imaging (MRI). Multiple axial cross-sections were calculated. RESULTS The age of the PCOS and control groups were [mean (SD)] 28.2 years (2.6) versus 33.7 years (2.3) P < 0.0001, respectively, and both groups were matched for BMI: 21.6 kg/m(2) (1.1) versus 21.8 kg/m(2) (2.1) (ns), fasting glucose, insulin, C-peptide, HOMA-insulin resistance (IR) levels and BIA parameters. PCOS cases had higher ovarian volumes and less visceral fat compared with controls. CONCLUSIONS Lean women with PCOS have higher MRI-determined ovarian volumes and less visceral fat content when compared with control women.

Magnesium supplementation, metabolic and inflammatory markers, and global genomic and proteomic profiling: a randomized, double-blind, controlled, crossover trial in overweight individuals

Dietary magnesium intake has been favorably associated with reduced risk of metabolic outcomes in observational studies; however, few randomized trials have introduced a systems-biology approach to explore molecular mechanisms of pleiotropic metabolic actions of magnesium supplementation. We examined the effects of oral magnesium supplementation on metabolic biomarkers and global genomic and proteomic profiling in overweight individuals. We undertook this randomized, crossover, pilot trial in 14 healthy, overweight volunteers [body mass index (in kg/m(2)) ≥25] who were randomly assigned to receive magnesium citrate (500 mg elemental Mg/d) or a placebo for 4 wk with a 1-mo washout period. Fasting blood and urine specimens were collected according to standardized protocols. Biochemical assays were conducted on blood specimens. RNA was extracted and subsequently hybridized with the Human Gene ST 1.0 array (Affymetrix, Santa Clara, CA). Urine proteomic profiling was analyzed with the CM10 ProteinChip array (Bio-Rad Laboratories, Hercules, CA). We observed that magnesium treatment significantly decreased fasting C-peptide concentrations (change: -0.4 ng/mL after magnesium treatment compared with +0.05 ng/mL after placebo treatment; P = 0.004) and appeared to decrease fasting insulin concentrations (change: -2.2 μU/mL after magnesium treatment compared with 0.0 μU/mL after placebo treatment; P = 0.25). No consistent patterns were observed across inflammatory biomarkers. Gene expression profiling revealed up-regulation of 24 genes and down-regulation of 36 genes including genes related to metabolic and inflammatory pathways such as C1q and tumor necrosis factor-related protein 9 (C1QTNF9) and pro-platelet basic protein (PPBP). Urine proteomic profiling showed significant differences in the expression amounts of several peptides and proteins after treatment. Magnesium supplementation for 4 wk in overweight individuals led to distinct changes in gene expression and proteomic profiling consistent with favorable effects on several metabolic pathways. This trial was registered at clinicaltrials.gov as NCT00737815.

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD(65) (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4years of follow-up. Seventy children and adolescents aged 10-18years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20μg of GAD-alum or placebo at baseline and 1month later. The study was blinded to participants and investigators until month30. The study was unblinded at 15months to the sponsor and statistician in order to evaluate the data. At follow-up after 30months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with <6months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15months after the prime injection for all participants per protocol set. In the GAD-alum group fasting C-peptide was 0.332 ± 0.032nmol/l at day1 and 0.215 ± 0.031nmol/l at month15. The corresponding figures for the placebo group were 0.354 ± 0.039 and 0.184 ± 0.033nmol/l, respectively. The decline in fasting C-peptide levels between day1 and month1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GAD-alum group than in the placebo-treated group after 4years. Four years after treatment with GAD-alum, children and adolescents with recent-onset type 1 diabetes continue to show no adverse events and possibly to show clinically relevant preservation of C-peptide. ClinicalTrials.gov NCT00435981 The study was funded by The Swedish Research Council K2008-55X-20652-01-3, Barndiabetesfonden (The Swedish Child Diabetes Foundation), the Research Council of Southeast Sweden, and an unrestricted grant from Diamyd Medical AB.

1082 Continuous Glucose Monitoring in Morbidly Obese Children with Normal Fasting Bg and Normal Ogtt

This study has been undertaken to assess the glucose metabolism disorder by CGMS in morbidly obese children (BMI > 28) who have normal fasting glucose level and normal oral glucose tolerance. Methods: Ten morbidly obese children were studied. Interstitial fluid (ISF) glucose levels were measured by CGMS for 72 hours as well as by self-monitored blood glucose (SMBG) (3-4 times per day). The circulating fasting glucose, insulin, c-peptide, free T4, TSH, and HbA1C concentrations were measured. Results: The glucose levels in ISF measured by CGMS were highly correlated with those in capillary samples (r=0.742, P 7.6 mmol/L 2 h after food intake) and one had a diabetic curve (T2DM) (BG > 11.2 mmol/L 2 h after food intake). None of the children had elevated HbA1C level. Hyperinsulinemia and/or high C-peptide was recorded in 9 out of the 10 children. Conclusions: Our data suggest that glucose metabolism disorder including impaired postprandial glycemia and type 2 DM can be early diagnosed in morbidly obese children using CGMS when fasting BG and HbA1C levels are still normal. Further studies are required to improve the criteria of early diagnosis of glycemic abnormalities using CGMS.

Management of cystic fibrosis-related diabetes in children and adolescents

TheDepartment of Pediatrics, University of Minnesota Children’sHospital, Minneapolis, USACorresponding author:Dr. Stephen MP O’Riordan MRCPI, MDThe Developmental Endocrinology and Research GroupThe Department of Clinical and Molecular GeneticsThe Institute of Child Health, University College London30 Guliford StreetLondon WC1N 1EH.Tel: +44-020-7242-9789, ext. 0732;fax: +44-020-7404-6191;e-mail: s.oriordan@ich.ucl.ac.ukAcknowledgments:PeterHindmarsh,MehulDattani,HilaryHoeyand Nicola Bridges.Conflicts of interest: The authors have declared no conflictsof interest.Editors of the ISPAD Clinical Practice Consensus Guide-lines 2009 Compendium: Ragnar Hanas, Kim Donaghue,Georgeanna Klingensmith, and Peter Swift.This article is a chapter in the

No Effect of the Altered Peptide Ligand NBI-6024 on β-Cell Residual Function and Insulin Needs in New-Onset Type 1 Diabetes

OBJECTIVEThis randomized, four-arm, placebo-controlled, dose-ranging phase 2 trial was conducted to determine whether repeated subcutaneous injections of the altered peptide ligand, NBI-6024, designed to inhibit autoreactive T-cells, improves β-cell function in patients with recently diagnosed type 1 diabetes.RESEARCH DESIGN AND METHODSA total of 188 patients, aged 10–35 years, with recently diagnosed type 1 diabetes were randomly assigned for a treatment consisting of the subcutaneous administration of placebo or 1, 0.5, or 0.1 mg NBI-6024 at baseline, weeks 2 and 4, and then monthly until month 24. Fasting, peak, and area under the curve (AUC) C-peptide concentrations during a 2-h mixed-meal tolerance test were measured at 3-month intervals during treatment. Immune function parameters (islet antibodies and CD4 and CD8 T-cells) were also studied.RESULTSThe mean peak C-peptide concentration at 24 months after study entry showed no significant difference between the groups treated with 0.1 mg (0.59 pmol/ml), 0.5 mg (0.57 pmol/ml), and 1.0 mg NBI-6024 (0.48 pmol/ml) and the placebo group (0.54 pmol/ml). Fasting, stimulated peak, and AUC C-peptide concentrations declined linearly in all groups by ∼60% over the 24-month treatment period. The average daily insulin needs at month 24 were also comparable between the four groups. No treatment-related changes in islet antibodies and T cell numbers were observed.CONCLUSIONSTreatment with altered peptide ligand NBI-6024 at repeated doses of 0.1, 0.5, or 1.0 mg did not improve or maintain β-cell function.

Age-dependent relationship of fasting C-peptide concentration and insulin secretion in non-obese subjects with normal glucose tolerance.

The age-dependent relationship of fasting immunomeasurable C-peptide to fasting immunomeasurable insulin (IRI) and IRI response to glucose was studied in 113 non-obese healthy subjects with normal glucose tolerance (oGTT according to the new WHO recommendations), ranging in age from 6 to 44 years. Fasting C-peptide concentration increased significantly in adolescents and adults when compared with children. The higher fasting C-peptide concentration in the adult group might be explained by the concomitant higher fasting blood glucose concentration whereas such relationship was lacking in adolescents. In contrast to this we failed to demonstrate such relationship with regard to fasting IRI levels. There was, however, a relationship between advancing age and early (IRI area 0-30 min), late (IRI area 30-120 min) and total (IRI area 0-120 min) insulin response to glucose. There was a significant correlation between fasting C-peptide concentration and estimates of IRI response in children and adolescents, whereas such relationship was lacking in adults. Based on these results, the present study demonstrates an age-related increase of the pancreatic beta-cell function which might be partly explained by the concomitant higher blood glucose concentration.

Complement-mediated cytotoxic effects of islet cell surface antibodies in non-diabetic subjects with antecedent mumps infection and diabetic risk.

We studied sera of 24 selected non-diabetic subjects in whom an antecedent mumps infection with either complications and/or with onset at older age occurred 10-27 month ago regarding the capability to lyse rat islets of Langerhans in vitro. Thirteen subjects were characterized by diabetes associated HLA antigens DR3 and/or DR4 whereas 11 of them had none of these HLA antigens. Islet cell surface antibodies (ICSA) could be detected in 11 out of 24 subjects. Isolated pancreatic islets from 8-10 days old Wistar rats were incubated in freshly prepared human serum. The insulin leakage under the conditions of pharmacologic blockade of insulin secretion by means of epinephrine and propranolol provides a measure of complement-mediated cytotoxicity of human serum against rats islets in vitro. Out of a total of 24 subjects the sera of 11 of them exhibited cytotoxicity. Mean cytolytic insulin leakage was significantly higher in subjects with DR3 and/or DR4 in comparison with subjects without these HLA antigens (6.82 +/- 0.77% vs 3.90 +/- 0.48%; p less than 0.05). Ten out of the 11 subjects with cytotoxic sera had HLA DR3 and/or DR4 whereas DR3 was present in three out of 13 subjects with non-cytotoxic sera. There was no relationship between beta cell function in vivo (fasting C-peptide concentration and insulin response to oral glucose challenge) and the capability of patients sera to damage islet cells in vitro. In conclusion the pathogenetic role of mumps virus and cytotoxic ICSA and their possible relation to slow progressive beta-cell destruction has still to be ascertained.

Rapamycin does not adversely affect intrahepatic islet engraftment in mice and improves early islet engraftment in humans

Objective: In this study we examined the effect of rapamycin (RAPA), a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function in vivo. Methods and results: Diabetic C57BL/6 or BALB/C recipient mice were transplanted with 350 syngeneic islets through the portal vein (PV-Tx; C57BL/6 n = 60; BALB/C n = 22) and treated with once-daily oral RAPA (1 mg/kg) or vehicle. No differences in post-transplant blood glucose concentrations and glucose tolerance were observed between RAPA- and vehicle-treated mice. The impact of RAPA on human islet engraftment was assessed in 10 patients with type 1 diabetes treated with 0.1 mg/kg/day rapamycin before islet transplantation. Compared to non pre-treated islet transplant recipents (n = 12), RAPA pre-treated patients had increased blood RAPA concentrations (p = 0.006) and fasting C-peptide concentrations (p = 0.005) in the two weeks post-transplant. RAPA pre-treatment was associated with a reduction in chemokines CCL2 and CCL3 concentrations pre-transplant (p < 0.01), and a dampened chemokine response (p = 0.005) post-transplant. Concordantly, in vitro RAPA inhibited the secretion of CCL2 and CCL3 by monocytes. Conclusion: Rapamycin does not adversely affect intrahepatic islet engraftment in the mouse, and potentially improves islet engraftment in humans by an anti-inflammatory mechanism.

Insulin resistance in non-diabetic obese patients

Obesity and hyperinsulinemia connected with insulin resistance are the most important factors to manage a diabetic patient. We aimed to investigate the differences in demographic characteristics, insulin, C-peptide, HOMA-IR and CRP levels and lipid abnormalities between diabetic and non-diabetic obese patients. This study was carried out in the outpatient clinic of Internal Medicine. Diabetics (n = 19) and non-diabetics (n = 81), 10 men and 90 women, participated in the study. Age, duration of obesity and body mass index (BMI) and other anthropomorphic data were collected. Venous blood samples were taken, after 12 h of fasting to determine fasting blood glucose (FBG), insulin, C-peptide, total cholesterol (TC), HDL cholesterol (HDL-C), triglyceride (TG) and C-reactive protein (CRP) concentrations. LDL cholesterol (LDL-C) was estimated by using Friedewald formula. Homeostasis model of insulin resistance (HOMA-IR) was calculated as [fasting insulin (μU/mL) × fasting glucose (mmol/L)/22.5]. Diabetics had longer duration of obesity (p < 0.05) and higher BMI (p < 0.001), waist circumference (p < 0.05) and hip circumference values (p < 0.05). CRP, TG levels and HOMA-IR were significantly higher in diabetics (p < 0.05, p < 0.01, p < 0.05, respectively) whereas LDL-C and HDL-C levels were lower (p > 0.05) and insulin and C-peptide levels were higher in diabetics without statistical significance (p > 0.05) as shown in the table below. Two group comparisons were performed with Mann–Whitney U test, using SPSS for windows 12.0. Although insulin and C-peptide levels were higher in diabetics without being statistically meaningful, HOMA-IR, as a golden test, was significantly high in diabetics. Obesity is the principal disorder in pathophysiology of diabetes and must be treated rigorously. But it should always be kept in mind that treatment of obesity is frustrating and frequently discouraging. Obese people should be followed up with HOMA-IR.

Staged diabetes management according to individual patient insulin resistance and β‐cell function ameliorates glycaemic control in type 2 diabetes mellitus

The current consensus algorithm for management of type 2 diabetes is based on the fasting glucose concentration and glycated haemoglobin A(1c) (HbA(1c)) level. We applied a new therapeutic strategy by assessing insulin secretion and insulin resistance, in addition to glucose concentrations in individual patients. We enrolled 193 patients with type 2 diabetes. The patients were assigned to one of six groups according to insulin secretion measured by the serum fasting C-peptide concentration and insulin resistance measured by an insulin tolerance test (ITT). The two groups were treated differently: 108 patients were treated using a new staged diabetes management (SDM) strategy and 85 patients continued with conventional therapy. We compared metabolic variables in the two groups at baseline and 12 months after enrollment. In patients treated with the SDM strategy, fasting glucose concentration decreased from 9.8 +/- 2.1 to 8.2 +/- 1.7 mmol/l (P < 0.001). Postprandial 2-h glucose concentration decreased from 14.19 +/- 3.34 to 12.27 +/- 3.24 mmol/l (P < 0.001). HbA(1c) level decreased from 8.37 +/- 1.42% to 7.72 +/- 1.39% (P < 0.001). About 43% of the new SDM group achieved an HbA(1c) of < 7.0% compared with 25% of patients in the conventional treatment group. The new SDM strategy, based on individual data on insulin resistance and insulin secretion, may provide valuable clinical benefits in non-obese Korean patients with type 2 diabetes.