Fasting C-peptide Concentrations Research Articles

Prolonged Remission Induced by FENofibrate in children with newly diagnosed type 1 diabetes (PRIFEN): protocol of a randomised controlled trial

IntroductionSphingolipids regulate proinsulin folding, insulin secretion and control beta cells apoptosis. Recent evidence has demonstrated that, among other factors, reduced amounts of sulfatide may be relevant in the development of...

HIV infection in adult Ugandans with new-onset type 2 diabetes: exploring its influence on the anthropometric and metabolic profile

ObjectiveHIV infection increases the risk of type 2 diabetes and may influence its phenotypic profile. In this study, we aimed to compare the anthropometric and metabolic characteristics of HIV-infected and uninfected adult Ugandans with new-onset type 2 diabetes to evaluate the influence of HIV infection on specific surrogate markers of adiposity, insulin resistance, and pancreatic beta-cell function.MethodsWe consecutively recruited 500 HIV-infected and uninfected adult Ugandans with new-onset type 2 diabetes (diagnosed in < 3 months) from seven tertiary hospitals over a 20-month period and compared their anthropometric and metabolic characteristics to identify any significant differences.ResultsOf the 500 participants with new-onset type 2 diabetes, 59 (11.8%) had a self-reported history of HIV infection. Compared with HIV-uninfected participants with type 2 diabetes, participants with HIV infection and type 2 diabetes had a lower median (IQR) hip circumference (97.8 [91.0-106.0] cm vs. 104.0 [96.0-112.0], p = 0.002) and visceral fat level (8 [6–11] vs. 10 [7–12], p < 0.001) assessed using bioimpedance analysis. No statistically significant difference was noted with the markers of pancreatic beta-cell function (fasting, 30-minute, and 120-minute C-peptide concentrations, oral insulinogenic index, and homeostatic model assessment 2-beta cell function) and insulin resistance (homeostatic model assessment 2-insulin resistance) between both groups.ConclusionIn our study population, HIV infection was not associated with increased adiposity, pancreatic beta-cell function, and insulin resistance. Large prospective studies are needed to investigate the effect of HIV on the pathogenesis of type 2 diabetes in adult Ugandans.

1646-P: The Effect of Glucagon-Like Peptide-1 Receptor Blockade and Acute Insulin Resistance on Islet Function and Glucose Metabolism in People without Diabetes

Intra-islet Glucagon-Like Peptide-1 (GLP-1) is increased by islet inflammation and diabetes. GLP-1 Receptor (GLP1R) blockade with exendin-9,39 impairs fasting islet function in people with and without type 2 diabetes (DM2). In addition, it decreases insulin secretion and glucagon suppression in response to hyperglycemia in people with DM2. We sought to examine if free fatty acid (FFA) elevation to induce acute insulin resistance in people without DM2 replicated the effects of GLP1R blockade seen in DM2. We studied 6 nondiabetic individuals (54 ± 4 years, 33 ± 1 kg/m2) on 4 occasions in random order. Glucose metabolism was measured after an overnight fast and during a hyperglycemic clamp (~9 mmol/l) using [3-3H] glucose. On two occasions Intralipid® and heparin were infused to raise FFA. Exendin-9,39 (300pmol/kg/min) was infused to block GLP1R in the presence or absence of FFA elevation, while on the other days saline was infused. In the absence of FFA elevation, exendin-9,39 infusion increased fasting glucose concentrations (5.0 ± 0.1 vs. 5.4 ± 0.1 mmol/l, saline vs. exendin-9,39 respectively, p = 0.01). This pattern was also observed when FFA were elevated (5.3 ± 0.1 vs. 5.7 ± 0.2 mmol/l, p = 0.02). Fasting insulin, C-peptide (without FFA: 0.9 ± 0.1 vs. 0.8 ± 0.1 nmol/l, p = 0.17; with FFA: 1.1 ± 0.1 vs. 1.0 ± 0.1 nmol/l, p = 0.08) and glucagon concentrations were unchanged, but inappropriate for the higher fasting glucose observed during exendin-9,39 infusion. Exendin-9,39 infusion did not alter islet hormone secretion during the clamp in the presence or absence of FFA elevation. The magnitude of changes induced by exendin-9,39 did not differ in the presence or absence of FFA elevation (p &amp;gt; 0.10). These experiments confirm the effects of GLP1R blockade on fasting α- and β-cell function in people without DM2. However, FFA elevation does not replicate the abnormalities of islet function observed in people with DM2 when exendin-9,39 is infused. Disclosure M. Zeini: None. R.A. Farahani: None. A.A. Welch: None. M.C. Laurenti: None. C. Cobelli: None. C. Dalla Man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company. A.M. Egan: None. A. Vella: Other Relationship; Novo Nordisk. Advisory Panel; Rezolute, Inc. Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S. Funding National Institutes of Health (DK126206)

Association between primary graft function and 5-year outcomes of islet allogeneic transplantation in type 1 diabetes: a retrospective, multicentre, observational cohort study in 1210 patients from the Collaborative Islet Transplant Registry

Allogeneic islet transplantation is a validated therapy in type 1 diabetes; however, there is decline of transplanted islet graft function over time and the mechanisms underlying this decline are unclear. We evaluated the distinct association between primary graft function (PGF) and 5-year islet transplantation outcomes. In this retrospective, multicentre, observational cohort study, we enrolled all patients from the Collaborative Islet Transplant Registry who received islet transplantation alone (ITA recipients) or islet-after-kidney transplantation (IAK recipients) between Jan 19, 1999, and July 17, 2020, with a calculable PGF (exposure of interest), measured 28 days after last islet infusion with a validated composite index of islet graft function (BETA-2 score). The primary outcome was cumulative incidence of unsuccessful islet transplantation, defined as an HbA1c of 7·0% (53 mmol/mol) or higher, or severe hypoglycaemia (ie, requiring third-party intervention to correct), or a fasting C-peptide concentration of less than 0·2 ng/mL. Secondary outcomes were graft exhaustion (fasting C-peptide <0·3 ng/mL); inadequate glucose control (HbA1c ≥7·0% [53 mmol/mol] or severe hypoglycaemia); and requirement for exogenous insulin therapy (≥14 consecutive days). Associations between PGF and islet transplantation outcomes were explored with a competing risk analysis adjusted for all covariates suspected or known to affect outcomes. A predictive model based on PGF was built and internally validated by using bootstraps resampling method. In 39 centres worldwide, we enrolled 1210 patients with a calculable PGF (of those without missing data, mean age 47 years [SD 10], 712 [59·5%] were female, and 865 (97·9%) were White), who received a median of 10·8 thousand islet-equivalents per kg of bodyweight (IQR 7·4-13·5). 986 (82·4%) were ITA recipients and 211 (17·6%) were IAK recipients. Of 1210 patients, 452 (37·4%) received a single islet infusion and 758 (62·6%) received multiple islet infusions. Mean PGF was 14·3 (SD 8·8). The 5-year cumulative incidence of unsuccessful islet transplantation was 70·7% (95% CI 67·2-73·9), and was inversely and linearly related to PGF, with an adjusted subhazard ratio (sHR) of 0·77 (95% CI 0·72-0·82) per 5-unit increase of BETA-2 score (p<0·0001). Secondary endpoints were similarly related to PGF. The model-adjusted median C-statistic values of PGF for predicting 5-year cumulative incidences of unsuccessful islet transplantation, graft exhaustion, inadequate glucose control, and exogenous insulin therapy were 0·70 (range 0·69-0·71), 0·76 (0·74-0·77), 0·65 (0·64-0·66), and 0·72 (0·71-0·73), respectively. This global multicentre study reports a linear and independent association between PGF and 5-year clinical outcomes of islet transplantation. The main study limitations are its retrospective design and the absence of analysis of complications. Public Health Service Research, National Institutes of Health, Juvenile Diabetes Research Foundation International, Agence National de la Recherche, Fondation de l'Avenir, and Fonds de Dotation Line Renaud-Loulou Gasté.

Fasting and meal-stimulated serum C-peptide in long-standing type 1 diabetes mellitus.

This study aims to evaluate the stability of C-peptide over time and to compare fasting C-peptide and C-peptide response after mixed-meal tolerance test (MMTT) at T90 or T120 with C-peptide area under the curve (AUC) in long-standing type 1 diabetes. We included 607 type 1 diabetes individuals with diabetes duration >5 years. C-peptide concentrations (ultrasensitive assay) were collected in the fasting state, and in a subpopulation after MMTT (T0, just prior to, T30-T60-T90-T120, 30-120 min after ingestion of mixed-meal) (n=168). Fasting C-peptide concentrations (in n=535) at Year 0 and Year 1 were compared. The clinical determinants associated with residual C-peptide secretion and the correspondence of C-peptide at MMTT T90 / T120 and total AUC were assessed. A total of 153 participants (25%) had detectable fasting serum C-peptide (i.e ≥ 3.8pmol/L). Fasting C-peptide was significantly lower at Year 1 (p < 0.001, effect size=-0.16). Participants with higher fasting C-peptide had a higher age at diagnosis and shorter disease duration and were less frequently insulin pump users. Overall, 109 of 168 (65%) participants had both non-detectable fasting and post-meal serum C-peptide concentrations. The T90 and T120 C-peptide values at MMTT were concordant with total AUC. In 17 (10%) individuals, C-peptide was only detectable at MMTT and not in the fasting state. Stimulated C-peptide was detectable in an additional 10% of individuals compared with fasting in individuals with >5 years of diabetes duration. T90 and T120 MMTT measurements showed good concordance with the MMTT total AUC. Overall, there was a decrease of C-peptide at 1-year follow-up.

Habitual coffee consumption and subsequent risk of type 2 diabetes in individuals with a history of gestational diabetes – a prospective study

Females with a history of gestational diabetes mellitus (GDM) are at higher risk of developing type 2 diabetes mellitus (T2D) later in life. This study prospectively examined whether greater habitual coffee consumption was related to a lower risk of T2D among females with a history of GDM. We followed 4522 participants with a history of GDM in the NHS II for incident T2D between 1991 and 2017. Demographic, lifestyle factors including diet, and disease outcomes were updated every 2-4 y. Participants reported consumption of caffeinated and decaffeinated coffee on validated FFQs. Fasting blood samples were collected in 2012-2014 from a subset of participants free of diabetes to measure glucose metabolism biomarkers (HbA1c, insulin, C-peptide; n=518). We used multivariable Cox regression models to calculate adjusted HRs and 95% CIs for the risk of T2D. We estimated the least squares mean of glucose metabolic biomarkers according to coffee consumption. A total of 979 participants developed T2D. Caffeinated coffee consumption was inversely associated with the risk of T2D. Adjusted HR (95% CI) for≤1 (nonzero), 2-3, and 4+cups/d compared with 0 cup/d (reference) was 0.91 (0.78, 1.06), 0.83 (0.69, 1.01), and 0.46 (0.28, 0.76), respectively (P-trend=0.004). Replacement of 1 serving/d of sugar-sweetened beverage and artificially sweetened beverage with 1 cup/d of caffeinated coffee was associated with a 17% (risk ratio [RR]=0.83, 95% CI: 0.75, 0.93) and 9% (RR=0.91, 95% CI: 0.84, 0.99) lower risk of T2D, respectively. Greater caffeinated coffee consumption was associated with lower fasting insulin and C-peptide concentrations (all P-trend<0.05). Decaffeinated coffee intake was not significantly related to T2D but was inversely associated with C-peptide concentrations (P-trend=0.003). Among predominantly Caucasian females with a history of GDM, greater consumption of caffeinated coffee was associated with a lower risk of T2D and a more favorable metabolic profile.

Apparent Insulin Deficiency in an Adult African Population With New-Onset Type 2 Diabetes.

Adult patients with new-onset diabetes were recruited from seven tertiary hospitals in Uganda. Participants who were positive for the three islet autoantibodies were excluded. Fasting C-peptide concentrations were measured in 494 adult patients, and insulin deficiency was defined as a fasting C-peptide concentration <0.76 ng/ml. The socio-demographic, clinical, and metabolic characteristics of participants with and without insulin deficiency were compared. Multivariate analysis was performed to identify independent predictors of insulin deficiency. The median (IQR) age, glycated haemoglobin (HbA1c), and fasting C-peptide of the participants was 48 (39-58) years,10.4 (7.7-12.5) % or 90 (61-113) mmol/mol, and 1.4 (0.8-2.1) ng/ml, respectively. Insulin deficiency was present in 108 (21.9%) participants. Participants with confirmed insulin deficiency were more likely to be male (53.7% vs 40.4%, p=0.01), and had a lower body mass index or BMI [p<0.001], were less likely to be hypertensive [p=0.03], had reduced levels of triglycerides, uric acid, and leptin concentrations [p<0.001]), but higher HbA1c concentration (p=0.004). On multivariate analysis, BMI (AOR 0.89, 95% CI 0.85-0.94, p<0.001), non-HDLC (AOR 0.77, 95% CI 0.61-0.97, p=0.026), and HbA1c concentrations (AOR 1.08, 95% CI 1.00-1.17, p=0.049) were independent predictors of insulin deficiency. Insulin deficiency was prevalent in this population, occurring in about 1 in every 5 patients. Participants with insulin deficiency were more likely to have high HbA1c and fewer markers of adiposity and metabolic syndrome. These features should increase suspicion of insulin deficiency and guide targeted testing and insulin replacement therapy.

Neck circumference is a better correlate of insulin resistance markers than other standard anthropometric indices in patients presenting severe obesity

BackgroundPrevious studies have demonstrated stronger associations between metabolic alterations and neck circumference (NC) than with body mass index (BMI) or waist circumference (WC). However, most of these studies were performed in individuals presenting overweight or mild obesity. ObjectiveTo determine which adiposity index among BMI, WC, NC and fat mass (FM) can best predict metabolic alterations in men and women presenting severe obesity. MethodsAnthropometric and plasma biochemical parameters were measured in 81 participants presenting severe obesity (19 men, 62 women; age: 44.5 ± 8.9 years; BMI: 43.5 ± 4.1 kg/m2). Multiple linear regressions were used to determine the best predictors of metabolic alterations among each adiposity index. ResultsNC was positively correlated with fasting insulin concentrations, C-peptide concentrations and HOMA-IR values and negatively correlated with HDL-C concentrations. NC was the best predictor of glucose homeostasis indices and HDL-C concentrations in models also including sex, BMI, WC, and FM. The ROC curve analysis indicated that a NC ≥ 37.8 cm best predicted type 2 diabetes. ConclusionsNC seems a better predictor of insulin resistance and lower HDL-C concentrations in patients presenting severe obesity compared to other standard anthropometric indices, and particularly in women. The small sample size in men prevent us to draw clear conclusions. NC could be useful in targeting patients with metabolic alterations who could benefit from medical or surgical treatment of obesity.

Dietary Micronutrients Reduce Insulin Resistance via Adipose Tissue Modulation in Mice Fed a High Fat Diet

ObjectivesObesity is associated with increased insulin resistance (IR) and white adipose tissue (WAT) dysregulation (e.g., decrease in PPAR-γ mRNA expression and impaired leptin sensitivity). Dietary vitamins A, B1, B6, and B12, selenium (Se) and zinc (Zn) have been shown to reduce IR in obesity in animals and humans, but mechanisms have not been defined. The objective of this study is to investigate the effects of selected micronutrients on adipose tissue metabolism and IR in a mouse model of diet-induced obesity (DIO). We hypothesize that these additions modulate genes regulating IR in WAT and improve leptin sensitivity.Methods28 DIO male mice were randomly assigned to two high fat (HF, 60 kcal % fat) diets with or without the inclusion of a mineral-vitamin mixture (MVM: 5 × vitamin A, B1, B6, B12, zinc, and 2 × selenium), respectively. Similarly, 28 lean mice were randomized into a low-fat diet (LF, 10 kcal % fat) with or without the MVM. Mice were fed diets ad libitum for 8 weeks. Bodyweight (BW), IR, serum glucose, fasting insulin, C-peptide, leptin, as well as mRNA expression of genes involved in insulin signaling and adipokine secretion were measured in epididymal white adipose tissue (eWAT).ResultsCompared to HF mice, HF-MVM mice exhibited reduced body weight gain over time (by 6%, P < 0.05), improved insulin sensitivity (P < 0.05), reduced fasting glucose (by 18%), insulin (by 45%), C-peptide concentrations (by 26%) and Homeostatic Model Assessment for Insulin Resistance (by 47%, HOMA-IR, P < 0.05 for all). Similarly, LF-MVM had reduced fasting glucose level (P < 0.05) compared to LF mice. As expected, serum leptin concentration (adjusted for a visceral fat mass) was 6-fold higher in HF mice compared to LF mice; HF-MVM mice had lower leptin level compared to the HF mice suggesting improved leptin sensitivity. Ppar-γ gene expression in eWAT was 77% lower in HF vs LF group, suggesting eWAT dysfunction and systemic IR in DIO mice; the addition of MVM to LF diet attenuated this effect.ConclusionsThis MVM mixture may reduce IR through the upregulation of the PPAR-γ system in WAT and improve leptin sensitivity in DIO. Understanding the mechanism of action of micronutrients in reducing IR in a highly relevant animal model will provide new avenues for identifying food component solutions to modify IR in humans.Funding SourcesSupport provided by Various Sponsors (unrestricted funds).

Awakened Beta-Cell Function Decreases the Risk of Hypoglycemia in Pregnant Women with Type 1 Diabetes Mellitus.

Diabetes in pregnancy creates many problems for both the mother and child. Pregnant women with type 1 diabetes experience more frequent hypoglycemic and hyperglycemic episodes. This study aimed to determine the risk of clinically significant biochemical hypoglycemia (CSBH) by HbA1c, fasting C-peptide, mean plasma glucose (PG), and insulin dose in pregnant women type 1 diabetes mellitus according to each trimester of the pregnancy. Methods. We conducted a prospective observational study of 84 pregnant women with type 1 diabetes in an academic hospital. To present the hypoglycemia, we divided the participants into two groups: those who did not have clinically significant biochemical hypoglycemia (CSBH−; n = 30) and those who had clinically significant biochemical hypoglycemia (CSBH+; n = 54). Results. In the first, second, and third trimesters, the duration of T1DM, fasting C-peptide, and mean glucose concentration was inversely associated with CSBH. Conclusions. Insulin overdose is the most common risk factor for hypoglycemia. In pregnant women with type 1 diabetes with elevated fasting C-peptide levels, the insulin dose should be diminished to reduce the risk of hypoglycemia.

Absence of a sexual dimorphism in postprandial glucose metabolism after administration of a balanced mixed meal in healthy young volunteers

Background/ObjectivesA different ability to regulate glucose homeostasis between men and women may contribute to their difference in diabetes prevalence and in its predisposing conditions. Data on this issue are controversial because of heterogeneous protocols and insufficient control of confounders affecting glucose metabolism like age, body composition, and physical activity level. To clarify this issue, we compared among sexes the postprandial glucose metabolism after the administration of a balanced mixed meal normalized to daily energy expenditure.Subjects/MethodsThirty-six healthy young volunteers (18 men and 18 women; age, 23.9 ± 2.8 years; BMI, 21.9 ± 1.7 kg/m2) were recruited for the experiment. After overnight fast, subjects consumed a mixed meal providing 40% of daily energy expenditure (60% carbohydrates, 25% lipids, 15% proteins) estimated multiplying resting energy expenditure, obtained by Harris & Benedict equation, for the corresponding physical activity level. Blood was sampled at 0, 10, 20, 30, 45, 60, 90, 120, and 180 min and serum concentrations of glucose, insulin, and C-peptide were measured.ResultsFasting serum glucose concentrations were lower in women than in men, while fasting insulin and C-peptide concentrations did not differ between sexes. Linear mixed models did not show any significant effect of sex and sex # time interaction on postprandial serum glucose, insulin, and C-peptide concentrations. The comparison of areas under the curve between the sexes revealed similar glycemic, insulinemic, and C-peptide postprandial responses between men and women.ConclusionsOur results do not support the hypothesis of a sexual dimorphism in the regulation of carbohydrate metabolism in young when a mixed meal normalized on individual daily energy expenditure is ingested.

Cholesterol and glucose profiles according to different fasting C-peptide levels: a cross-sectional analysis in a healthy cohort from the Czech Republic.

The relationship between glycaemia and lipoprotein metabolism has not been completely clarified, and slight differences may be found between local authors, trials and evaluated parameters. Therefore this cross-sectional study investigated fasting cholesterol and glucose levels along with the determination of atherogenic index in a cohort of healthy individuals from the Czech Republic in relation to their fasting C-peptide levels. Data were collected between 2009 and 2018 and a total of 3189 individuals were stratified by C-peptide reference range (260-1730 pmol/l) into three groups - below (n = 111), within (n = 2952) and above (n = 126). Total, HDL, LDL cholesterol and atherogenic index were used to compare lipoprotein levels by relevant C-peptide concentrations. Participants using the supplements to affect lipid or glycaemia metabolism were excluded from this study. The evaluation of blood parameters in a fasting state included correlations between C-peptide and cholesterols, differences of variances (F-test) and the comparison of lipoprotein mean values (t-test) between the groups created by the C-peptide reference range. Mean values of total (4.9, 5.1, 5.3 mmol/l), LDL (2.6, 3.1, 3.4 mmol/l) cholesterol and atherogenic index (2.1, 2.8, 3.7) were higher with increasing C-peptide levels, whereas HDL was inversely associated with fasting C-peptide concentration. A positive and negative correlation between atherogenic index (rxy = 0.36) and HDL level (rxy = -0.36) with C-peptide values was found. Differences of HDL, LDL and atherogenic index were, in particular, recorded between the groups below and above the reference range of C-peptide (p ≤ 0.001). Considerable differences (p ≤ 0.001) were also observed for the same lipoprotein characteristics between the groups above and within the C-peptide reference. Generally, the type of cholesterol is crucial for the evaluation of specific changes concerning the C-peptide range. Lipoprotein concentrations differ in relation to C-peptide - not only below and above the physiological range, but also inside and outside of it. Conclusions: Fasting levels of cholesterol, plasma glucose, and atherogenic index were strongly associated with fasting C-peptide levels in healthy individuals. Our data suggest that fasting C-peptide could serve as a biomarker for the early detection of metabolic syndrome and/or insulin resistance prior to the manifestation of type 2 diabetes.

The utility of assessing C-peptide in patients with insulin-treated type 2 diabetes: a cross-sectional study.

Weaimed at evaluating residual β-cell function in insulin-treated patients with type 2 diabetes (T2D) while determining for the first time the difference in C-peptide level between patients on basal-bolus compared to those on the basal insulin scheme, considered as an early stage of insulin treatment, together with assessing its correlation with the presence of complications. A total of 93 candidates with T2D were enrolled in this cross-sectional study and were categorized into two groups based on the insulin regimen: Basal-Bolus (BB) if on both basal and rapid acting insulin, and Basal (B) if on basal insulin only, without rapid acting injections. HbA1c, fasting C-peptide concentration and other metabolic parameters were recorded, as well as the patient medical history. The average fasting C-peptide was 1.81 ± 0.15ng/mL, and its levels showed a significant inverse correlation with the duration of diabetes (r = -0.24, p = 0.03). Despite similar disease duration and metabolic control, BB participants displayed lower fasting C-peptide (p < 0.005) and higher fasting glucose (P = 0.01) compared with B patients. Concentrations below 1.09ng/mL could predict the adoption of a basal-bolus treatment (Area 0.64, 95%CI:0.521-0.759, p = 0.038, sensitivity 45% and specificity 81%). Insulin-treated patients with long-standing T2D showed detectable level of fasting C-peptide. Measuring the β-cell function may therefore guide toward effective therapeutic options when oral hypoglycemic agents prove unsuccessful.

313-OR: Diurnal Pattern of Meal Tolerance in Type 2 Diabetes

The existence of a diurnal pattern of post prandial glucose tolerance is relevant for management of patients with type 2 diabetes (T2D). We studied 10 healthy (4M) and 9 T2D (6M) subjects matched for age (56±3 vs. 58±3 yrs) and BMI (29±2 vs. 32±2 kg/m2). OGTT was done in healthy subjects to rule out diabetes. Identical mixed meals (8 kcal/kg/meal; 75 gm carb) were ingested during breakfast (B), lunch (L), and dinner (D) at 0700, 1300, and 1900 h in randomized latin square order with one labeled test meal/day on 3 consecutive days. Physical activity was kept same. Postprandial glucose turnover was measured utilizing the triple tracer technique modified with all stable isotopes ([1-13C] Glucose, [2-13C] Glucose and [6, 6-2H2] Glucose). Results shown in Fig 1. Fasting and post-meal glucose were higher while fasting and post-meal insulin and C-peptide concentrations lower in T2D for all three meals compared to healthy. Although meal glucose appearance did not differ between meals in either group, fasting endogenous glucose production (EGP) was higher, percent suppression of EGP lower in T2D and glucose disappearance (corrected for urine glucose loss) lower in T2D than healthy for all meals consumed. This data correlates with lower insulin sensitivity, B-cell responsivity to glucose and disposition index in T2D than healthy throughout the day. Our results suggest an emerging diurnal pattern to glucose tolerance and fluxes in humans, and that the pattern is different in T2D. Disclosure Y.R. Yadav: None. D. Romeres: None. F. Ruchi: None. S. Sawleh: None. R. Carter: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

1076-P: A 12-Week Treatment with Ciclosporin A Improves Insulin Secretion in Patients with Adult-Onset Autoimmune Diabetes: An Open-Label, Single-Arm, Pilot Study

Objectives: Adult-onset autoimmune diabetes, defined as having latent autoimmune diabetes in adults (LADA), is characterized by a less intensive autoimmune process, in which a lymphocytic infiltration of the exocrine pancreas is involved. immunosuppressive agents may have potential therapeutic benefit. This is a pilot study examining the therapeutic effects of ciclosporin A on insulin secretion in patients with LADA. Methods: The study was an open label, single arm, pilot trial. A total of 18 patients (12 men and 6 women with mean age of 40.6 yrs old) diagnosed with LADA were prospectively evaluated. All patients underwent insulin treatment at least for 3 months without any oral anti-hyperglycemic agent. All patients were prescribed ciclosporin A (50mg/day) for 12 weeks. Serum C-peptide concentrations were measured at baseline and 3 months after ciclosporin A intervention. We also evaluated total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine (Cre) before and after ciclosporin A treatment. The primary outcome of the study was the change in serum C-peptide concentrations. Results: A total of 17 patients completed the study. One patient was withdrawn at day 32 due to discontinuation of medication. Serum fasting C-peptide concentrations significantly increased from 0.12 ng/ml up to 0.32 ng/ml (P&amp;lt;0.001). After 12-week ciclosporin A intervention, there was no significant difference on TBIL (14.65 vs. 12.83umol/L, P&amp;gt;0.05), DBIL (4.70 vs. 4.65 umol/L, P&amp;gt;0.05), AST (17.41 vs. 17.82 U/L, p&amp;gt;0.05), ALT (18.19 vs. 18.08 U/L, p&amp;gt;0.05), or Cre (67.40 vs. 67.53 umol/L, P&amp;gt;0.05) compared with the corresponding baseline levels. Conclusions: This pilot study demonstrates the potential therapeutic effects of oral administration of ciclosporin A for patients with LADA. Larger, controlled studies are needed to verify the findings. Disclosure L. Zhang: None. W. Meng: None. S. Chen: None. Y. Yang: None. J. Wang: None. Y. Dong: None.

SAT-631 Increased Incidence of Diabetic Nephropathy in Veterans with Severe Insulin Resistance

Recently, cluster analysis has been used to classify adult onset diabetes based on pathophysiologic profile. Using autoimmunity status, BMI, insulin resistance, and beta cell function, this classification system can predict diabetes associated complications. Individuals with primarily insulin resistant phenotype have been associated with increased incidence of nephropathy while those with insulin deficient phenotype are associated with retinopathy. Clinically, patients with severe insulin resistance can be defined as those who require high doses of insulin to achieve glycemic control, such as patients on U-500 insulin requiring more than 200 units of insulin a day. To characterize the clinical and metabolic phenotype of insulin-resistant patients from a South Texas VA diabetes clinic, we evaluated presence of macro or microvascular complications and beta-cell autoimmunity and function in this population. A retrospective cohort study was completed at the South Texas VA Diabetes Clinic. Charts were reviewed for anthropometric measurements, presence of macro and microvascular complications, anti-diabetic medication, lipid profile and HbA1c over 3 visits, autoimmunity (anti-GADab), and beta-cell function (fasting C-peptide). Patients with insulin doses >200 U/day or on U-500 insulin were categorized as “severe insulin-resistant”. Those with insulin doses < 0.5 U/kg/day were categorized as “mild insulin resistance” as a control group. Out of 120 patients, 30 met criteria for severe insulin resistance (n=30, M/F=29/1 age 61±1.6 years (yr), BMI 41±0.9 kg/m2, duration of diabetes 18.3±0.3 yr, HbA1c -8.4±0.2%, total daily insulin dose (TDD) 301±31U). 30 patients with insulin use <0.5 U/kg/day met criteria for mild insulin resistance (N=30, M/F: 28/2, age 62±2 yr, BMI 30±1 kg/m2, duration of diabetes 12±1.2 yr, HbA1c 7.2±0.2%, TDD 17±2U). Prevalence of nephropathy was higher in the insulin resistant group vs the mild insulin resistant group (76% vs 43%, p<0.05). There was no difference in prevalence of retinopathy (p=0.095) or CAD (p=0.6) between the groups. There was no difference in use of ACE-i or SGLT-2i between the groups. Insulin resistant subjects had a higher plasma triglyceride (325±0.3 vs 202±0.3 mg/dl, p=0.04). Prevalence of GAD ab was not different between the groups (3% vs 0%). Fasting C-peptide concentrations were similar in both groups (5.6±0.3 vs 5.2±0.25 ng/ml, p=0.3). HbA1c in the insulin resistant group improved between visits 1 and 3 (p<0.01). Weight increased over three visits in the severe insulin resistant group as opposed to mild weight loss in the mild insulin resistant group.Our results support the high prevalence of diabetic nephropathy in patients with severe insulin resistance, although it is unclear that insulin resistance is the etiology. Long-term follow up of these patients may provide insight into the underlying mechanisms of these complications.

C-peptide concentrations in patients with type 2 diabetes treated with insulin

AimsTo determine beta cell reserves of patients with type 2 diabetes who are treated with insulin by using fasting C-peptide concentrations and to investigate the clinical features related to C-peptide concentrations. Materials and methodsPatients with type 2 diabetes, who were using insulin as monotherapy or in combination therapy, were divided into three groups; those with an insufficient beta cell reserve (C-peptide: <0.5 ng/mL), borderline reserve (C-peptide: 0.5–2 ng/mL) and sufficient reserve (C-peptide:> 2 ng/mL). ResultsIn the 249 patients (mean age, 61.77 ± 9.34 years; 40.6% male), the mean duration of diabetes was 13.9 ± 8.43 years. The mean HbA1c concentrations, fasting glucose and C-peptide concentrations were 8.88 ± 1.87%, 184.29 ± 77.88 mg/dL and 1.95 ± 1.37 ng/mL, respectively. Fifty-seven percent of patients (n = 142) had a borderline beta cell reserve and 37% (n = 92) had high C-peptide concentrations. Only 6% of patients (n = 15) had an insufficient beta cell reserve. C-peptide levels were positively correlated with waist circumference (r: 0.282; p = 0.001), hip circumference (r: 0.251; p = 0.001), body mass index (r: 0.279; p = 0.001), fasting glucose concentrations (r: 0.309; p = 0.001) and triglyceride concentrations (r: 0.358; p = 0.001). ConclusionIn this study, almost all patients with type 2 diabetes using insulin were found to have sufficient or borderline beta cell reserves and insulin resistance-related parameters were prominent in those with adequate beta cell reserve. Clinical trials noNCT04005261

Investigating optimal β-cell-preserving treatment in latent autoimmune diabetes in adults: Results from a 21-month randomized trial.

To compare outcomes of glucagon-stimulated C-peptide tests (GSCTs) in people with latent autoimmune diabetes in adults (LADA) after a 21-month intervention with either insulin or the dipeptidyl peptidase-4 inhibitor sitagliptin. We included 64 glutamic acid decarboxylase (GAD) antibody-positive individuals, who were diagnosed with diabetes <3 years before the study, aged 30 to 70 years, and without clinical need for insulin treatment. We stratified participants by age and body mass index (BMI) and evaluated β-cell function by GSCT after a 48-hour temporary withdrawal of study medication. Age at randomization (mean 53 years), BMI (mean 27 kg/m2 ) and metabolic markers were similar between treatment arms. Glycated haemoglobin concentrations during intervention did not differ between arms. Fasting C-peptide concentrations after the intervention were similar, as were stimulated C-peptide levels (0.82 ± 0.63 nmol/L after insulin, 0.82 ± 0.46 nmol/L after sitagliptin; nonsignificant). Autoimmunity in the study population (estimated from GAD antibody titres and positivity/no positivity for zinc transporter 8 and islet antigen 2 antibodies) affected the evolution of the GSCT results significantly, which deteriorated in participants with high but not in those with low autoimmunity. Adjustment using analysis of covariance for the degree of autoimmunity did not alter the findings of no difference between treatment arms. β-cell function after intervention was similar in patients with insulin- and sitagliptin-treated LADA, regardless of the strength of autoimmunity. Further, participants with low levels of GAD antibodies did not experience progressive deterioration of β-cell function over a 21-month period. Taken together, these findings could be useful for clinicians' choices of treatment in people with LADA.

1147-P: Effect of Short-Term Ciclosporin A Treatment on Insulin Secretion in Patients with Adult-Onset Autoimmune Diabetes: An Open-Label, Single-Arm, Pilot Study in China

Adult-onset autoimmune diabetes, defined as having latent autoimmune diabetes in adults (LADA), is characterized by a less intensive autoimmune process, in which a lymphocytic infiltration of the exocrine pancreas is involved. Immunosuppressive agents may have potential therapeutic benefit. This is a pilot study examining the therapeutic effects of oral administration of ciclosporin A on insulin secretion in patients with LADA. The study was an open label, single arm, pilot trial. A total of 12 patients (8 men and 4 women with mean age of 40.2 years old) diagnosed with LADA were prospectively evaluated. All patients underwent insulin treatment at least for 3 months without any oral anti-hyperglycemic agent. Serum C-peptide concentrations were measured at baseline and after ciclosporin A intervention. We also evaluated clinical parameters including total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine (Cre) before and after ciclosporin A treatment. The primary outcome of the study was the change in serum C-peptide concentrations. A total of 12 patients completed the study. No patient was withdrawn. Serum fasting C-peptide concentrations significantly increased from 0.10 ng/ml up to 0.32 ng/ml, following treatment with ciclosporin A (50mg/day) for 4 weeks (P&amp;lt;0.001). After 4-week ciclosporin A intervention, there was no significant difference on TBIL (14.33 vs. 13.70 umol/L, P=0.59), DBIL(4.31 vs. 4.63 umol/L, P=0.48), AST(16.83 vs. 18.50 U/L, p=0.09), ALT(17.17 vs. 18.16 U/L, p=0.35), or Cre (67.17 vs. 66.01 umol/L, P=0.25) compared with the corresponding baseline levels. This pilot study demonstrates the potential therapeutic effects of oral administration of ciclosporin A for patients with LADA. No significant adverse effects of the drug were observed. Larger, controlled studies are needed to verify the results. Disclosure L. Zhang: None. J. Wang: None. N. Wang: None. Y. Yang: None. X. Yin: None. Y. Dong: None.

Do contraindications to metformin therapy deprive type 2 diabetic patients of its benefits?

Background: Metformin is considered to be the drug of choice in overweight, newly diagnosed type 2 diabetes. Lactic acidosis is stated to be the most serious side effects of metformin therapy. Current available guidelines contain so many ambiguous terms in describing the contraindications to metformin use that they do little to assist in addressing this problem. Moreover, these ambiguous contraindications may deprive many diabetic patients from the benefit of metformin. Objectives: The aim of the current study was to evaluate the safety of metformin use in the presence of “standard” contraindications to its use. Research design and methods: This was a cross sectional study that involved type 2 diabetic patients who were on chronic treatment with metformin. A fasting blood sample was taken from each subject to determine levels of serum creatinine levels, bicarbonate, fasting blood sugar, lactate, insulin, C-Peptide, and metformin plasma concentration. Results: 106 patients were recruited in the study with 68 (64%) females. The mean age was 58 ± 13 years. The results illustrate that metformin has been prescribed for patients who are listed in the guidelines as having standard contraindications to its use. There were 30 (28%) patients with impaired renal function (Clcr < 60ml/min.) and five with Clcr < 30ml/min. Moreover, 30 (28%) had ischemic heart disease, six (5%) patients were diagnosed as having congestive heart failure, five (4%) with chronic obstruction pulmonary disease, and three (2%) with peripheral vascular disease. Although the numbers of those patients were not large enough to establish and confirm the safety of metformin in the presence of these standard contraindications and precautions, there were no cases of lactic acidosis observed. Conclusions: This study along with other studies has revealed that there is vagueness in the available guidelines in prescribing metformin, which led to the different observed practices. This study revealed that metformin is still prescribed to patients with listed contraindications. Clearer guidelines are needed for prescribing metformin with more specific contraindications. For example it would be more beneficial if the degree of heart failure, classified according to the New York Heart Association is specified.