Beta-cell Function In Patients Research Articles

Preserved C-peptide secretion in patients with type 1 diabetes and incipient chronic complications is associated with lower serum resistin and higher uric acid levels.

Previous studies suggested that long-term perseverance of beta-cell function in patients with type 1 diabetes (T1DM) is associated with lower incidence of microvascular complications. The objective of this study was to evaluate preserved C-peptide secretion in patients with T1DM without overt chronic complications and to explore associations with resistin and uric acid as biomarkers of microvascular complication pathogenesis. We assessed residual beta-cell function in 164 T1DM patients (male/female = 91/73; age/diabetes duration range = 18-70/1-30years) using an ultrasensitive C-peptide ELISA assay with detection limit of 2.5pmol/L and total coefficient of variation (CV) 5,8% (Mercodia, Sweden). Serum level of uric acid was measured by enzymatic method (AU680, Beckman Coulter, USA) while resistin concentration was determined by the ELISA assay (Biovendor, Czech Republic). C-peptide secretors had shorter diabetes duration (5.1 vs. 16years; p< 0,001), lower resistin (4.53 vs. 4.93mg/mL p= 0.045), and higher uric acid (259 vs 238μmol/L, p= 0.048) level than T1DM patients with no detectable C-peptide levels, while no differences in routine anthropometric and laboratory variables, including HbA1c, were observed. Although the proportion of C-peptide secretors significantly decreased across categories of diabetes duration (70%, 38%, 17% and 15% for <5, 5-10, 10-20 and 20-30years of duration, respectively; p< 0,001), detectable C-peptide was found in 5/23 T1DM patients who were diagnosed with T1DM more than 20years ago. The results of our study revealed that patients with detectable C-peptide had lower resistin and higher uric acid level compared to patients with undetectable C-peptide.

Inhibition of miR-153, an IL-1β-responsive miRNA, prevents beta cell failure and inflammation-associated diabetes

ObjectiveSystemic levels of up-regulated IL-1β and IL-1 receptors promote the pathogenesis of inflammation-associated diabetes. IL-1 receptor antagonist (IL-Ra) has shown slightly elevated beta cell function in patients with type 2 diabetes without significant improvement of hyperglycaemia. We investigated whether miR-153, an IL-1β responsive miRNA, could mimic IL-1β effects and whether its interruption would improve blood glucose control then offer an assistant curative approach to inflammation-associated diabetes. Materials/methodsAntago-miR-153 and Ago-miR-153 were injected into the abdominal aorta of leptin receptor-mutant db/db mice and C57BL/6 J mice, respectively. Blood glucose levels, glucose tolerance tests, insulin tolerance tests and insulin levels were regularly checked. Proteomic profiling combined with unbiased bioinformatics analysis, as well as experimental techniques, were utilized to identify target genes of miR-153. Anti-miR-153 and plasmid-based recovery assays were also performed using primary mouse islets and beta cell lines. ResultsThe miR-153 expression level was increased in IL-1β–treated beta cells and primary islets from the diabetic rodents. Pancreas overexpression of miR-153 caused glucose intolerance in C57BL/6 J mice but no alterations in body weight or insulin sensitivity. The inhibition of miR-153 temporarily reduced hyperglycaemia of db/db mice due to enhanced insulin secretion. Antago-miR-153 treatment ameliorated glucose intolerance in db/db mice during our observation period but did not improve insulin sensitivity. Mechanistically, miR-153 targeted three members of SNAREs to disturb insulin granule docking, thereby decreasing basal insulin secretion. Overexpression of anti-miR-153 or SNARE rescued the IL-1β–induced basal insulin secretion defect. Furthermore, miR-153 targeted beta cell–specific transcriptional factors and survival molecules to inhibit insulin biosynthesis and cell viability. ConclusionsThe IL-1β-responsive miR-153 targets SNAREs, beta cell specific TFs and other key factors to eventually causes beta cell failure. Inhibiting miR-153 with Antago-miR-153 prevents hyperglycaemia in db/db mice, indicating that miR-153 may be a promising therapeutic target for the treatment of inflammation-associated diabetes.

254-OR: Islet Autoimmunity Is Highly Prevalent and Associated with Diminished Beta-Cell Function in Patients with Type 2 Diabetes (T2D) in the GRADE Study

We hypothesized that islet autoimmunity, hitherto considered the pathophysiologic basis of type 1 diabetes (T1D) and latent autoimmune diabetes of adults (LADA), could contribute to ß cell dysfunction in patients with type 2 diabetes (T2D). To evaluate this question, the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study - Beta Cell Ancillary Study Network measured humoral islet autoimmunity (autoantibodies against 65 kDa glutamic acid decarboxylase (GAD65-Ab), islet autoantigen-2 (IA2-Ab) and zinc transporter-8 (ZnT8-Ab)) in 392 participants (age 57.2 ± 10.1 y; BMI 33.5 ± 6.2 kg/m2; diabetes duration 4.0 ± 3.0 y; HbA1c 7.5 ± 0.5 %; on metformin as the sole glucose-lowering medication), and cellular islet autoimmunity (T cell autoreactivity against a broad range of islet antigens) in 322 of the same participants. 41.4% had evidence of cellular islet autoimmunity and 13.5% had evidence of humoral islet autoimmunity, but only 5.4% had both. T cell autoreactivity to islet antigens, but not autoantibody-positivity, was associated with diminished ß cell function, as assessed by the ratio of incremental area under the curve (iAUC) of C-peptide to iAUC of glucose during 0-120 min of an OGTT (ß = -0.1403; se = 0.0612; p = 0.0219) or ∆C-peptide/∆glucose during 0-30 min of an OGTT (ß = -0.2113; se = 0.0728; p = 0.0037), adjusted for insulin sensitivity. T cell positive participants also had higher fasting plasma glucose (p = 0.045) and HbA1c (p = 0.001) than T cell negative participants. These findings indicate that islet autoimmunity in T2D patients is far more prevalent than previously recognized; T cell mediated islet autoimmunity is associated with diminished ß cell function. Disclosure B. Brooks-Worrell: None. C.S. Hampe: None. E.V. Gonzalez: None. B.M. Palomino: None. S.Z. Zangeneh: None. K. Utzschneider: Other Relationship; Self; Medtronic. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc. M.E. Larkin: None. M.L. Johnson: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, JDRF, Lilly Diabetes, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc. K.J. Mather: Research Support; Self; Abbott, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. N. Younes: None. N. Rasouli: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., Novo Nordisk Inc. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb. J.Y. Park: None. H. Florez: None. W. Valencia: None. A. Shojaie: None. J.P. Palmer: None. A. Balasubramanyam: None. Funding National Institutes of Health (R01DK104832, U01DK098246)

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route.

Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

IL-6 is present in beta and alpha cells in human pancreatic islets: Expression is reduced in subjects with type 1 diabetes

IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreas from non-diabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed.

Slowly Progressive Type 1 Diabetes Mellitus: Current Knowledge And Future Perspectives.

Slowly progressive type 1 insulin-dependent diabetes mellitus (SPIDDM), sometimes referred to as latent autoimmune diabetes in adults (LADA), is a heterogeneous disease that is often confused with type 1 and type 2 diabetes. As a result, there were few diagnostic criteria for this disorder until 2012, when the Japan Diabetes Society established criteria that could be used in clinical practice. A primary question is whether pathologic markers for type 1 or type 2 diabetes are present in the pancreas of patients with SPIDDM, because the phenotype of SPIDDM is similar to both type 1 and type 2 diabetes. Recent studies clarified pathologic findings in the pancreas of patients with SPIDDM, which included T-cell-mediated insulitis, a marker of type 1 diabetes; pseudoatrophic islets (islets specifically devoid of beta cells), another hallmark of type 1 diabetes; and a lack of amylin (ie, islet amyloid polypeptide) deposition to the islet cells, a pathologic marker of type 2 diabetes. In terms of preventing the loss of beta-cell function in patients with SPIDDM, several studies have shown that some drugs, including dipeptidyl peptidase-4 inhibitors, are effective. There is an increased need for early diagnosis of SPIDDM to preserve beta-cell function. This review presents updated findings on the pathogenesis and immunologic findings of the affected pancreas, diagnostic markers, risk factors for progression of beta-cell dysfunction, epidemiology, clinical features, diagnostic strategies, prevention strategies, and clinical options for patients with SPIDDM.

561-P: Serum C-Peptide Concentrations Are Inversely Associated with Cardiovascular Autonomic Neuropathy in Type 2 Diabetic Individuals With and Without Renal Impairment Independently of Estimated Glomerular Filtration Rate

Cardiovascular autonomic neuropathy (CAN) is a significant cause of cardiovascular morbidity and mortality in patients with type 2 DM. C-peptide is suggested as a bioactive peptide with protective roles on microangiopathy. However, due to renal metabolism of C-peptide, previous studies have been limited to diabetic patients without renal impairment. Serum C-peptide levels might be increased despite reduced beta cell function in patients with renal impairment. Therefore, we tested the hypothesis that C peptide would relate to the risk of CAN in patients with type 2 DM independently of renal function. A total of 1070 type 2 diabetic patients were investigated in this cross-sectional study. Prior dialysis or renal transplantation was excluded. CAN was diagnosed by a cardiovascular reflex test. Fasting C-peptide, 2-hour postprandial C-peptide, and ΔC-peptide levels were measured. The estimated glomerular filtration rate (eGFR) was calculated from CKD-EPI equation. In individuals with and without renal impairment, patients with CAN showed lower levels of fasting C-peptide, postprandial C-peptide and ΔC-peptide. In multivariate analysis, serum C-peptide levels were significantly associated with CAN (OR, 0.80; 95% CI, 0.67-0.96 for fasting C-peptide, p=0.014; OR, 0.78; 95% CI, 0.64-0.95 for postprandial C-peptide, p=0.013; OR, 0.80; 95% CI, 0.66-0.97 for ΔC-peptide, p=0.023) after adjustment for age, gender and other confounders including eGFR. Our results show that serum C-peptide levels are inversely associated with CAN in type 2 diabetic patients with and without renal impairment independently of eGFR. These findings might suggest the beneficial effects of serum C-peptide levels on CAN independently of eGFR. Disclosure J. Chung: None. S. Park: None. D. Cho: None. D. Chung: None. M. Chung: None.

994-P: Effects of Dulaglutide and Trelagliptin on ß-Cell Function after One Year in Patients with Type 2 Diabetes: DUET-Beta Extension Study

Studies on glucagon-like peptide 1 receptor agonists (GLP-1-RA) and dipeptidyl peptidase-4 inhibitors (DPP-4-I) have suggested positive effects on beta-cells. However, direct comparison between weekly GLP-1-RA: dulaglutide (Dula) and weekly DPP-4-I: trelagliptin (Trela) effects on beta-cell function is not known. Thus, we compared the effects of Dula and Trela on beta-cell function in patients with type 2 diabetes (T2D) in an open-label, parallel-group, randomized controlled 24-week trial, with an additional 28 weeks of extension follow-up. Beta-cell function and insulin resistance were assessed by HOMA2-%β and HOMA2-IR, respectively. Body composition was also assessed by the bioelectrical impedance method. Fifty metformin ± basal insulin-treated patients with type 2 diabetes (T2D) were randomized to Dula 0.75 mg/week or Trela 100 mg/week. Forty-eight patients entered the 28-weeks extension study and continued their allocated therapy. Forty-six completed (Dula: n = 23, Trela: n = 23) the 52-week exposure and were included in the analysis. HOMA2-%β was higher in the Dula group than in the Trela group throughout the 52 weeks (24 weeks: Dula: +50.6 ± 9.9% vs. Trela: +7.5 ± 9.5%, p = 0.003; 52 weeks: Dula: +54.5 ± 8.7% vs. Trela: +3.0 ± 8.7%, p &amp;lt;0.001). HOMA2-IR was not significantly different between both groups (24 weeks: Dula: -0.29 ± 0.50 vs. Trela: -0.19 ± 0.50, p = 0.88; 52 weeks: Dula: +0.79 ± 0.52 vs. Trela: +0.45 ± 0.52, p = 0.64). At 52 weeks, HbA1c had a larger decrease with the Dula group (Dula: -0.52 ± 0.11%, Trela: -0.13 ± 0.12%, p = 0.02). Body fat mass was reduced more in the Dula group than the Trela group (52 weeks: Dula: -1.5 ± 0.3 kg vs. Trela: +0.4 ± 0.3 kg, p &amp;lt;0.001). However, Dula patients did not have a reduction in skeletal muscle mass (52 weeks: 0.0 ± 0.3 kg, p = 0.94). In conclusion, Dula increased HOMA2-%β level more than Trela over the 52 weeks, without a significant change in HOMA2-IR level. Dula reduced body fat mass without skeletal muscle mass loss. Disclosure Y. Kondo: None. S. Satoh: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi &amp; Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.

149-LB: The MetAP2 Inhibitor, ZGN-1061, Improves Insulin Sensitivity and Beta-Cell Function in Patients with Type 2 Diabetes

ZGN-1061 is a second-generation methionine aminopeptidase 2 (MetAP2) inhibitor in development for treatment of T2D. Full results of a Phase 2 clinical trial of ZGN-1061 vs. placebo (PBO) administered SC for 12 weeks on change from baseline in A1C in subjects with T2D are reported elsewhere. Baseline (ITT population N=175) A1C 8.6±1.1%, BMI 37±7 kg/m2, T2D duration 8±6 y. ZGN-1061 was generally well tolerated; 93% completed the trial. LS mean±SE A1C change was 0.2±0.1% for PBO vs. ±0.4±0.1% and -0.9±0.2% for 0.9 and 1.8 mg ZGN-1061 (both p&amp;lt;0.001 vs. PBO). PBO weight change was -0.6±0.3 kg vs. -1.4±0.3 kg (p=ns) and ±2.8±0.5 kg (p&amp;lt;0.001) for 0.9 and 1.8 mg ZGN-1061. This analysis included a subset of subjects who participated in a mixed-meal tolerance test (MMTT) at baseline and week 12. ZGN-1061 produced dose-dependent improvements in fasting and postprandial glucose (p&amp;lt;0.05 vs. PBO). Minimal model analysis showed improvements in insulin sensitivity (SI) and disposition index (DI_OB; a measure of β-cell compensation) from baseline to week 12 with ZGN-1061 (Table). In an exploratory combined analysis of 0.9+1.8 mg ZGN-1061, SI and DI_OB increased (p=0.02 and p=0.07). SI and DI_OB were unchanged with PBO. In patients with T2D, improved glycemic control with ZGN-1061 may be driven by changes in insulin sensitivity and β-cell function. These results support future assessments using other definitive methods. Disclosure R. Fabunmi: None. R.N. Bergman: Consultant; Self; Zafgen, Inc. F. Piccinini: None. T. Kim: Employee; Spouse/Partner; Celgene Corporation. Employee; Self; Zafgen, Inc. D. Zhuang: Employee; Self; Zafgen, Inc. K. Taylor: Employee; Self; Zafgen, Inc. D.D. Kim: Employee; Self; Zafgen, Inc. Funding Zafgen, Inc.

Liraglutide improves the beta-cell function without increasing insulin secretion during a mixed meal in patients, who exhibit well-controlled type 2 diabetes and coronary artery disease

BackgroundHyperinsulinemia aggravates insulin resistance and cardio-vascular disease. How the insulinotropic glucagon-like peptide-1 receptor agonist liraglutide in a physiologic post-prandial setting may act on pancreatic alpha and beta-cell function in patients with coronary artery disease (CAD) and type 2 diabetes (T2DM) is less clear.MethodsInsulin resistant patients with established CAD and newly diagnosed well-controlled T2DM were recruited to a placebo-controlled, cross-over trial with two treatment periods of 12 weeks and a 2 weeks wash-out period before and in-between. Treatment was liraglutide or placebo titrated from 0.6 mg q.d. to 1.8 mg q.d. within 4 weeks and metformin titrated from 500 mg b.i.d to 1000 mg b.i.d. within 4 weeks. Before and after intervention in both 12 weeks periods insulin, C-peptide, glucose, and glucagon were measured during a meal test. Beta-cell function derived from the oral glucose tolerance setting was calculated as changes in insulin secretion per unit changes in glucose concentration (Btotal) and whole-body insulin resistance using ISIcomposite.ResultsLiraglutide increased the disposition index [Btotal × ISIcomposite, by 40% (n = 24, p < 0.001)] compared to placebo. Post-prandial insulin and glucose was reduced by metformin in combination with liraglutide and differed, but not significantly different from placebo, moreover, glucagon concentration was unaffected. Additionally, insulin clearance tended to increase during liraglutide therapy (n = 26, p = 0.06).ConclusionsThe insulinotropic drug liraglutide may without increasing the insulin concentration reduce postprandial glucose but not glucagon excursions and improve beta-cell function in newly diagnosed and well-controlled T2DM.Trial registration Clinicaltrials.gov ID: NCT01595789

Metabolomic Characteristics of Fatty Pancreas.

Pancreatic steatosis is associated with impaired beta cell function in patients with prediabetes. The pathomechanisms underlying this association still remain to be elucidated. Recent data show that adipocytes are situated within the pancreatic parenchyma and therefore give raise to hypothesize that pancreatic fat together with known and unknown metabolites such as hepatokines affect insulin secretion. Applying a targeted metabolomic approach we investigated possible circulating markers of pancreatic fat in order to better understand its role in the pathophysiology of impaired beta cell function. We included 361 Caucasians, at increased risk of type 2 diabetes, from the Tübingen Family Study. All participants underwent a frequently sampled oral glucose tolerance test to assess insulin secretion and a magnetic resonance imaging to quantify pancreatic fat content, total body fat and visceral fat. Among the 152 subjects with prediabetes (IFG and/or IGT), two groups each with 20 individuals, having the lowest and highest pancreatic fat content were selected. The groups were matched for sex, age, BMI, total fat content, visceral fat content, liver fat content and insulin sensitivity. Metabolites were analyzed using the AbsoluteIDQ® p400 HR Kit by Biocrates. Pancreatic fat content of all 152 subjects with prediabetes was negatively associated with insulin secretion represented by AUCC-peptide 0-120/AUCGlucose 0-120 (p=0.04; β=- 3.24). Furthermore, pancreatic fat content was positively associated with BMI, total body and visceral fat (all p<0.005). Levels of aminoacids, biogenic amines and monosaccharides were similar between the groups with high/low pancreatic fat content (p>0.90). Also, levels of polar lipids such as lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides did not differ significantly between the groups (p>0.90). Investigating the levels of neutral lipids such as aclycarnitines, diglycerides, triglycerides and cholesteryl esters also revealed no differences between the groups (p>0.90). The amount of pancreatic fat is not associated with the metabolomic pattern in individuals with prediabetes. This might be due to the relatively low pancreatic fat content compared to the total amount of fat stored in other depots. The impact of pancreatic steatosis on insulin secretion might be mediated by paracrine effects which cannot be detected in the circulation.

OR31-6 Insulin Sensitivity and Pancreatic Beta-Cell Function in Patients with Primary Aldosteronism

Insulin sensitivity and pancreatic beta-cell function are primary determinants of glucose tolerance. Primary aldosteronism (PA) is associated with increased risk for glucose intolerance. However, its effects on insulin sensitivity and β-cell function have shown mixed results. In this study, we compared indices of insulin sensitivity and pancreatic β-cell function derived from an oral glucose tolerance test (OGTT) in patients from two cohorts: subjects with PA (n=25) and essential hypertension control (EHC) subjects. The EHC controls (n=25) were similar in age and BMI range, gender composition (female, n=14), and number of subjects with type 2 diabetes (n=3). Group comparisons were performed after adjusting for age, sex, and BMI; data is presented as unadjusted mean ± SD. As expected, the PA group show lower potassium concentrations compared to the EHC group, as well as elevated aldosterone and reduced renin levels. Mean arterial pressure was not significantly different between the groups (PA:100.6 ± 11.7, EHC: 96.7 ± 15.5 mm Hg, p=0.22). The area under the curve (AUC) for insulin during an OGTT, but not glucose, was higher in the PA group (insulin AUC: 14831 ± 9545 vs. 8582 ± 4948, μU/mL∙min, p<0.05). Whole-body and hepatic insulin sensitivity were determined using surrogate indices and oral minimal model (SIMM) analysis. PA individuals were found to be less insulin sensitive compared to EHC subjects (Quantitative insulin sensitivity check index (QUICKI): 0.337 ± 0.035 vs. 0.367 ± 0.062, p<0.001; Matsuda Index: 3.98 ± 2.33 vs. 7.24 ± 6.50, p<0.001; and SIMM: 1.01x10-3 ± 2.01x10-3 vs. 1.87x10-3 ± 2.71x10-3, min-1 per μU/mL, p=0.08). The hepatic insulin resistance index (HIRI) was significantly higher in PA individuals (HIRI: 5.62 ± 4.52 vs. 4.02 ± 2.78, mg/dL∙ μU/mL ∙ 106, p<0.001), suggesting decreased hepatic insulin sensitivity. Insulinogenic index (IGI), a measure of β -cell function is calculated as change in insulin concentrations divided by change in glucose from 0 to 30 min (ΔI0-30/ΔG0-30). IGI was slightly higher in the PA cohort (169 ± 150 vs. 124 ± 122, pmol/mmol, p=0.06). Oral disposition index (DI), a marker of integrated islet β-cell function, is the product of insulin secretion and sensitivity derived from OGTT. DI was similar between the groups (561 ± 434 vs. 605 ± 517, p=0.80). This accounts for the similar glucose tolerance between the groups. In summary, insulin sensitivity is significantly lower in PA and is accompanied by a compensatory increase in β-cell function. These results suggest that excess aldosterone and/or other steroids in the context of PA may negatively affect insulin action without adversely impacting beta-cell function.

Insulin Sensitivity and Beta-Cell Function in Graves’ Disease and Their Changes with the Carbimazole-Induced Euthyroid State

Background and Objective: Thyroid hormones play an important role in intermediate metabolism, and abnormal glucose tolerance is often observed in patients with hyperthyroidism. Several pathogenic mechanisms have been proposed as contributors. However, there is no conclusive evidence in the existing literature regarding the predominant underlying pathophysiology. Our objective was to determine the changes in insulin resistance parameters and beta-cell function in patients with Graves’ disease following restoration of a euthyroid state. Methodology: This was an observational study with a before-after study design. Forty-five treatment-naïve adults with Graves’ diseases were included and 36 completed the study. An oral glucose tolerance test was performed at baseline and after 3 months of achieving a stable euthyroid state to assess glucose tolerance, insulin sensitivity, and beta-cell function. All patients were treated with antithyroid medication. The outcome measures studied were the Homeostasis Model Assessment-2 Insulin Resistance (HOMA2-IR), Matsuda index, and Insulin Secretion-Sensitivity Index (ISSI)-2. Results: Two-thirds of the patients had abnormal glucose tolerance at baseline. Among those with abnormal glucose tolerance at baseline, 34.7% had persistent abnormality during follow-up. During follow-up, no significant change was noted in the indices of insulin resistance. Patients with abnormal glucose tolerance had a significantly lower ISSI-2 index at baseline and it improved after achieving a euthyroid state. Conclusions: Abnormal glucose tolerance is a significant metabolic consequence in patients with Graves’ disease. Decreased beta-cell function was observed among those with abnormal glucose tolerance and it improved during follow-up. In a proportion of patients, abnormal glucose tolerance persisted after 3 months, emphasizing the need for continued follow-up.

Effects of Sitagliptin on Pancreatic Beta-Cells in Type 2 Diabetes With Sulfonylurea Treatment: A Prospective Randomized Study.

BackgroundThis prospective randomized, multicenter, open-label, comparative study was performed to analyze the effects of sitagliptin on glycemic control and maintenance of beta-cell function in patients with poorly controlled type 2 diabetes treated with low-dose glimepiride.MethodsForty-one patients with type 2 diabetes mellitus treated with low-dose glimepiride (≤ 2 mg/day) were prospectively enrolled in this study (age: 20 - 75 years; hemoglobin A1c (HbA1c): 7.4- 9.4%). The patients were randomized into two groups: the glimepiride (G) group, in which glimepiride dose was increased gradually to 6 mg/day, and the sitagliptin (S) group, in which sitagliptin was added at a dose of 50 mg/day.ResultsHbA1c level was significantly decreased after 24 weeks, but not 12 weeks, in the G group, while a significant decrease was seen after 12 weeks in the S group. Although there were no significant differences in HbA1c level at 24 weeks between the two groups (P = 0.057). The overall trend of changes in HbA1c level suggested that the glucose-lowering effects were superior in the S group. Furthermore, a significant change in fasting glucose was seen in the S group, but not in the G group. Glycemic control target was achieved in 36.7% and 16.7% patients in the S group and the G group, respectively. The proinsulin/insulin (P/I) ratio was significantly increased in the G group, whereas it tended to decrease in the S group. After 24 weeks of treatment, no significant difference was observed in the P/I ratio between the two groups, whereas a significant difference was noted in the ΔP/I (amount of change). Albuminuria tended to increase in the G group compared with the S group.ConclusionThe results of the present study suggested that sitagliptin effectively lowered hyperglycemia and that it may have a protective effect on pancreatic beta-cells when combined with a low dose of glimepiride. Therefore, sitagliptin may represent a useful combination therapy with low-dose sulfonylurea, not only for achieving glycemic control but also for protection of pancreatic beta-cells.

An 8-week diet high in cereal fiber and coffee but free of red meat does not improve beta-cell function in patients with type 2 diabetes mellitus: a randomized controlled trial

BackgroundHigher dietary intake of fibers and coffee, but lower red meat intake is associated with reduced risk for type 2 diabetes in epidemiological studies. We hypothesized that a calorie-restricted diet, which is high in fiber and coffee, but free of red meat, improves beta-cell function in patients with T2D.MethodsIn a randomized parallel-group pilot trial, obese type 2 diabetes patients were randomly allocated to consume either a diet high in cereal fiber and coffee, but free of red meat (n = 17) (L-RISK) or a diet low in fiber, free of coffee but high in red meat (n = 20) (H-RISK) for 8 weeks. Insulin secretion was assessed from glucagon stimulation tests (GST) and mixed-meal tolerance tests (MMTT) before and after dietary intervention.ResultsBoth diets resulted in comparable reduction of fasting concentrations of insulin (H-RISK -28% vs. L-RISK -32%, bothp < 0.01), C-peptide (H-RISK -26% vs. L-RISK -30%, bothp < 0.01) and blood glucose (H-RISK -6.8%, p < 0.05 vs. L-RISK -10%, p < 0.01). Gastric inhibitory peptide (GIP) secretion increased by 24% after 8 weeks in the L-RISK only (p < 0.01). However, GST and MMTT showed no differences in insulin secretion after intervention.ConclusionsCalorie restriction independent of the intake of fiber, coffee or meat failed to improve beta-cell function, but improved GIP secretion in obese patients with type 2 diabetes.Trial registrationRegistration at Clinicaltrials.gov, Identifier number: NCT01409330, Registered 4 August 2011 – Retrospectively registered.

The suppression of TXNIP and miR-200c improve beta-cell function in patients with Type 2 diabetes: A randomized, double-blind, placebo-controlled trial

The past decade has witnessed for high prevalence of various metabolic, lifestyle, and diet-related maladies such as diabetes. Currently, one of the new treatment methods and approaches for controlling chronic degenerative diseases such as diabetes is dissecting the disease’s molecular mechanisms. The aim of this study was to evaluate the beneficial effects of sodium butyrate and inulin supplementation on the beta-cell function and inflammatory responses through molecule-based mechanisms in patients with Type 2 diabetes.In this clinical trial, 60 patients with Type 2 diabetes were recruited from the north-western part of Iran. The participants were allocated to one of the four treatment orders. Group A took six capsules of 100 mg of NaBut daily, group B took 10 g of HP inulin supplement powder daily, group C consumed both the supplements, and group D took placebo. Before and after the intervention, we assessed the thioredoxin-interacting protein (TXNIP), interleukin-6, and interleukin-10 mRNA expression, as well as noting the plasmatic levels of the miR-204, miR-200c, and miR-21. A homeostasis model assessment of beta-cells (HOMA-β) was used to evaluate the function of the pancreatic beta-cells. The results showed that TXNIP expression was over three times higher in the placebo group as compared to the butyrate + inulin group (p = 0.045). Furthermore, the plasmatic levels of miR-200c expression decreased in the groups A (butyrate) and C (butyrate + inulin) (p < 0.001), as opposed to its constant level in the placebo. Interestingly, IL-6 mRNA expression decreased after butyrate (p < 0.001) and butyrate + inulin supplementation (p < 0.001). Our results revealed new insights into how TXNIP functions have a role in controlling diabetes. The newly identified TXNIP-miR-200c-IL-6-beta-cell function pathway may contribute to diabetes progression. Inhibiting TXNIP and miR-200c activity may be a potential pharmacological target to promote beta-cell function.

Effects of Dulaglutide and Trelagliptin on Beta-Cell Function in Patients with Type 2 Diabetes—The DUET-Beta Study

Some studies of glucagon-like peptide 1 receptor agonists (GLP-1-RA) and dipeptidyl peptidase-4 inhibitors (DPP-4-I) have shown positive effects on beta-cells. A direct comparison between weekly GLP-1-RA: dulaglutide (Dula) and weekly DPP-4-I: trelagliptin (Trela) effects on beta-cell function has not yet been performed. We compared the effects of Dula and Trela on beta-cell function in type 2 diabetes (T2D) patients in an open-label, parallel-group, randomized controlled trial. Patients received Dula 0.75 mg/week or Trela 100 mg/week for 24 weeks. Beta-cell function was assessed using a glucagon stimulation test (GST)-based disposition index (DI = area under the curve of C-peptide during 6 min GST ÷ HOMA2-IR). The primary endpoint was the difference between the two groups in the change in DI over the 24-week treatment period. Body composition was assessed using the bioelectrical impedance method. Fifty metformin ± basal insulin-treated patients with T2D were randomized to Dula or Trela. Forty-eight patients completed 24 weeks of weekly administration of Dula (n = 23) or Trela (n = 25). The change in DI during 24 weeks was not different between the groups (Dula: +0.34 ± 0.49, Trela: +0.57 ± 0.47, p = 0.74). However, the change in HOMA2-%β was higher in the Dula group than in the Trela group (Dula: +50.6 ± 9.9% vs. Trela: +7.5 ± 9.5%, p = 0.003). HbA1c decreased to a greater extent in the Dula group (Dula: -0.77 ± 0.07%, Trela: -0.57 ± 0.07%, p = 0.04). Body weight reduced more in the Dula group than the Trela group (Dula: -1.4 ± 0.3 kg vs. Trela: -0.3 ± 0.3 kg, p = 0.02). Body fat mass reduced more in the Dula group than the Trela group (Dula: -1.2 ± 0.3 kg vs. Trela: -0.3 ± 0.2 kg, p = 0.02). Dula did not reduce skeletal muscle mass (-0.2 ± 0.1 kg, p = 0.31). In conclusion, the effects of Dula and Trela on beta-cell function were not different in GST-based DI. However, Dula increased the HOMA2-%β level more than Trela. Dula reduced body fat mass without causing skeletal muscle mass loss. Disclosure Y. Kondo: None. S. Satoh: None. Y. Terauchi: Research Support; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K.. Advisory Panel; Self; MSD K.K.. Research Support; Self; Ono Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Advisory Panel; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Shionogi &amp; Co., Ltd.. Speaker's Bureau; Self; Shionogi &amp; Co., Ltd., Bayer Yakuhin, Ltd., Astellas Pharma US, Inc., AstraZeneca. Advisory Panel; Self; AstraZeneca, Teijin Pharma Limited.

Sequential Treatment Escalation with Dapagliflozin and Saxagliptin Improves Beta Cell Function in Type 2 Diabetic Patients on Previous Metformin Treatment: An Exploratory Mechanistic Study.

We investigated the effect of sequential treatment escalation with dapagliflozin and saxagliptin on beta cell function in patients with T2DM insufficiently controlled on metformin monotherapy during a hyperglycaemic clamp investigation. Twenty-six patients (19 males, age 63.5±7.0 years; duration of diabetes 8.8±4.7 years; HbA1c 63.9±15.8 mmol/mol; mean±SD) were enrolled in the study. During a first treatment period (TP1) all patients received 10 mg dapagliflozin for one month, followed by the addition of 5 mg saxagliptin or placebo for another month (TP2). At baseline and at the end of each treatment period, fasting glucose and insulin levels were analysed, and a hyperglycaemic clamp with the measurement of plasma C-peptide, insulin, proinsulin, and glucagon was performed. Treatment with dapagliflozin reduced fasting glucose levels and insulin resistance (TP1). Within the hyperglycaemic clamp, C-peptide and insulin concentrations increased after the addition of dapagliflozin in TP1 (0.48±0.45 nmol*h/l; 6.24±17.9 mU*h/l) and further improved after the addition of saxagliptin in TP2 (0.38±0.34 nmol*h/l; 6.59±10.15 mU*h/l). Acute insulin response did not change after the addition of dapagliflozin (TP1), but significantly improved after the addition of saxagliptin in TP2 (0.89±0.76 mU*h/l). Both drugs improved the C-peptide/proinsulin ratio. After the addition of saxagliptin, the glucagon/insulin ratio significantly declined (TP2). Treatment escalation with dapagliflozin and saxagliptin exhibit additive effects on beta cell capacity, and improves alpha and beta cell integrity.

Study of Beta Cell Function in Patients of Diabetes and It’s Association with Prevalence of NAFLD

Study of Beta Cell Function in Patients of Diabetes and It’s Association with Prevalence of NAFLD

Comparison of Insulin Resistance and Beta Cell Function in Patients With Type 3c (Pancreatogenic) and Type 2 Diabetes Mellitus Using Homeostatic Model Assessment (HOMA): 2017 Presidential Poster Award

Introduction: Diabetes mellitus (DM) resulting from chronic pancreatitis(CP) and pancreatic ductal adenocarcinoma (PDAC) is classified by the American Diabetes Association as a form of pancreatogenic DM, which has also been referred to as type 3c DM.However, there are no data on the comparison of insulin resistance(IR) and β-cell function(BCF) among patients with Type 3c versus Type 2 DM(T2DM). Also,new-onset DM (< 2 yrs from diagnosis) resulting from PDAC(PDAC-NOD) may have a distinct pathophysiology from CP-DM.The Homeostatic Model Assessment (HOMA) estimates IR and BCF using fasting serum glucose and insulin values. Using HOMA,we aimed to distinguish:a) Type 3c DM from T2DM,b) Among CP-DM,PDAC-DM and T2DM, and c)between PDAC-NOD and new-onset T2DM(Type2NOD). Methods: A total of 265 patients with PDAC,112 with CP and 118 controls seen at our center between 1996 and 2011 had fasting levels of glucose,insulin and c-peptide measured as part of other studies. Patients with unknown glycemic status, impaired fasting glucose,no DM and those on insulin were excluded. Overall, 90 patients with PDAC-DM, 24 with CP-DM and 46 with T2DM were included in the final analysis. IR and BCF were measured using standard formulae for HOMA. Results: Mean age of CP patients(53.35 years) was lower than that of PDAC(66.22 years) and T2DM (66.10 years) respectively (P<0.0001*).Patients with T2DM had higher BMI(29.24 kg/m2) vs CP(24.52 kg/m2) and PDAC (26.28 kg/m2) respectively; P<0.0001*. Among patients with Type3c and T2DM, while there was no difference in age- and BMI-adjusted mean HOMA-IR(4.00 vs 6.21 respectively, P=0.5051), HOMA-BCF was lower in patients with Type3cDM(45.09% vs 73.90% respectively, P=0.0356*).No differences were observed in age and BMI- adjusted HOMA-IR and HOMA-BCF between PDAC-DM,CP-DM and T2DM(Table 1).Notably,patients with PDAC-NOD(n=41) had lower age- and BMI-adjusted HOMA-BCF as compared to those with Type 2 NOD(n=39)(43.89% vs 74.61%; P=0.0163*),with similar HOMA-IR (3.86 vs 6.34; P=0.1388).Table: Table. Comparison of Mean Glucose, C-peptide, Insulin, HOMA-IR and HOMA-BCF values between patients with PDAC-DM, CP-DM and Type 2 DMConclusion: IR and BCF are similar in CP-DM,PDAC-DM and T2DM.However,lower HOMA-BCF in patients with Type 3c DM and PDAC-NOD might suggest a significant role of β-cell dysfunction in their pathogenesis, as opposed to T2DM which is driven primarily by insulin resistance, with β-cell dysfunction at later stages.Identification of biomarkers responsible for these differences might allow for earlier detection of PDAC by distinguishing PDAC-NOD from Type 2NOD and other forms of Type 3c DM.