Markers Of Β-cell Function Research Articles

C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes: an individual participant meta-analysis

Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent β-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of β-cell function and metabolic outcomes in new-onset type 1 diabetes. 21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA1c, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A1c, total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test. 6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA1c (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA1c. For HbA1c, IDAAC, and BETA-2 score, sample size predictions indicated that 2-3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods. Interventions that preserve β-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA1c are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials. JDRF and Diabetes UK.

Proinsulin-to-C-Peptide Ratio as a Marker of β-Cell Function in African American and European American Adults.

The primary purpose of the current study was to test the hypothesis that the proinsulin-to-C-peptide (PI-to-CP) ratio, as an index of proinsulin secretion, would be higher and associated with indices of β-cell function in African American adults relative to European American adults without type 2 diabetes. Participants were 114 African American and European American adult men and women. A 2-h oral glucose tolerance test was conducted to measure glucose, insulin, C-peptide, and proinsulin and derive indices of β-cell response to glucose. The Matsuda index was calculated as a measure of insulin sensitivity. The disposition index (DI), the product of insulin sensitivity and β-cell response, was calculated for each phase of β-cell responsivity. Pearson correlations were used to investigate the relationship of the PI-to-CP ratio with each phase of β-cell response (basal, Φb; dynamic, Φd; static, Φs; total, Φtot), disposition indices (DId, DIs, DItot), and insulin sensitivity. Multiple linear regression analysis was used to evaluate independent contributions of race, BMI, and glucose tolerance status on PI-to-CP levels before and after adjustment for insulin sensitivity. African American participants had higher fasting and 2-h PI-to-CP ratios. The fasting PI-to-CP ratio was positively associated with Φb, and the fasting PI-to-CP ratio and 2-h PI-to-CP ratio were inversely associated with DId and insulin sensitivity only in African American participants. The PI-to-CP ratio could be useful in identifying African American individuals at highest risk for β-cell dysfunction and ultimately type 2 diabetes.

715-P: Tirzepatide as Monotherapy Improved Markers of Beta-Cell Function and Insulin Sensitivity in People with Type 2 Diabetes (SURPASS-1)

Tirzepatide (TZP) , a novel dual GIP/GLP-1 receptor agonist, led to greater HbA1c, fasting serum glucose and body weight reductions vs. placebo (PBO) in people with early T2D (baseline mean T2D duration 4.7 y and 54% no prior diabetes medications) from the 40-wk SURPASS-1 trial. In a Phase 2b trial, TZP also improved β-cell function and insulin sensitivity (IS) vs. PBO and selective GLP-1 receptor agonist, dulaglutide 1.5 mg. Similarly, in SURPASS-1, TZP improved β-cell function, as indicated by a 75-80% increase in HOMA2-B, and insulin resistance, as indicated by a 2-12% decrease in fasting insulin and 8-20% decrease in HOMA2-IR. In this analysis, we aimed to explore changes in additional biomarkers of β-cell function and IS after TZP monotherapy (5, and 15 mg) . At 40 wks, proinsulin/C-peptide ratios, a marker of insulin processing, β-cell stress and β-cell function improved with decrease by 47-49% with TZP vs. -0.1% with PBO (p&amp;lt;0.001, all doses) (Table) . Fasting proinsulin decreased by 49-55% with TZP vs. no change with PBO (p&amp;lt;0.001, all doses) . Decreases in fasting C-peptide by 3-9% with TZP did not differ vs. PBO. TZP vs. PBO improved biomarkers of IS evidenced by increases in adiponectin (16-23% vs. -0.2%; p≤0.028, all doses) and IGFBP-2 (38-70% vs. 4.1%; p&amp;lt;0.001, all doses) . As a monotherapy for early T2D, TZP achieved significant improvement in markers of β-cell function and IS. Disclosure C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. H.Mao: Employee; Eli Lilly and Company. V.Thieu: None. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

662-P: Glycemic Variability Patterns Strongly Correlate with Partial Remission Status in Children with Newly Diagnosed Type 1 Diabetes

Residual β-cell secretion is commonly used as primary endpoint of β-cell mass prevention trials. Recently, peak C-peptide was challenged as a clinically relevant marker of β-cell function considering its poor integration of insulin sensitivity and β-cell glucose responsiveness. In our DIATAG study, we evaluated the correlations between metrics of glycemic variability (GV) and markers of diabetes control (i.e. A1C, insulin daily dose, insulin dose-adjusted A1C [IDAA1C]) to identify whether GV indexes may overcome residual β-cell secretion estimates (BSE) in the evaluation of glucose homeostasis during the first year of type 1 diabetes (e.g. remission period) . Data from 78 new-onset type 1 diabetes pediatric patients were collected from diabetes onset (Δ) and cross-sectionally compared using adjusted mixed-effects models at Δ+3, +12 months for BSE (n=119) and Δ+3, +6, +9, +12 months for glucose control and CGM metrics (n=169) . BSE demonstrated weak-to-moderate correlations with clinical parameters and CGM metrics (r2= 0.05-0.25; p&amp;lt;0.05) . CGM metrics strongly correlated with clinical parameters (r2 &amp;gt;0.52; p&amp;lt;0.05) and were sufficient to distinguish remitters from non-remitters (i.e. IDAA1C respectively &amp;lt;9 or ≥9) . Moreover, CGM metrics from remitters exhibited specific nycthemeral patterns characterized by increased glycemic stability (in 63-160 mg/dL range) across days in the early morning period and decreased grade II hypoglycemia during the day (p&amp;lt;0.01) . Using hierarchical clustering on 46 CGM metrics and clinical parameters (n=169) , we identified four unique glucotypes (p&amp;lt;0.001) during the first year of diabetes that allowed better segregation of intermediate values of IDAA1C from Δ+3 months (38% in Group 1, 26% in Group 2, 29% in Group 3, 7% in Group 4) . We conclude that a combination of CGM metrics and clinical parameters unraveled key clinical milestones of glucose homeostasis and remission status during the first year of type 1 diabetes. Disclosure O.G. Polle: None. A.A. Delfosse: None. M. Martin: None. I. Gies: None. M. Iebrethon: None. J. Louis: None. N. Seret: None. L. Gatto: None. Funding Fond National de la Recherche Scientifique (FRIA grant, FSR starting grant) Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED) Société Francophone du Diabète (SFD)

Exploring a Suitable Marker of Glycemic Response to Dulaglutide in Patients with Type2 Diabetes: A Retrospective Study.

IntroductionPrevious studies suggested that β-cell function markers such as fasting and postprandial serum C-peptide and C-peptide increment (FCPR, PCPR, and ΔCPR, respectively) may be useful in estimating glycemic response to glucagon-like peptide-1 receptor agonists. However, it remains elusive whether baseline glycemic control confounds these markers. Here we aimed to identify the least confounded β-cell function markers and investigate whether these markers could predict glycemic response to dulaglutide.MethodsWe evaluated FCPR, PCPR, and ΔCPR levels in patients with type 2 diabetes who initiated dulaglutide treatment after a standardized meal tolerance test (MTT). We first investigated the confounding effects of baseline HbA1c on β-cell function markers using Pearson’s correlation test. Then, we evaluated the association between each β-cell function marker and glycemic response (HbA1c change 0–6 months) to dulaglutide using generalized linear model and logistic regression analysis with adjustment for baseline HbA1c.ResultsIn 141 patients, baseline HbA1c was significantly inversely correlated with PCPR and ΔCPR (P < 0.01 for both) but not with FCPR (r = 0.02; P = 0.853), suggesting that FCPR was the marker least confounded by baseline glycemic control. Of all patients, 59 continued dulaglutide for at least 6 months without initiating any additional glucose-lowering medications. Mean ± SE HbA1c change 0–6 months was − 1.16 ± 0.17% (P < 0.001 vs. baseline). The β-cell function markers were significantly associated with HbA1c change 0–6 months in the generalized linear model. FCPR was also a significant predictor for achieving a reduction in HbA1c of at least 1% (P = 0.044) with an area under the receiver operating characteristic curve of 0.83 (sensitivity = 0.81 and specificity = 0.79).ConclusionFasting and meal-induced C-peptide levels are associated with glycemic response to dulaglutide, among which FCPR is least confounded by baseline glycemic control, suggesting its utility as a marker for glycemic response to dulaglutide.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01231-1.

Human Islet Expression Levels of Prostaglandin E2 Synthetic Enzymes, But Not Prostaglandin EP3 Receptor, Are Positively Correlated with Markers of β-Cell Function and Mass in Nondiabetic Obesity.

Elevated islet production of prostaglandin E2 (PGE2), an arachidonic acid metabolite, and expression of prostaglandin E2 receptor subtype EP3 (EP3) are well-known contributors to the β-cell dysfunction of type 2 diabetes (T2D). Yet, many of the same pathophysiological conditions exist in obesity, and little is known about how the PGE2 production and signaling pathway influences nondiabetic β-cell function. In this work, plasma arachidonic acid and PGE2 metabolite levels were quantified in a cohort of nondiabetic and T2D human subjects to identify their relationship with glycemic control, obesity, and systemic inflammation. In order to link these findings to processes happening at the islet level, cadaveric human islets were subject to gene expression and functional assays. Interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) mRNA levels, but not those of EP3, positively correlated with donor body mass index (BMI). IL-6 expression also strongly correlated with the expression of COX-2 and other PGE2 synthetic pathway genes. Insulin secretion assays using an EP3-specific antagonist confirmed functionally relevant upregulation of PGE2 production. Yet, islets from obese donors were not dysfunctional, secreting just as much insulin in basal and stimulatory conditions as those from nonobese donors as a percent of content. Islet insulin content, on the other hand, was increased with both donor BMI and islet COX-2 expression, while EP3 expression was unaffected. We conclude that upregulated islet PGE2 production may be part of the β-cell adaption response to obesity and insulin resistance that only becomes dysfunctional when both ligand and receptor are highly expressed in T2D.

687-P: ß-Cell Function and Glycemic Response to Dulaglutide in Patients with Type 2 Diabetes

Aims: The effect of β-cell function on glycemic response to dulaglutide (DU) is not fully understood in clinical settings. We explored a suitable clinical marker of β-cell function to predict glycemic response to DU in patients with type 2 diabetes (T2D). Methods: We retrospectively analyzed 141 patients who commenced once-weekly DU 0.75 mg after undergoing a meal tolerance test (MTT) with a standardized meal from September 2015 to December 2019 at our hospital. β-cell function was assessed by fasting and 2h postprandial serum C-peptide immunoreactivity (CPR) as well as increment of CPR (dCPR) in the MTT. We analyzed the suitability of each measurement as a marker for β-cell function and its association with glycemic response to DU using linear and logistic regression with adjustment for baseline HbA1c. Results: In 141 patients, 2h postprandial CPR (PCPR) and dCPR showed significant inverse correlation with baseline HbA1c (r = -0.25 and -0.33, respectively; P &amp;lt; 0.01 for both), while fasting CPR (FCPR) did not (r = 0.02; P = 0.853). Given the association of high baseline HbA1c and impairment of meal-stimulated insulin secretion measured with PCPR and dCPR, we adopted FCPR as a marker for β-cell function with less influence from baseline HbA1c in the following analysis. Of the 141 patients, 59 patients continued DU without initiating any additional glucose-lowering agents for more than 6 months. The baseline mean ± SD HbA1c, fasting plasma glucose, and FCPR of the 59 patients were 8.9 ± 1.2%, 9.2 ± 2.3 mmol/L, 0.50 ± 0.29 nmol/L, respectively. The mean ± SE change in HbA1c 0-6 months was -1.2 ± 0.2%. FCPR was significantly associated with a reduction in HbA1c (P = 0.031). Furthermore, FCPR was a significant predictor for achieving a reduction in HbA1c ≥ 1% over 6 months (OR, 1.40; 95% CI, 1.14-1.71; P = 0.039) with the area under the receiver operating characteristics curve of 0.83. Conclusions: FCPR is less affected by baseline HbA1c than PCPR and dCPR, and can be a useful marker for predicting glycemic response to DU. Disclosure M. Hasebe: None. S. Honjo: None. J. Fujikawa: None. A. Hamasaki: None. S. Yoshiji: None. Y. Iwasaki: None. S. Kimura: None. Y. Seno: None. Y. Keidai: None. T. Haraguchi: None. K. Iwasaki: None. Y. Wada: None.

Limitations of the fasting proinsulin to insulin ratio as a measure of β-cell health in people with and without impaired glucose tolerance.

The fasting proinsulin to insulin ratio is elevated in people with type 2 diabetes and has been suggested as a marker of β-cell health. However, its utility in discriminating between individuals with varying degrees of β-cell dysfunction is unclear. Proinsulin has a very different half-life to insulin and unlike insulin does not undergo hepatic extraction prior to reaching the systemic circulation. Given these limitations, we sought to examine the relationship between fasting and postprandial concentrations of β-cell polypeptides (proinsulin, insulin and C-peptide) in people with normal and impaired glucose tolerance in differing metabolic environments. Subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, free fatty acids were elevated (to induce insulin resistance) by infusion of Intralipid with heparin. Proinsulin to insulin and proinsulin to C-peptide ratios were calculated for the 0-, 30-, 60- and 240-minute time points. Insulin action (Si) and β-cell responsivity (Φ) indices were calculated using the oral minimal model. The fasting proinsulin to c-peptide or fasting proinsulin to insulin ratios did not differ between groups and did not predict subsequent β-cell responsivity to glucose during the glycerol or Intralipid study days in either group. Among nondiabetic individuals, the fasting proinsulin to insulin ratio is not a useful marker of β-cell function.

Amino acid restriction increasesβ-cell death under challenging conditions.

Malnutrition programs metabolism, favor dysfunction of β cells. We aimed to establish an in vitro protocol of malnutrition, assessing the effect of amino acid restriction upon the β cells. Insulin-producing cells INS-1E and pancreatic islets were maintained in RPMI 1640 medium containing 1× (Ctl) or 0.25× (AaR) of amino acids. We evaluated several markers of β-cell function and viability. AaR Insulin secretion was reduced, whereas cell viability was unaltered. Calcium oscillations in response to glucose increased in AaR. AaR showed lower Ins1 RNAm, snap 25, and PKC (protein kinase C) protein content, whereas phospho-eIF2α was increased. AaR cells exposed to nutrient or chemical challenges displayed higher apoptosis rates. We showed that amino acid restriction programmed β cell and induced functional changes. This model might be useful for the study of molecular mechanisms involved with β-cell programming helping to establish novel therapeutic targets to prevent harmful outcomes of malnutrition.

Ventilation inhomogeneity is associated with OGTT-derived insulin secretory defects in cystic fibrosis.

Progressive deterioration of β-cell function is the main mechanism underlying diabetes in cystic fibrosis (CF). Diabetes negatively impacts the clinical status of CF patients years before its onset. We aimed to evaluate if OGTT-derived indices of β-cell function are associated with early markers of lung disease. We carried out a cross-sectional study on 80 CF patients who performed OGTT, spirometry, and nitrogen-multiple breath washout test. β-cell glucose sensitivity and the insulinogenic indices were used as markers of β-cell function and first-phase insulin response to glucose stimulus. We used sex- and age-adjusted multiple linear regression models to estimate the association between OGTT-derived indices and lung function measures. An increment of β-cell glucose sensitivity equal to its interquartile range was associated with an increase in ppFEV1 of 7.6 points (95%CI: 0.8; 14.4) as well as with a decrease in LCI of -1.96 units (95%CI: -3.40; -0.51) and in Scond of -0.016 L-1 (95%CI: -0.026; -0.007). The corresponding figures for insulinogenic index were: 8.6 (95%CI: 3.4; 13.9) for ppFEV1 , -2.03 (95%CI: -3.13; -0.94) for LCI, and -0.014 L-1 (95%CI: -0.021; -0.071) for Scond . When adjusting also for 2-h plasma glucose, both β-cell glucose sensitivity and insulinogenic index remained inversely associated with Scond . Deterioration of β-cell function is related to early lung disease in young patients with mild to normal pulmonary function. This relationship is independent from hyperglycemia and mainly involves conductive airways.

No Correlation of Pancreatic Fat and β-Cell Function in Young Women With and Without a History of Gestational Diabetes.

Pancreatic steatosis may contribute to β-cell dysfunction in type 2 diabetes (T2D), but data are controversial. Women who had gestational diabetes mellitus (GDM) are at high risk for developing T2D. To examine the association of pancreatic fat content with early/first-phase insulin secretion (as markers of β-cell function). Cross-sectional analysis of a subcohort of the monocentric, prospective cohort study titled Prediction, Prevention, and Subclassification of Type 2 Diabetes. Ludwig Maximilians University Hospital, Munich, Germany. Ninety-seven women, 3 to 16 months after pregnancy [41 normoglycemic women post-GDM, 19 women post-GDM with pathological glucose metabolism, and 37 normoglycemic women after a normoglycemic pregnancy (controls)]. Correlation of MRI-measured pancreatic fat content with early insulin release in an oral glucose tolerance test (OGGT) [insulin increment within the first 30 minutes of the OGTT (IR30)] and first-phase insulin response (FPIR) in an intravenous glucose tolerance test (n = 65), both adjusted for insulin sensitivity index (ISI). Pancreatic fat content did not correlate with IR30 and FPIR adjusted for ISI. It correlated positively with body mass index, waist circumference, liver fat, and intraabdominal fat volume. Pancreatic fat content does not correlate with β-cell function in a cohort of young women with different degrees of T2D risk.

Altering Glucose Variability with Low- or High-Glycemic–Index Diets in Adults with Prediabetes Does Not Affect Beta-Cell Function or Markers of Oxidative Stress

High glycemic variability has been associated with increased oxidative stress and β-cell dysfunction. To test whether changes in glycemic variability impact β-cell function and oxidative stress markers in adults with prediabetes, we conducted an RCT where we provided study subjects controlled diets varying in glycemic index (GI) to experimentally manipulate post-prandial glucose excursions. After 2 weeks on a control diet (mean GI= 55-58), subjects were randomized to 1 of 3 groups for 4 weeks: low (LGI &amp;lt;35) GI diet, high (HGI &amp;gt;70) GI diet plus the anti-oxidant N-acetylcysteine (HGI/NAC) 600 mg BID or HGI diet plus placebo (HGI/PLAC). Subjects underwent CGMS (iPro), fasting markers of oxidative stress (GSH/GSSG and TBARS) and an IVGTT at the end of each diet. Independent t-test was used to test the intervention effect on the change in disposition index (DI), a marker of β-cell function. Fifty-two subjects (26M/26F, age 53±10 y, BMI 32.1±6.2 kg/m2) with IFG and/or IGT completed the study (18 LGI, 17 HGI/NAC, 17 HGI/PLAC). The 3 groups did not differ by sex, age, BMI, A1c, fasting or 2 h glucose (ANOVA). On the control diet, DI was inversely correlated with CGMS mean daily glucose (r=-0.33, p=0.02) and daily SD glucose (r=-0.31, p=0.03) and the GSH/GSSG ratio (r=-0.35, p=0.01), but not TBARS (r=0.13, p=0.4). Compared to LGI, HGI/PLAC increased mean CGMS glucose (change -1.4±1.9 LGI vs. 4.6±2.4 HGI/PLAC mg/dl, p=0.05) and SD (change -2.6±1.3 vs. 5.0±2.2, p=0.005). Results did not differ between HGI/PLAC and HGI/NAC. There were no significant intervention effects on DI, TBARS or GSH/GSSG ratio. Changes in CGMS mean glucose and SD and oxidative stress markers did not correlate with changes in DI. In conclusion, GI diet-induced changes in glucose concentrations and variability did not impact β-cell function or oxidative stress markers. These results suggest that glucose variability may be a consequence of β-cell dysfunction rather than a cause. Disclosure K. Utzschneider: Consultant; Self; Novo Nordisk Inc.. T.N. Johnson: None. K. Breymeyer: None. M.L. Neuhouser: None.

Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin on Atherosclerosis, β-Cell Function, and Glycemic Control in Japanese Patients with Type 2 Diabetes Mellitus Who are Treatment Naïve or Poorly Responsive to Antidiabetes Agents: A Multicenter, Prospective Observational, Uncontrolled Study

BackgroundSitagliptin, a dipeptidyl peptidase-4 inhibitor, is widely used in patients with type 2 diabetes. However, the pleiotropic effects of sitagliptin is not well understood. ObjectiveTo assess the clinical efficacy and safety of sitagliptin on atherosclerosis, β-cell function, and glycemic control in Japanese patients with type 2 diabetes. MethodsA prospective observational study of 270 patients with type 2 diabetes mellitus was carried out. Patients (aged 64.3 [12.4] years, body mas index 25.2 [4.3]) with glycated hemoglobin >6.9% (52 mmol/mol) or fasting plasma glucose >130 mg/dL were treated with sitagliptin for 12 months. The primary end point was glycated hemoglobin level changes from baseline to 3 months. The secondary end points included changes in several biomarkers related to inflammation and β-cell function from baseline to 3 months, as well as changes in glycated hemoglobin level from baseline to 12 months. ResultsGlycated hemoglobin levels were significantly lower in patients treated with sitagliptin for 3 months than at baseline (8.1% [1.4%]–7.3% [1.2%]) (65 [16.9]–56 [13.1] mmol/mol]) (P < 0.0001), which continued after 12 months (7.4% [1.3%]) (56 [15.2] mmol/mol) (P < 0.0001). In addition, a marker of vascular-specific inflammation, pentraxin-3, and a marker of β-cell function (proinsulin/insulin ratio), respectively, were lower after treatment with sitagliptin for 3 months than at baseline (1.88 [0.78]–1.65 [0.63] ng/mL [P = 0.0038] and 0.20 [0.14]–0.17 [0.11] [P = 0.01], respectively). On the other hand, a biomarker reflecting whole body inflammation; that is, high-sensitivity C-reactive protein level, was unchanged. Adverse events occurred in 14 patients (5.18%). ConclusionsSitagliptin may have beneficial effects on vascular inflammation and β-cell function in Japanese patients with type 2 diabetes. Pentraxin-3 may be an early predictive marker for detecting the antiatherosclerotic effects of dipeptidyl peptidase-4.

Impact of Three Oral Antidiabetic Drugs on Markers of β-Cell Function in Patients with Type 2 Diabetes: A Meta-Analysis

BackgroundThe effect of metformin, pioglitazone and sitagliptin on β-cell function in the treatment of type 2 diabetes is controversial. Therefore, we performed a systematic review and meta-analysis to obtain a better understanding in the β-cell effects of metformin, pioglitazone and sitagliptin.MethodsWe searched Pubmed and the Cochrane Center Register of Controlled Trials to identify relevant studies. Trials investigating effects of sitagliptin, metformin or pioglitazone on β-cell function were identified. The primary outcomes were homeostasis model assessment of β-cells (HOMA-β) and proinsulin/insulin ratio (PI/IR). Secondary outcome was hemoglobin A1c level. We used version 2 of the Comprehensive Meta Analysis software for all statistical analyses.ResultsMetformin monotherapy was more effective than sitagliptin in improving HOMA-β (18.01% (95% CI 11.09% to 24.94%) vs. 11.29% (95% CI 9.21% to 13.37%), P = 0.040) and more effective (−0.137 (95% CI −0.082 to −0.192)) than both sitagliptin (−0.064 (95% CI −0.036 to −0.092), P = 0.019) and pioglitazone (−0.068 (95% CI −0.044 to −0.093), P = 0.015) in decreasing PI/IR. Metformin and sitagliptin combined (40.23% (95%CI 32.30% to 48.16%)) were more effective than sitagliptin and pioglitazone (11.82% (95% CI 6.61% to 17.04%), P = 0.000) and pioglitazone and metformin(9.81% (95% CI 1.67% to 17.95%), P = 0.022) in improving HOMA-β and decreasing PI/IR (−0.177 (95% CI −0.118 to −0.237); −0.080 (95% CI −0.045 to −0.114), P = 0.007; −0.038 (95% CI, −0.005 to 0.071), P = 0.023).LimitationsThe included RCTs were of short duration (12–54 weeks). We could not determine long term effects on β-cells.ConclusionsMetformin improves β-cell function more effectively than pioglitazone or sitagliptin in type 2 diabetes patients. Metformin and sitagliptin improved HOMA-β and PI/IR more than other combinations.

Low levels of C-peptide may not be a sign of pancreatic β-cell death or apoptosis: New insight into pancreatic endocrine function and indications for metabolic surgery

Type 2 diabetes mellitus (T2 DM) is characterized by a decline in insulin secretion and increased hepatic and peripheral insulin resistance, resulting in poor glycemic control and several long-term complications [1]. C-peptide fulfills an important function in the synthesis of insulin. After cleavage of proinsulin in pancreatic β-cells, the 31-aminoacid protein C-peptide is secreted into the portal circulation in equimolar concentrations with insulin. C-peptide has been used as a surrogate marker for β-cell function in patients with type 1 and 2 diabetes mellitus [2]. Indeed, recent studies aimed at the development of new T2 DM treatment modalities have monitored the levels of C-peptide and other markers [3] with the goal of identifying severe β-cell dysfunction. In addition, fasting C-peptide levels have been used as a criterion for determining inclusion or exclusion in several T2 DM treatment protocols [4–6]. Several clinical trials have arbitrarily adopted a C-peptide level of 1 ng/dL as the threshold for protocol inclusion [6–9]. Levels below this threshold were predicted to lead to poor outcomes in patients selected for surgical treatment. In clinical practice, fasting C-peptide levels have been used as a marker of β-cell function before bariatric/metabolic procedures in T2 DM patients, and also as a prognostic factor for predicting success after metabolic surgery. Higher levels of C-peptide have been shown to indicate better outcomes, leading to the suggestion that the selection of surgical technique should be based on fasting C-peptide levels [8,10]. Unlike latent autoimmune diabetes of adulthood, in which the diabetes results from a cellular-mediated autoimmune

Research in brief

A DNA vaccine encoding proinsulin could be a potential treatment for established type 1 diabetes. Proinsulin is a target of the autoimmune response that contributes to type 1 diabetes. In a new study, 80 patients aged 18 years or older who had had type 1 diabetes for at least 5 years were injected with an engineered DNA plasmid encoding proinsulin or placebo every week for 12 weeks. After 15 weeks, the frequency of proinsulin-specific CD8+ T cells was reduced and C-peptide levels (a marker of β-cell function) were increased in patients who received the vaccine compared with those in the placebo group.

Effects of High-Protein Versus High-Carbohydrate Diets on Markers of β-Cell Function, Oxidative Stress, Lipid Peroxidation, Proinflammatory Cytokines, and Adipokines in Obese, Premenopausal Women Without Diabetes

OBJECTIVETo study the effects of high-protein versus high-carbohydrate diets on various metabolic end points (glucoregulation, oxidative stress [dichlorofluorescein], lipid peroxidation [malondialdehyde], proinflammatory cytokines [tumor necrosis factor-α and interleukin-6], adipokines, and resting energy expenditure [REE]) with high protein–low carbohydrate (HP) and high carbohydrate–low protein (HC) diets at baseline and after 6 months of dietary intervention.RESEARCH DESIGN AND METHODSWe recruited obese, premenopausal women aged 20–50 years with no diabetes or prediabetes who were randomized to HC (55% carbohydrates, 30% fat, and 15% protein) or HP (40% carbohydrates, 30% fat, and 30% protein) diets for 6 months. The diets were provided in prepackaged food, which provided 500 kcal restrictions per day. The above metabolic end points were measured with HP and HC diet at baseline and after 6 months of dietary intervention.RESULTSAfter 6 months of the HP versus HC diet (12 in each group), the following changes were significantly different by Wilcoxon rank sum test for the following parameters: dichlorofluorescein (−0.8 vs. −0.3 µmol/L, P < 0.0001), malondialdehyde (−0.4 vs. −0.2 μmol/L, P = 0.0004), C-reactive protein (−2.1 vs. −0.8 mg/L, P = 0.0003), E-selectin (−8.6 vs. −3.7 ng/mL, P = 0.0007), adiponectin (1,284 vs. 504 ng/mL, P = 0.0011), tumor necrosis factor-α (−1.8 vs. −0.9 pg/mL, P < 0.0001), IL-6 (−1.3 vs. −0.4 pg/mL, P < 0.0001), free fatty acid (−0.12 vs. 0.16 mmol/L, P = 0.0002), REE (259 vs. 26 kcal, P < 0.0001), insulin sensitivity (4 vs. 0.9, P < 0.0001), and β-cell function (7.4 vs. 2.1, P < 0.0001).CONCLUSIONSTo our knowledge, this is the first report on the significant advantages of a 6-month hypocaloric HP diet versus hypocaloric HC diet on markers of β-cell function, oxidative stress, lipid peroxidation, proinflammatory cytokines, and adipokines in normal, obese females without diabetes.

Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial

To assess the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment-naive or who had received one oral antidiabetes drug (OAD). This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ≥ 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ≥0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of -3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of β-cell function. The safety profile of linagliptin was comparable with that of placebo.

Impact of Sitagliptin on Markers of β-cell Function: A Meta-Analysis

BackgroundProgressive β-cell dysfunction and β-cell failure are fundamental pathogenic consequences of type 2 diabetes. Dipeptidyl peptidase-IV inhibitors may exhibit improvement on preclinical measures of both β-cell function, homeostasis model assessment of β-cell (HOMA-β) index, and β-cell dysfunction, proinsulin/insulin ratio (PI/IR), correlating to β-cell survival. Research Design and MethodsA systematic literature search through July 2008 was conducted to extract a consensus of randomized, controlled trials of sitagliptin therapy on measures of β-cell function. A random-effects model meta-analysis evaluated effects on HOMA-β and PI/IR versus placebo. Several subgroup analyses, including active control, were conducted. Studies were included if they met the following criteria: (1) randomized trials on sitagliptin; (2) placebo or active control; and (3) data reported on HOMA-β or PI/IR. ResultsA total of 11 trials (n=3039) reported effects on HOMA-β and 8 trials (n=2325) on PI/IR versus placebo. Four trials (n=1425) were included in the active control subgroup analysis. Sitagliptin significantly improved HOMA-β index by 12.03% [95% confidence interval (CI), 9.45-14.60] versus placebo. Sitagliptin also significantly decreased PI/IR −0.06 (95% CI, −0.08 to −0.04). Sitagliptin was inferior to active control for HOMA-β index [5.64% (95% CI, 0.38-10.90)], but not different in terms of PI/IR [0.01 (95% CI, −0.04 to 0.06)]. ConclusionsDespite significant improvement in HOMA-β index and PI/IR from placebo, there does not seem to be a benefit of dipeptidyl peptidase-IV inhibitors over other agents with respect to β-cell function/activity. Long-term prevention of β-cell dysfunction cannot be ruled out.

Insulin Response in Relation to Insulin Sensitivity

OBJECTIVEThe purpose of this study was to characterize differences in the acute insulin response to glucose (AIRg) relative to insulin sensitivity (SI) in black and white premenopausal normoglycemic South African women matched for body fatness.RESEARCH DESIGN AND METHODSCross-sectional analysis including 57 black and white South African women matched for BMI, SI, AIRg, and the disposition index (AIRg × SI) were performed using a frequently sampled intravenous glucose tolerance test with minimal model analysis, and similar measures were analyzed using an oral glucose tolerance test (OGTT). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography.RESULTSSI was significantly lower (4.4 ± 0.8 vs. 9.4 ± 0.8 and 2.9 ± 0.8 vs. 6.0 ± 0. 8 × 10−5 min−1/[pmol/l], P < 0.001) and AIRg was significantly higher (1,028 ± 255 vs. 352 ± 246 and 1,968 ± 229 vs. 469 ± 246 pmol/l, P < 0.001), despite similar body fatness (30.9 ± 1.4 vs. 29.7 ± 1.3 and 46.8 ± 1.2 vs. 44.4 ± 1.3%) in the normal-weight and obese black women compared with their white counterparts, respectively. Disposition index, a marker of β-cell function, was not different between ethnic groups (3,811 ± 538 vs. 2,966 ± 518 and 3,646 ± 485 vs. 2,353 ± 518 × 10−5 min, P = 0.10). Similar results were obtained for the OGTT-derived measures.CONCLUSIONSBlack South African women are more insulin resistant than their white counterparts but compensate by increasing their insulin response to maintain normal glucose levels, suggesting an appropriate β-cell response for the level of insulin sensitivity.