Association of soluble apoptotic biomarkers (FAS,TNFR1 and TRAIL-R2) with β-cell dysfunction in early glucose dysregulation

Several surrogate estimates have been used to define relationships between insulin action and pancreatic β-cell function in healthy individuals. Because it is unclear how conclusions about insulin secretory function depend on specific estimates used, we evaluated the effect of different approaches to measurement of insulin action and secretion on observations of pancreatic β-cell function in individuals whose fasting plasma glucose (FPG) was <7.0 mmol/L (126 mg/dL). We determined 2 indices of insulin secretion [homeostasis model assessment of β-cell function (HOMA-β) and daylong insulin response to mixed meals], insulin action [homeostasis model assessment of insulin resistance (HOMA-IR) and steady-state plasma glucose (SSPG) concentration during the insulin suppression test], and degree of glycemia [fasting plasma glucose (FPG) and daylong glucose response to mixed meals] in 285 individuals with FPG <7.0 mmol/L. We compared the relationship between the 2 measures of insulin secretion as a function of the measures of insulin action and degree of glycemia. Assessment of insulin secretion varied dramatically as a function of which of the 2 methods was used and which measure of insulin resistance or glycemia served as the independent variable. For example, the correlation between insulin secretion (HOMA-β) and insulin resistance varied from an r value of 0.74 (when HOMA-IR was used) to 0.22 (when SSPG concentration was used). Conclusions about β-cell function in nondiabetic individuals depend on the measurements used to assess insulin action and insulin secretion. Viewing estimates of insulin secretion in relationship to measures of insulin resistance and/or degree of glycemia does not mean that an unequivocal measure of pancreatic β-cell function has been obtained.

Journal of Diabetes NEWS

How Basal Insulin Analogs Have Changed Diabetes Care

Introduction: To assess the changes in glycemic control after initiating or switching to a basal insulin analogue in patients with diabetes mellitus. Methods: A retrospective, observational analysis was conducted using electronic data from a Hong Kong regional hospital. Data from adult patients with type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively) who had been prescribed with basal insulin glargine in 2008-2010, with recorded HbA1c levels at the time of initiation, at 6 and 12 months thereafter, were analysed. Results: Data from 106 eligible patients were analysed. Substantial reduction in HbA1c and fasting sugar levels were reported in both T1DM (Δ HbA1c = 1.5%, Δ FBG = 1.3 mmol/L p < 0.05) and T2DM (Δ HbA1c = 1.2%, Δ FBG = 2.9 mmol/L p < 0.05) patients after 12 months of therapy. A total of 42% of T1DM and 26% of T2DM patients achieved HbA1c levels < 7.0%. After adjustment, T2DM patients who were insulin naive achieved a statistically greater HbA1c reduction (Δ = 1.7%) than those who previous treated with premixed or basal bolus insulin (Δ = 0.3%) (p < 0.05). Percentage of patients experiencing hypoglycaemia reduced from 69% to 62% in T1DM but increased from 26% to 36% in T2DM patients. All hypoglycaemic episodes recorded were either asymptomatic or mild and self-limiting. Only 4% of the patients discontinued treatment at the end of 12 months. Conclusions: In real life clinical practice, a single daily basal insulin analogue therapy provided effective glycemic control with an acceptable risk of mild hypoglycaemia.

Background/Objective: Individuals with a family history of type 1 diabetes mellitus (T1D) are at increased genetic risk for T1D. Previous studies identified the presence of β-cell dysfunction before clinical onset and diagnosis of T1D. However, it is unclear if β-cell dysfunction predates islet autoimmunity in individuals at high genetic risk. Our objective was to test β-cell function in islet antibody negative adults who have a first-degree relative with T1D. We hypothesized that individuals at genetic risk for T1D would exhibit β-cell dysfunction even without detectable islet autoimmunity.Methods: We used ordinary one-way and Brown-Forsythe ANOVA to compare the repeated mixed meal tolerance test (MMTT) and hyperglycemic clamp glucose-stimulated β-cell response and function measures between three groups of individuals: normoglycemic adults without T1D family history age, sex, and BMI-matched islet antibody negative first-degree relatives of individuals with T1D, and islet antibody positive first-degree relatives of individuals with T1D.Results: Neither the MMTT first-phase insulin secretion measures (c-peptide0-15 minutes, c-peptide0-30 minutes, insulin0-15 minutes, insulin0-30 minutes), nor second-phase measures (c-peptide0-120 minutes, insulin0-120 minutes, and glucose0-120 minutes) showed a statistically significant difference between groups. The clamp acute c-peptide response to glucose, insulin sensitivity, c-peptide steady state, first-phase β-cell function, and second-phase β-cell function were similar between subject groups in both visits. Fasting proinsulin:c-peptide ratios, a biomarker of β-cell stress, were also similar between participant groups.Conclusion and Impact: Our data suggest that genetically at-risk autoantibody negative adult relatives of individuals with T1D do not demonstrate β-cell dysfunction compared to controls. Studies show that β-cell ER dysfunction preceding T1D onset is more striking in younger children. Thus, our findings may reflect the use of an adult study population. Alternatively, β-cell dysfunction in T1D may require initial autoimmune activation. This study will contribute to the growing understanding of risk factors contributing to T1D development.This project was funded, in part, with support from the Research Training Program in Diabetes and Obesity funded, in part by grant 3T32DK064466 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding also provided by JDRF grant 2-SRA-2017-498-M-B.

IntroductionPatients with type 2 diabetes mellitus (T2DM) who cannot achieve normal glycosylated hemoglobin (HbA1c) levels are sometimes given the combined therapeutic regimen of polyethylene glycol loxenatide (PEG-Loxe) + basal insulin. The aim of this study was to investigate the efficacy and safety of PEG-Loxe combined with basal insulin in patients with T2DM.MethodsThis retrospective, real-world study included patients with T2DM aged ≥ 18 years for whom basal insulin therapy was ineffective, whose HbA1c levels were between 7.0% and 11.0%, and who were on either continued basal insulin dose adjustment or who had received PEG-Loxe + basal insulin combined therapy for at least 24 weeks. The primary endpoint was change in HbA1c level after 24 weeks treatment. Secondary endpoints included HbA1c achievement target rate, change in fasting plasma glucose and body weight, respectively, and change in HbA1c stratified by sex, age, disease duration, and baseline HbA1c level.ResultsOverall, 307 patients were identified. After propensity score matching, 44 patients each were included in the basal insulin and PEG-Loxe + basal insulin group. After 24 weeks, a significant difference in Hb1Ac reduction between the groups (P = 0.003) was observed. Also, patients treated with PEG-Loxe + basal insulin combined therapy experienced greater body weight reduction compared those treated with basal insulin only (intergroup difference: − 3.2 kg; 95% confidence interval [95% CI] − 5.4, − 1.0]; P = 0.005). There was a significant intergroup difference in weight reduction in patients with body mass index ≥ 28 kg/m2 (− 8.4 kg; 95% CI − 13.9, − 3.0; P = 0.004). HbA1c levels in female patients aged < 65 years with HbA1c ≥ 8.5% and with a disease duration ≥ 10 years were significantly different between the two treatment groups (P < 0.005). Hypoglycemic events occurred in 10.4% of patients treated with PEG-Loxe + basal insulin with no cases of level 3 hypoglycemia.ConclusionPEG-Loxe + basal insulin combined therapy was safe and effective in patients with T2DM who did not achieve optimal glycemic control with insulin therapy alone.Trial RegistrationClinicalTrials.gov identifier: ChiCTR2400086699.

We investigated whether glucotoxicity of β-cell function could be eliminated after medical nutrition therapy (MNT) without forced correction of hyperglycemia by anti-diabetic medications including exogenous insulin administration. We analyzed newly diagnosed type 2 diabetic outpatients with hemoglobin A1c (HbA1c) of 10.1 ± 1.5%, who were treated by MNT at least for three months, without any aid of anti-diabetic medications. The β-cell function was calculated as the product of the ΔIns0-120/ΔGlu0-120 and the Matsuda index, where ΔIns0-120/ΔGlu0-120 represents the ratio of the incremental concentrations of insulin to those of glucose during the 0- to 120-min time periods under a 75-g oral glucose tolerance test. After MNT, HbA1c levels were reduced to 7.0 ± 1.0% (p < 0.001). The β-cell function was significantly improved (n = 13; p = 0.001; effect size d = 1.9). Fasting plasma glucose became below 7.0 mmol/l in 57% (8/13), and 120-minute plasma glucose became below 11.1 mmol/l in 43% (6/13). The β-cell function after MNT was significantly correlated with HbA1c levels achieved after MNT (Pearson's correlation coefficient r = -0.62, p = 0.025). In conclusion, the β-cell dysfunction was ameliorated after MNT without glucose-lowering pharmacotherapy in newly diagnosed type 2 diabetic outpatients who presented extreme hyperglycemia.

To evaluate the diagnostic value of glycosylated hemoglobin A1c (HbA1c) and glycated albumin(GA) in hyperglycemia patients with liver cirrhosis (LCH). One hundred LCH patients were divided into anemia and no-anemia group by Hb 110 g/L. The no-anemia group was further divided into low albumin (serum albumin <30 g/L), and high albumin group (serum albumin 30-<40 g/L). One hundred type 2 diabetes without liver cirrhosis were included as control group (T2DM). HbA1c, GA, fasting plasma glucose (FPG), postprandial 2h plasma glucose (2hPG) were collected for statistical analysis. (1) The HbA1c level in LCH with anemia tended lower than that in T2DM subjects [(6.76 ± 2.20)% vs (7.34 ± 1.23)%, P=0.06]; though the level of GA [(19.10 ± 7.47)% vs (16.68 ± 2.90)%, P<0.01] and 2hPG [(12.09 ± 3.39) mmol/L vs (10.84 ± 2.95) mmol/L, P<0.05] were significantly higher than that in T2DM group. (2) No-anemia subjects in LCH group with albumin <30 g/L had obviously higher GA levels than those with albumin 30-<40 g/L and T2DM (albumin ≥ 40 g/L) [(18.79 ± 2.28)% vs (16.71 ± 2.42)% and (16.73 ± 2.96)%, P<0.01]; though the level of HbA1c of three groups above has no significant difference. (3) The level of HbA1c between LCH without anemia group and T2DM group had no significant difference (P>0.05); and the level of GA between LCH without anemia group with albumin 30-<40 g/L and T2DM group had no significant difference (P>0.05). (4) The HbA1c has a positive correlation with FPG and 2hPG in LCH (FPG:r=0.45, P<0.001; 2hPG:r=0.33, P=0.001) and T2DM subjects (FPG: r=0.76, P<0.001; 2hPG: r=0.81, P<0.001). GA also has a positive correlation with FPG and 2hPG in LCH (FPG: r=0.48, P<0.001; 2hPG: r=0.39, P<0.001) and T2DM subjects (FPG: r=0.74, P<0.001; 2hPG: r=0.76, P<0.001). It is unfavorable to use HbA1c to evaluate the blood glucose level in liver cirrhosis patients with Hb<110 g/L and to use GA in patients with serum albumin <30 g/L.

To explore the efficacies of liraglutide and glargine in type 2 diabetes patients with malignant tumors treated with glucocorticoids. Overall, 120 patients were recruited, 60 patients were divided into the glargine group (chemotherapy with glucocorticoids and hypoglycemic therapy including glargine) and 60 patients were divided into the liraglutide group (chemotherapy with glucocorticoids and hypoglycemic therapy including liraglutide). Fasting plasma glucose, 2 h postprandial plasma glucose, glycosylated hemoglobin, body mass index, systolic blood pressure, diastolic blood pressure, C peptide, insulin resistance index, insulin secretion index, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, Karnofsky performance status score, rehospitalization rate, average hospitalization days and adverse reactions before and after intervention were compared between the two groups. After treatment, total cholesterol, highdensity lipoprotein, C peptide, systolic blood pressure, diastolic blood pressure and homeostatic model assessment of insulin resistance were not significantly different between the groups. The body mass index, fasting plasma glucose, 2 h postprandial plasma glucose, glycosylated hemoglobin test (A1c) and homeostasis model assessment of beta cell function were significantly lower in the glargine group than the liraglutide group (p<0.05). The hypoglycemia rate was lower in the liraglutide group than the glargine group (p<0.05). The Karnofsky performance status score was increased (p<0.05) and the rehospitalization rate and average hospitalization days (p<0.05) were decreased in the liraglutide group. Pearson and linear regression analyses indicated that liraglutide treatment was associated with better glucose control, a better homeostasis model assessment of beta cell function, hypoglycemia rate and Karnofsky performance status score and reduced rehospitalization rate and average hospitalization days. Liraglutide treatment significantly improved glucose control, homeostasis model assessment of beta cell function and the hypoglycemia rate and Karnofsky performance status score and reduced the rehospitalization rate and average hospitalization days of type 2 diabetes patients with malignant tumors treated with glucocorticoids.

The aim of the present 24-week multicentre randomized non-inferiority trial was to compare the efficacy and safety of two insulin intensification strategies in uncontrolled type 2 diabetes despite optimized basal insulin therapy. Patients with fasting plasma glucose (FPG) <130 mg/dL and HbA1c 7.0%-10.0% while on insulin glargine were randomized to a basal-prandial group (stepwise addition of insulin glulisine) or a premixed insulin group (insulin aspart/insulin aspart protamine 30/70 starting with 6 IU twice daily). The primary endpoint was the change in HbA1c after 24 weeks (non-inferiority margin 0.4%). At Week 24, the adjusted mean change from baseline HbA1c was -0.94 ± 0.09% and -1.04 ± 0.09% in basal-prandial and premixed insulin groups, respectively, with a mean difference of -0.09% (95% confidence interval [CI] -0.35, 0.16). A lower rate of hypoglycemia with a similar reduction in HbA1c was observed during stabilization of the total daily insulin dose in the premixed insulin group (Weeks 0-12). After stabilization of the total daily insulin dose, the rate of hypoglycemia and the total daily insulin dose were similar in the two groups. The efficacy and safety of the two intensifying regimens were similar after stabilization of the total daily insulin dose when oral agents were maintained. Starting with a lower total daily insulin dose with a gradual change in the treatment regimen was helpful in reducing the rate of hypoglycemia during initial stabilization of the total daily insulin dose.

Background: Type 2 Diabetes Mellitus (T2DM) is a progressive metabolic disorder characterized by insulin resistance and β-cell dysfunction. C-peptide, a marker of endogenous insulin secretion, plays a crucial role in assessing β-cell function. This study evaluates the correlation between fasting and postprandial C-peptide levels with glycemic markers in T2DM patients to better understand β-cell function and its relationship with glycemic control. Methods: A cross-sectional study was conducted in the Department of Biochemistry, Patna Medical College, Bihar, India, with 86 T2DM patients. Fasting and postprandial plasma glucose, C-peptide levels, and HbA1c were measured. Correlation analysis was performed between C-peptide levels and glycemic parameters using Pearson’s correlation coefficient. Results: The mean age of participants was 52.3 ± 10.4 years, with a male-to-female ratio of 1.2:1. The mean fasting and postprandial plasma glucose levels were 152.6 ± 28.4 mg/dL and 225.7 ± 35.2 mg/dL, respectively, while the mean HbA1c was 8.3 ± 1.5%. A significant negative correlation was observed between fasting C-peptide and HbA1c (r = -0.42, p &lt; 0.001) and postprandial C-peptide and HbA1c (r = -0.48, p &lt; 0.001), indicating declining β-cell function with worsening glycemia. Conclusion: C-peptide levels negatively correlate with HbA1c and plasma glucose levels, highlighting the progressive decline in β-cell function in T2DM. These findings suggest that C-peptide assessment can serve as a valuable tool in evaluating β-cell reserve and optimizing treatment strategies. Further, longitudinal studies are warranted to explore its prognostic significance.

Objective To investigate the natural history and related factors of the pancreatic β-cell function in Chinese type 1 diabetic patients from 3C study Shantou center. Method Stimulated C-peptide levels from follow-up data of 201 individuals in 3C study Shantou subgroup starting in 2012 were used. Residual β-cell function was defined as stimulated C − peptide level ≥ 0.2 pmol/mL, on the basis of cut-points derived from the Diabetes Control and Complications Trial (DCCT). Results 36.8% of patients had residual β-cell function, and the percentage was 68.2% in newly diagnosed diabetic patients. COX regression analysis indicated that the age of diagnosis, HbA1C level, and duration were independent factors of residual β-cell function in individuals with ≤5 years duration, but in those with duration ≥5 years, only the age of diagnosis was a predictor. The pancreatic β-cell function mainly declined in the first 5 years of the duration, and the rate of decline was correlated negatively with the duration and age of diagnosis. Receiver operating characteristic (ROC) analysis indicated that the cut-off point of stimulated C-peptide was 0.615 pmol/mL in patients with <5 years duration to have 7% HbA1c. Conclusion Age at diagnosis was the strongest predictor for residual C-peptide. There was a more rapid decline of stimulated C-peptide in duration ≤5 years and younger patients. Therefore, intervention therapies of β-cells should start from the early stage, and the recommended target goal of stimulated C-peptide is 0.615 pmol/mL or above.

Introduction: Globally, 1 billion people are suffering with deficiency or insufficiency of vitamin D. Vitamin D deficiency is also associated with metabolic disorders. This study evaluates Vitamin D levels in prediabetes, T2DM patients and its correlation with HbA1c. Materials and Methods: This study was done in Department of Physiology in association with Department of Endocrinology, JNU Institute of Medical Sciences & Research Center, Jaipur. A total of 155 subjected were enrolled into the study. They were divided into three groups, 65 age and gender matched healthy subjects were taken as group I (controls) (HbA1c: 5.5 to 6.5 %), 45 prediabetic subjects were taken as group II (HbA1c: 6.5 to 7.5 %) and 45 T2DM subjects were taken as group III (HbA1c: >7.5%). Age of the study subjects was 45 to 65 years. Serum sample was used for the estimation of random sugar (GOD-POD method) by using ERBA chemistry analyzer, vitamin D by ELISA method, using mini VIDAS and EDTA sample for HbA1c by using BIORAD D10. Results: In this study, random blood sugar and HbA1c levels were significantly elevated in pre diabetic (group II), T2DM (group III) subjects compared with controls (group I). Significant reduction was observed in prediabetic, T2DM subjects compared to controls in respect to vitamin D levels. Negative correlation was observed between HbA1c and vitamin D. Conclusion: In conclusion, the results of this study showed, significant reduction and negative correlation between serum vitamin D levels and HbA1c in prediabetic and T2DM patients. This study results indicates that there may be need to screen pre diabetic and T2DM patients with poor glycemic control for Vitamin D status. Keywords: Glycated hemoglobin, Glycemic control, T2DM, Vitamin D deficiency.

Objective To investigate the association between sleep disorder and islet α-cell and βcell function in patients with type 2 diabetes. Methods Four hundred and forty patients with type 2 diabetes treated from July 2011 to July 2013 were divided into two groups according to Pittsburgh Sleep Quality Index(PSQI): patients without sleep disorder and patients with sleep disorder. The blood glucose and glycated hemoglobin A1c(HbA1c) was detected in the two groups. Oral glucose tolerance test(OGTT), insulin releasing test and glucagon releasing test were performed to investigate the differences of the β-cell function, glucagon and glucagon/insulin ratio between groups after fasting and glucose-load. The correlation and regression analysis were performed between PSQI and other indicators. Results The level of HbA1c, fasting plasma glucose, fasting plasma insulin and HOMA-IR were significantly higher in patients with sleep disorder compared to those in patients without sleep disorder(8.6%±2.4% vs 7.5%±1.9%, (8.5±2.1) vs (6.7±1.3) mmol/L, (14.4±4.4) vs (12.9±4.6) mU/L, 5.2±1.0 vs 3.8±1.0, t=5.358, 11.085, 3.578,14.448, all P< 0.05). Insulin sensitivity index(ISI) was lower in patients with sleep disorder than that in patients without sleep disorder(-4.3±0.9 vs-4.0±0.6, t=3.379, P<0.05). There was no significant differences in basal and early-phase insulin secretion between the two groups, while the insulin area under curve was higher in patients with sleep disorder than that in petients without(t=2.489, P<0.05). Blood glucagon, area under curve of glucagon and glucagon/insulin ratio were significantly higher in patients with sleep disorder than those in patients without(t=2.047-8.131, P<0.05). Multiple stepwise regression analysis showed that PSQI score was positively related to glucagon/insulin ratio, HOMA-IR and age(β =0.244,0.281,0.307, all P<0.05), and negatively related to ISI (β =-0.105, P<0.05). Conclusions Sleep disorder is associated with the dysfunction of islet α-cells and β-cells. Improving sleep disorder may help to reduce thedawn phenomenonand optimize glycemic control. Key words: Diabetes mellitus, type 2; Sleep disorders; Islet α-cell; Islet β-cell

OBJECTIVE—Insulin resistance, associated with increased lipolysis, results in a high exposure of nonadipose tissue to lipids. Experimental data indicate that fatty infiltration of pancreatic islets may also contribute to β-cell dysfunction, but whether this occurs in humans in vivo is unknown. RESEARCH DESIGN AND METHODS—Using proton magnetic resonance spectroscopy and oral glucose tolerance tests, we studied the association of pancreatic lipid accumulation in vivo and various aspects of β-cell function in 12 insulin-naive type 2 diabetic and 24 age- and BMI-matched nondiabetic men. RESULTS—Patients versus control subjects had higher A1C, fasting plasma glucose, and insulin and triglyceride levels and lower HDL cholesterol, but similar waist circumference. Median (interquartile range) pancreatic fat content in patients and control subjects was 20.4% (13.4–43.6) and 9.7% (7.0–20.2), respectively (P = 0.032). Pancreatic fat correlated negatively with β-cell function parameters, including the insulinogenic index adjusted for insulin resistance, early glucose-stimulated insulin secretion, β-cell glucose sensitivity, and rate sensitivity (all P &amp;lt; 0.05), but not potentiation. However, these associations were significantly affected by the diabetic state, such that a significant association of pancreatic fat with β-cell dysfunction was only present in the nondiabetic group (all P &amp;lt; 0.01), suggesting that once diabetes occurs, factors additional to pancreatic fat account for further β-cell function decline. In control subjects, the association of pancreatic fat and β-cell function remained significant after correction for BMI, fasting plasma glucose, and triglycerides (P = 0.006). CONCLUSIONS—These findings indicate that pancreatic lipid content may contribute to β-cell dysfunction and possibly to the subsequent development of type 2 diabetes in susceptible humans.