Higher Beta-cell Function Research Articles

Sex hormone-binding globulin, testosterone and type 2 diabetes risk in middle-aged African women: exploring the impact of HIV and menopause.

Sex hormone-binding globulin (SHBG) and testosterone are differentially associated with type 2 diabetes (T2D) risk. We investigated whether these associations differ by HIV and menopausal status in Black South African women living with (WLWH) and without HIV (WLWOH). Cross-sectional observational. Eighty one premenopausal (57 WLWOH, 24 WLWH) and 280 postmenopausal (236 WLWOH, 44 WLWH) women from the Middle-Aged Soweto Cohort (MASC) completed the following measures: circulating SHBG and sex hormones, body composition (dual energy x-ray absorptiometry), oral glucose tolerance test to estimate insulin sensitivity (Matsuda index), secretion (insulinogenic index, IGI) and clearance, and beta-cell function (disposition index, DI). Dysglycaemia was defined as either impaired fasting or postprandial glucose or T2D. SHBG was higher and total and free testosterone were lower in postmenopausal WLWH than WLWOH (all p≤0.023). Irrespective of HIV serostatus, SHBG was positively associated with Matsuda index, insulin clearance and DI and inversely with HOMA-IR (all p<0.011). The association between SHBG and Matsuda index was stronger in premenopausal than postmenopausal women (p=0.043 for interaction). Free testosterone (and not total testosterone) was only negatively associated with basal insulin clearance (p=0.021), and positively associated with HOMA-IR in premenopausal and not post-menopausal women (p=0.015 for interaction). We show for the first time that midlife African WLWH have higher SHBG and lower total and free testosterone than WLWOH, which corresponded to their higher beta-cell function, suggesting a putative protective effect of SHBG on T2D risk in WLWH.

Elevated risk of infection in individuals with hyperinsulinaemic type 2 diabetes: a Danish 12 year cohort study.

A better understanding of the mechanisms underlying an elevated infection risk in individuals with type 2 diabetes is needed to guide risk stratification and prevention. We investigated the risk of infection in subgroups of individuals with type 2 diabetes according to indices of insulin sensitivity and beta cell function. We classified 7265 individuals with recently diagnosed type 2 diabetes (median duration 1.4 years, IQR 0.5-2.9 years) into hyperinsulinaemic (high beta cell function [HOMA 2-beta-cell function, HOMA2-B], low insulin sensitivity [HOMA 2-insulin sensitivity, HOMA2-S]), classical (low HOMA2-B, low HOMA2-S) and insulinopenic (low HOMA2-B, high HOMA2-S) type 2 diabetes. Individuals were followed until first hospital-treated infection or first prescription for an anti-infective agent (community-treated infection). We used Cox regression analysis to estimate HRs adjusted for age, sex, index year, diabetes duration and treatment, lifestyle behaviours and comorbidities. Among study participants, 28% had hyperinsulinaemic, 63% had classical and 9% had insulinopenic type 2 diabetes. The 10 year risks of hospital-treated infections were 42.3%, 36.8% and 31.0% in the three subgroups, respectively. Compared with the insulinopenic subgroup, adjusted HRs for hospital-treated infections were elevated for hyperinsulinaemic (1.38 [95% CI 1.16, 1.65]) and classical type 2 diabetes (1.20 [95% CI 1.02, 1.42]). The 10 year risks of community-treated infections were high in all three subgroups at 91.6%, 90.1% and 88.3%, respectively, corresponding to adjusted HRs of 1.20 (95% CI 1.08, 1.33) for the hyperinsulinaemic and 1.10 (95% CI 1.00, 1.21) for the classical subgroup. Infection risk in the hyperinsulinaemic subgroup decreased substantially when further adjusted for abdominal obesity, metabolic derangements and low-grade inflammation. The risk of severe infections is clearly elevated in individuals with type 2 diabetes characterised by a higher degree of insulin resistance/hyperinsulinaemia.

12600 Predictors Of Diabetes Remission: The Impact Of Early Intervention Through A Digital Twin Platform

Abstract Disclosure: S.R. Joshi: None. M. Dharmalingam: None. A. Vadavi: None. A. Keshavamurthy: None. S. Bhonsley: None. M. Thajudeen: None. A. Balasubramanian: None. M. Panandikar: None. P. Shamanna: None. Introduction and Objective: Digital twin (DT) platform uses Artificial Intelligence (AI) and Internet of Things, to integrate multi-dimensional data for precision nutrition and health recommendations via the mobile app. We aimed to identify the pre-intervention anthropometric and biochemical parameters that predict diabetes remission (HbA1c &amp;lt; 6.5% without medications for over 3 months). Methods: 209 patients with T2D completed 540 days (18 months) of DT intervention. Results: 129 (61.7%) achieved remission of T2DM (R group). At baseline, patients in R group, compared with patients in the Non-remission Group (group NR) (n=80) had shorter duration of diabetes (yrs) (R: 2.9±2.6, 95% CI 2.5 to 3.4) vs. (NR: 4.7±2.2, 95% CI 4.2 to 5.2), p= &amp;lt;0.0001; lower baseline HbA1c % (R: 8.6±1.9, 95% CI 8.3 to 9) vs. (NR: 9.5±1.7, 95% CI 9.1 to 9.9), p=0.0008; lower estimated HbA1c (eA1C) (R: 7.6±2.2, 95% CI 7.2 to 8) vs. (NR: 8.9±2.3, 95% CI 8.4 to 9.4), p= &amp;lt;0.0001; lower glucose management indicator (GMI) % (R: 7.5±1.6, 95% CI 7.2 to 7.8) vs. (NR: 8.4±1.8, 95% CI 7.9 to 8.8), p=0.0006; ; lower Time Above Range level 1 (TAR1 %; target 180-250 mg/dl &amp;lt; 25% time) (R:21.3±17.6, 95% CI 18.2 to 24.4) vs. (NR: 31.2±17.2, 95% CI 27.3 to 35), p&amp;lt;0.0001; lower Time Above Range level 2 (TAR2 %; target &amp;gt;250 mg/dl &amp;lt; 5% time) (R: 15±24.5, 95% CI 10.8 to 19.3) vs. (NR: 24.2±26.3, 95% CI 18.2 to 29.9), p=0.01; higher Time In Range (TIR; target 70-180 mg/dl &amp;gt;70% time) (R: 59.5±31.5, 95% CI 54 to 65) vs. (NR: 43.3±30.9, 95% CI 36.4 to 50.2), p=0.0003; lower fasting plasma glucose (mg/dl) (R: 161±53.4, 95% CI 151.7 to 170.3) vs. (NR: 186.4±69.3, 95% CI 171 to 201.8), p=0.003; higher HOMA2B (%) (R: 56.6±31.7, 95% CI 51.1 to 62.1) Vs (NR: 43.6±27.5, 95% CI 37.4 to 49.6), p=0.002; and comparable fasting insulin (mIU/L) (R: 13.9±10.1, 95% CI 12.2 to 15.7) vs. (NR: 11.8±7.2, 95% CI 10.2 to 13.4), p=0.09 (ns), HOMA2IR (%) (R:1.9±0.93, 95% CI 1.8 to 2.1) vs (NR:1.8±0.84, 95% CI 1.6 to 2), p=0.33 (ns); weight (kg) (R:78.9±14.4, 95% CI 76.2 to 81.6) vs (NR:78.1±12.8, 95% CI 75.3 to 81), p=0.71 (ns). The mean baseline anti-diabetic drug count was lower in R (1.4) Vs NR (2.1). At 540 days the change was as follows: comparable Time Below Range1 - TBR1 %(&amp;lt; 70-54 mg/dl) &amp;lt; 4% (R: 3.5±14.9, 95% CI 0.92 to 6.1) Vs (NR: 1.9±8.3, 95% CI 0.07 to 3.8), p=0.38 (ns); lower HbA1c (R: 5.9±0.35, 95% CI 5.8 to 6) Vs (NR: 7.2±1.1, 95% CI 7 to 7.5), p&amp;lt;0.0001. Conclusion: Shorter diabetes duration, lower baseline HbA1c, eA1C, GMI, and TAR, higher TIR, lower fasting plasma glucose, and higher beta-cell function are key predictors of diabetes remission. Presentation: 6/3/2024

Comparison of clustering and phenotyping approaches for subclassification of type 2 diabetes and its association with remission in Indian population

Identification of novel subgroups of type 2 diabetes (T2D) has helped improve its management. Most classification techniques focus on clustering or subphenotyping but not on both. This study aimed to compare both these methods and examine the rate of T2D remission in these subgroups in the Indian population. K-means clustering (using age at onset, HbA1C, BMI, HOMA2 IR and HOMA2%B) and subphenotyping (using homeostatic model assessment (HOMA) estimates) analysis was done on the baseline data of 281 patients with recently diagnosed T2D who participated in a 1-year online diabetes management program. Cluster analysis revealed three distinct clusters: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), and mild obesity-related diabetes (MOD) while subphenotyping showed four distinct categories: hyperinsulinemic, insulinopenic, classical, and nascent T2D. Comparison of the two approaches revealed that the clusters aligned with phenotypes based on shared characteristics of insulin sensitivity (IS) and beta cell function (BCF). Clustering correctly identified individuals in nascent group (high IS and BCF) as having mild obesity related diabetes which subphenotyping did not. Post-one-year intervention, higher remission rates were observed in the MOD cluster (p = 0.383) and the nascent phenotype showing high IS and BCF (p = 0.061, Chi-Square test). In conclusion, clustering based on a comprehensive set of parameters appears to be a superior method for classifying T2D compared with pathophysiological subphenotyping. Personalized interventions may be highly effective for newly diagnosed individuals with high IS and BCF and may result in higher remission rates in these individuals. Further large-scale studies are required to validate these findings.

Interplay Between the American Diabetes Association's ABC Targets for Diabetes, Insulin Resistance Indices, and Dyslipidemia in Indian Type 2 Diabetes Patients.

Background The increasing incidence of type 2 diabetes (T2D) in India underscores the pressing need for effective management strategies. Meeting the American Diabetes Association (ADA) ABC targets for diabetes (glycated hemoglobin (HbA1c), blood pressure, and serum low-density lipoprotein cholesterol (LDL-C)) is crucial for effectively managing T2D, as it reflects the optimal control of key metabolic parameters. Insulin resistance (IR) and impaired beta cell function (BCF) have been found to have a significant impact on glycemic control, lipid metabolism, and hypertension, contributing to the complex cardiovascular risk profile of patients with T2D. This study aimed to explore the association between ABC targets for diabetes, IR, BCF, and dyslipidemia in a cross-sectional cohort of T2D patients. Methods This retrospective study examined data from 681 T2D patients with comorbid hypertension and dyslipidemia. The patients were part of a one-year online lifestyle intervention program for diabetes management at the Freedom from Diabetes Clinic in Pune, India, between January 2021 and December 2022. Baseline data (at the time of enrollment in the program) on medical history and anthropometric and biochemical parameters were retrospectively extracted from medical records and used to assess ABC targets and other clinical parameters. The ABC targets for diabetes include three goals: an HbA1c level of less than 7.0%, a blood pressure level of less than 140/90 mmHg, and an LDL-C level of less than 100 mg/dL. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Homeostatic Model Assessment of Beta Cell Function (HOMA-B), and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated using standard formulas. Results Cross-sectional analysis at baseline showed that 152 (22.3%) participants met all three ABC targets, 306 (45.0%) and 183 (26.8%) participants met two or one targets, respectively, and 40 (5.9%) did not meet any of the ABC targets. Participants meeting all three targets showed significantly lower IR, higher sensitivity (HOMA-IR, median 2.1; QUICKI, median 0.34), higher BCF (HOMA-B, median 62.9), and healthier lipid profiles (mg/dL) (total cholesterol, median 126; triglycerides, median 114; and non-high-density lipoprotein (HDL), median 84) than those who did not meet any of the ABC targets (HOMA-IR, median 3.4; QUICKI, median 0.31; HOMA-B, median 31.7; total cholesterol, median 221; triglycerides, median 187; and non-HDL, median 182) (p < 0.01). A significant association was observed between lower BMI (< 25 kg/m2), lower IR (HOMA-IR <2.5), and meeting all three ABC targets (p < 0.01). No significant association was observed between the duration of diabetes and ABC target status (p > 0.1). Lower IR was identified as a predictor of achievement of all three ABC targets (p < 0.01). Conclusion This study highlights the significance of meeting ABC targets for diabetes in relation to not only a better lipid profile but also lower IR and higher BCF. These preliminary findings provide novel insights into the interplay between IR, BCF, dyslipidemia, and meeting ABC targets in an Indian T2D population. These findings highlight the need for effective diabetes management strategies and improved patient outcomes, considering factors such as BMI and IR indices.

Determinants of sustained stabilization of beta-cell function following short-term insulin therapy in type 2 diabetes

In early type 2 diabetes, the strategy of “induction” with short-term intensive insulin therapy followed by “maintenance” with metformin can stabilize pancreatic beta-cell function in some patients but not others. We thus sought to elucidate determinants of sustained stabilization of beta-cell function. In this secondary analysis of ClinicalTrials.Gov NCT02192424, adults with ≤5-years diabetes duration were randomized to 3-weeks induction insulin therapy (glargine/lispro) followed by metformin maintenance either with or without intermittent 2-week courses of insulin every 3-months for 2-years. Sustained stabilization (higher beta-cell function at 2-years than at baseline) was achieved in 55 of 99 participants. Independent predictors of sustained stabilization were the change in beta-cell function during induction and changes in hepatic insulin resistance and alanine aminotransferase during maintenance. Thus, initial reversibility of beta-cell dysfunction during induction and subsequent preservation of hepatic insulin sensitivity during maintenance are associated with sustained stabilization of beta-cell function following short-term insulin and metformin.ClinicalTrials.Gov NCT02192424

621-P: Subphenotyping of Type 2 Diabetes Based on Pathophysiology and Its Association with Diabetes Remission in Urban Indians

Background and Aim: Sub-classification of type 2 diabetes (T2D) based on pathophysiological abnormalities is documented to facilitate better T2D management. Aim of the study was to classify 270 Indian patients with recently diagnosed T2D based on phenotype and the impact of each phenotype on the rate of remission, after a structured diabetes remission program. Methods: We retrospectively extracted and analyzed baseline data of patients with T2D (diagnosed as per WHO criteria) enrolled for a one-year diabetes management program at the Freedom from Diabetes Clinic, India. Inclusion criteria included a recent diagnosis of T2D (&amp;lt;2 years). Using the homeostatic assessment model, patients were categorized into 3 sub-phenotypes: insulinopenic (high insulin sensitivity (IS) and low beta cell function (BCF)), classical (low IS and low BCF), and hyperinsulinemic (low IS and high BCF) T2D. Post-intervention, remission was defined as maintaining HbA1c&amp;lt;48 mmol/mol without the use of glucose-lowering medications for at least 3 months. Results: Of the 270 patients, the majority were hyperinsulinemic (35.9%) followed by insulinopenic 17.4% and classical (13.3%) T2D. Additionally, a novel category of patients with both high IS and high BCF was observed (labeled ‘Unclassified’-33%). Hyperinsulinemic patients had the highest BMI (median 28 kg/m2), dyslipidemia, hypertension, and history of heart disease with the lowest remission rate (14.4%). One in four classical patients was on oral hypoglycemic agents and showed poor glycemic control but 25% remission. Unclassified patients showed the highest remission (28.1%). Conclusion: Pathophysiological sub-phenotyping could assist caregivers in better management of T2D through targeted treatment options. Remission rates were observed to be better in classical and unclassified (high insulin sensitivity and beta function) T2D. Further large-scale studies to understand the unclassified group are warranted. Disclosure P.Tripathi: Board Member; Freedom from Diabetes Clinic. A.R.Vyawahare: Research Support; Freedom From Diabetes. N.S.Kadam: Research Support; Freedom from Diabetes Clinic. B.Sharma: Research Support; Freedom From Diabetes clinic. M.H.Ganla: Employee; Freedom from Diabetes Clinic. M.Das biswas: Employee; Freedom from Diabetes Clinic. B.D.Saboo: None.

177-OR: Worsening Insulin Resistance Is Key Pathological Contributor to Dysglycemia in Lean Koreans—A Longitudinal Validation Study in the Korean Genome and Epidemiology Study (KoGES)

Insulin resistance (IR) is a modest but important pathophysiological factor in the development of type 2 diabetes (T2D) in East Asians and manageable through lifestyle intervention. The degree to which worsening insulin resistance independent of beta cell dysfunction, contributes to diabetes progression in lean Koreans is unknown. With a 10-year longitudinal study from a Korean cohort, we investigated whether worsening insulin resistance contributes to disease progression in individuals who had normal glucose tolerance at baseline (N=3700, Age=50.1±8.3 y, BMI= 24.1±2.9 kg/m2). We identified metabolic characteristics of progressors and non-progressors to prediabetes (PreDM) or T2D at baseline and 10 year-longitudinal changes in IR and BMI. To assess whether longitudinal changes of IR, independent of beta-cell function (BCF), contributed to progression, the cohort was divided into low and high BCF groups, using group median at baseline. Progressors to PreDM or T2D had weaker BCF and more insulin resistance, compared to non-progressors (Panel A) at baseline. Insulin sensitivity declined more, 30.7 vs 46.5 vs 16.7% and BMI increased in progressors to PreDM or T2D, but not in nonprogressor (Panels A and B). Conclusion: Worsening insulin resistance even for lean people is a key pathological factor to PreDM and T2D progression. Disclosure D.Kim: None. H.Kang: None. A.Sherman: None. S.T.Chung: None. S.Kim: None. J.Ha: None. J.Kim: None. M.Im: None. S.Ryang: None. W.Yi: None. M.Kim: None. Y.Kim: None. I.Kim: None. Y.Kim: None. Funding Busan Economic Promotion Agency; National Research Foundation of Korea (2022H1D3A2A01063552); Korea Health Industry Development Institute (HI18C2383); dkNET New Investigator Pilot Program in Bioinformatics; National Institute of Diabetes and Digestive and Kidney Diseases

Risk of cardiovascular events associated with pathophysiological phenotypes of type 2 diabetes.

Hyperglycaemia in type 2 diabetes is caused by varying degrees of two defects: low insulin sensitivity and beta-cell dysfunction. We assessed if subgrouping of patients into three pathophysiological phenotypes according to these defects could identify individuals with high or low risk of future cardiovascular events. This is a prospective cohort study. We assessed estimates of insulin sensitivity and beta-cell function from the homeostasis model assessment-2 in 4209 individuals with recently diagnosed type 2 diabetes enrolled from general practitioners and outpatient clinics in Denmark. Individuals were followed for a composite cardiovascular endpoint (either atherosclerotic outcomes (myocardial infarction, unstable angina pectoris, stroke, coronary or peripheral revascularization), heart failure, or cardiovascular death) and all-cause mortality. Totally 417 individuals with the insulinopenic phenotype (high insulin sensitivity and low beta-cell function) had substantially lower risk of cardiovascular events (5-year cumulative incidence: 4.6% vs 10.1%; age-/sex-adjusted hazard ratio (aHR): 0.49; 95% CI: 0.30-0.82) compared with 2685 individuals with the classical phenotype (low insulin sensitivity and low beta-cell function), driven by atherosclerotic events. Conversely, 1107 individuals with the hyperinsulinaemic phenotype (low insulin sensitivity and high beta-cell function) had more cardiovascular events (5-year cumulative incidence: 12.6%; aHR: 1.33; 95% CI: 1.05-1.69), primarily driven by increased heart failure and cardiovascular death and increased all-cause mortality. Simple phenotyping based on insulin sensitivity and beta-cell function predicts distinct future risks of cardiovascular events and death in patients with type 2 diabetes. These results suggest that precision medicine according to underlying type 2 pathophysiology potentially can reduce diabetes complications.

Dipeptidyl-Peptidase-IV Inhibitors, Imigliptin and Alogliptin, Improve Beta-Cell Function in Type 2 Diabetes

ObjectsImigliptin is a novel dipeptidyl peptidase-4 inhibitor. In the present study, we aimed to evaluate the effects of imigliptin and alogliptin on insulin resistance and beta-cell function in Chinese patients with type-2 diabetes mellitus (T2DM).MethodsA total of 37 Chinese T2DM patients were randomized to receive 25 mg imigliptin, 50 mg imigliptin, placebo, and 25 mg alogliptin (positive drug) for 13 days. Oral glucose tolerance tests were conducted at baseline and on day 13, followed by the oral minimal model (OMM).ResultsImigliptin or alogliptin treatment, compared with their baseline or placebo, was associated with higher beta-cell function parameters (φ s and φ tot) and lower glucose area under the curve (AUC) and postprandial glucose levels. The changes in the AUC for the glucose appearance rate between 0 and 120 min also showed a decrease in imigliptin or alogliptin groups. However, the insulin resistance parameter, fasting glucose, was not changed. For the homeostatic model assessment (HOMA-β and HOMA-IR) parameters or secretory units of islets in transplantation index (SUIT), no statistically significant changes were found both within treatments and between treatments.ConclusionsAfter 13 days of treatment, imigliptin and alogliptin could decrease glycemic levels by improving beta-cell function. By comparing OMM with HOMA or SUIT results, glucose stimulation might be more sensitive for detecting changes in beta-cell function.

Clinical phenotyping of newly diagnosed type 2 diabetes in Yemen

ObjectiveTo identify clinical phenotypes of type 2 diabetes (T2D) among adults presenting with a first diagnosis of diabetes.Research design and methodsA total of 500 consecutive patients were subject to clinical...

A proteomic signature that reflects pancreatic beta-cell function

AimProteomics has the potential to enhance early identification of beta-cell dysfunction, in conjunction with monitoring the various stages of type 2 diabetes onset. The most routine method of assessing pancreatic beta-cell function is an oral glucose tolerance test, however this method is time consuming and carries a participant burden. The objectives of this research were to identify protein signatures and pathways related to pancreatic beta-cell function in fasting blood samples.MethodsBeta-cell function measures were calculated for MECHE study participants who completed an oral glucose tolerance test and had proteomic data (n = 100). Information on 1,129 protein levels was obtained using the SOMAscan assay. Receiver operating characteristic curves were used to assess discriminatory ability of proteins of interest. Subsequent in vitro experiments were performed using the BRIN-BD11 pancreatic beta-cell line. Replication of findings were achieved in a second human cohort where possible.ResultsTwenty-two proteins measured by aptamer technology were significantly associated with beta-cell function/HOMA-IR while 17 proteins were significantly associated with the disposition index (p ≤ 0.01). Receiver operator characteristic curves determined the protein panels to have excellent discrimination between low and high beta-cell function. Linear regression analysis determined that beta-endorphin and IL-17F have strong associations with beta-cell function/HOMA-IR, β = 0.039 (p = 0.005) and β = -0.027 (p = 0.013) respectively. Calcineurin and CRTAM were strongly associated with the disposition index (β = 0.005 and β = 0.005 respectively, p = 0.012). In vitro experiments confirmed that IL-17F modulated insulin secretion in the BRIN-BD11 cell line, with the lower concentration of 10 ng/mL significantly increasing glucose stimulated insulin secretion (p = 0.043).ConclusionsEarly detection of compromised beta-cell function could allow for implementation of nutritional and lifestyle interventions before progression to type 2 diabetes.

Pathophysiology-based phenotyping in type 2 diabetes: A clinical classification tool.

Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the characteristics of different phenotypes among 5813 Danish patients with new clinically diagnosed type 2 diabetes. We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid-associated diabetes. We then used the homeostatic assessment model to subphenotype all remaining patients into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), or hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. Among 5813 patients diagnosed with incident type 2 diabetes in the community clinical setting, 0.4% had rare subtypes of diabetes, 2.8% had LADA, 0.7% had secondary diabetes, 2.4% had glucocorticoid-associated diabetes, and 93.7% had WHO-defined type 2 diabetes. In the latter group, 9.7% had insulinopenic, 63.1% had classical, and 27.2% had hyperinsulinemic type 2 diabetes. Classical patients were obese (median waist 105cm), and 20.5% had cardiovascular disease (CVD) at diagnosis, while insulinopenic patients were fairly lean (waist 92cm) and 17.5% had CVD (P=0.14 vs classical diabetes). Hyperinsulinemic patients were severely obese (waist 112cm), and 25.5% had CVD (P<0.0001 vs classical diabetes). Patients clinically diagnosed with type 2 diabetes are a heterogeneous group. In the future, targeted treatment based on pathophysiological characteristics rather than the current "one size fits all" approach may improve patient prognosis.

Trajectories of BMI change impact glucose and insulin metabolism

Background and aimsThe aim of this study was to examine, in a community setting, whether trajectory of weight change over twelve years is associated with glucose and insulin metabolism at twelve years. Methods and resultsParticipants were 532 community-living middle-aged and elderly adults from the Personality and Total Health (PATH) Through Life study. They spanned the full weight range (underweight/normal/overweight/obese). Latent class analysis and multivariate generalised linear models were used to investigate the association of Body Mass Index (BMI, kg/m2) trajectory over twelve years with plasma insulin (μlU/ml), plasma glucose (mmol/L), and HOMA2 insulin resistance and beta cell function at follow-up. All models were adjusted for age, gender, hypertension, pre-clinical diabetes status (normal fasting glucose or impaired fasting glucose) and physical activity. Four weight trajectories were extracted; constant normal (mean baseline BMI = 25; follow-up BMI = 25), constant high (mean baseline BMI = 36; follow-up BMI = 37), increase (mean baseline BMI = 26; follow-up BMI = 32) and decrease (mean baseline BMI = 34; follow-up BMI = 28). At any given current BMI, individuals in the constant high and increase trajectories had significantly higher plasma insulin, greater insulin resistance, and higher beta cell function than those in the constant normal trajectory. Individuals in the decrease trajectory did not differ from the constant normal trajectory. Current BMI significantly interacted with preceding BMI trajectory in its association with plasma insulin, insulin resistance, and beta cell function. ConclusionThe trajectory of preceding weight has an independent effect on blood glucose metabolism beyond body weight measured at any given point in time.

Protocol for the specialist supervised individualised multifactorial treatment of new clinically diagnosed type 2 diabetes in general practice (IDA): a prospective controlled multicentre open-label intervention study

IntroductionWe present the protocol for a multifactorial intervention study designed to test whether individualised treatment, based on pathophysiological phenotyping and individualised treatment goals, improves type 2 diabetes (T2D) outcomes.Methods and...

Relationships of pancreatic beta-cell function with microalbuminuria and glomerular filtration rate in middle-aged and elderly population without type 2 diabetes mellitus: a Chinese community-based analysis.

BackgroundRelationships of pancreatic beta-cell function abnormality with microalbuminuria (MA) and glomerular filtration rate (GFR) may differ by age, ethnicity and accompanied diseases. Previous studies were generally conducted in Western adult patients with type 2 diabetes mellitus (T2DM), and it is uncertain whether pancreatic beta-cell function is associated with MA and GFR in Chinese community-dwelling middle-aged and elderly population without T2DM. We therefore examined the relationships of pancreatic beta-cell function with two indices of renal damage, MA and GFR, in Chinese community-dwelling middle-aged and elderly population without T2DM.MethodsThis analysis focused on 380 Beijing residents older than 45 years who were free of T2DM and completed the evaluation of pancreatic beta-cell function.ResultsMedian age was 67 (49–80) years. Levels of triglyceride, diastolic blood pressure and homeostasis model assessment-beta (HOMA-beta) index were positively related to urine microalbumin (P<0.05 for all). Age, low-density lipoprotein cholesterol levels and HOMA-beta index were inversely correlated with GFR, while high-density lipoprotein cholesterol levels were positively correlated with GFR (P<0.05 for all). In all three adjustment models, there was a significant positive association between HOMA-beta index and MA; subjects with higher beta-cell function had higher odds of MA (P<0.05 for all). There was no association between HOMA-beta index and GFR <60 mL/min/1.73 m2 in any model (P>0.05 for all).ConclusionModeling the pancreatic beta-cell function with different adjusted variables provided the same conclusion of association with MA; beta-cell function was positively associated with MA. Additionally, there was a specific difference in the adjusted associations of pancreatic beta-cell function with MA and GFR <60 mL/min/1.73 m2; beta-cell function was not independently associated with GFR <60 mL/min/1.73 m2. This result indicated that abnormal pancreatic beta-cell function plays an important role in the development of MA.

Incidence and Predictive Factors of Postprandial Hyperinsulinemic Hypoglycemia After Roux-en-Y Gastric Bypass: A Five year Longitudinal Study.

Postprandial hyperinsulinemic hypoglycemia (PHH) is often reported after Roux-en-Y gastric bypass (RYGB). In the absence of a prospective study, the clinical and biological determinants of PHH remain unclear. To determine the incidence and predictive factors of PHH after RYGB. Participants were 957 RYGB patients enrolled in an ongoing longitudinal cohort study. We analyzed the results of an oral glucose tolerance test (OGTT) routinely performed before surgery and 1 and/or 5 years after. PHH was defined as blood glucose < 50 mg/dL AND plasma insulin > 3 mU/L at 120 minutes post glucose challenge. Validated indices of insulin sensitivity (Matsuda index), beta-cell function (Insulinogenic index), and beta-cell mass (fasting C-peptide: glucose ratio) were calculated, from glucose, insulin, and c-peptide values measured during OGTT. OGTT results were available in all patients at baseline, in 85.6% at 12 months and 52.8% at 60 months. The incidence of PHH was 0.5% at baseline, 9.1% * and 7.9%* at 12 months and 60 months following RYGB (*: P < 0.001). In multivariate logistic regression analysis, PHH after RYGB was independently associated with lower age (P = 0.005), greater weight loss (P = 0.031), as well as higher beta-cell function (P = 0.002) and insulin sensitivity (P < 0.001), but not with beta-cell mass (P = 0.381). A preoperative elevated beta-cell function was an independent predictor of PHH after RYGB (receiver operating characteristics curve area under the curve 0.68, P = 0.04). The incidence of PHH significantly increased after RYGB but remained stable between 1 and 5 years. The estimation of beta-cell function with an OGTT before surgery can identify patients at risk for developing PHH after RYGB.

Primary Unresponsiveness to Pioglitazone is not Related to PPAR-ϒ and is Co-activator Gene Exon SNP Markers

The objective of this prospective observational study was to assess inter-individual variations in lipid and glycemic response to pioglitazone (30 mg OD) and their predictors in newly diagnosed T2DM patients. Out of 104 patients recruited, 88 completed 12 weeks follow up and were included in the Short Research Article Mathur et al.; BJPR, 11(3): 1-9, 2016; Article no.BJPR.25480 2 final analysis. The patient characterstics studied were: BMI, W: H ratio, HbA1c, fasting and post meal glucose, lipid profile, HOMA-R, HOMAbeta and high resolution melting curve analysis (HRM) of PCR amplified DNA fragments flanking SNP markers of PPARγ and its co-activator gene. The mean decrease in HbA1c observed was 2.61% with wide inter-individual variation (coefficient of variance 66.44%, 95.75%, and 75.22% respectively for FPG, 2 hours PPG and HbA1c). Positive association between decrease in glycemic parameters and baseline HOMAβ, FPG, PPG HbA1c1 was observed. This finding suggest better glycemic response could be expected in those with higher beta cell function and severe hyperglycemia. Though lipid parameters improved significantly, they did not show any association with baseline characteristics studied as well as change in glycemic parameters. Eighteen (20.45%) patients were primary non-responder for glycemic, lipid and weight changes. This unresponsive could not be predicted on the basis of clinical and genetic parameters studied.

KCNQ1 Haplotypes Associate with Type 2 Diabetes in Malaysian Chinese Subjects

The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) and haplotypes of potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) with type 2 diabetes (T2D) in Malaysian Chinese subjects. The KCNQ1 SNPs rs2237892, rs2283228 and rs2237895 were genotyped in 300 T2D patients and 230 control subjects without diabetes and metabolic syndrome. Two logistic regression models of analysis were applied, the first adjusted for age and gender while the second adjusted for age, gender and body mass index. The additive genetic analysis showed that adjusting for body mass index (BMI) even strengthened association of rs2237892, rs2283228 and rs2237895 with T2D (OR = 2.0, P = 5.1 × 10−5; OR = 1.9, P = 5.2 × 10−5; OR = 1.9, P = 7.8 × 10−5, respectively). The haplotype TCA containing the allele of rs2237892 (T), rs2283228 (C) and rs2237895 (A) was highly protective against T2D (Second model; OR = 0.17, P = 3.7 × 10−11). The KCNQ1 rs2237892 (TT), and the protective haplotype (TCA) were associated with higher beta-cell function (HOMA-B) in normal subjects (P = 0.0002; 0.014, respectively). This study found that KCNQ1 SNPs was associated with T2D susceptibility in Malaysian Chinese subjects. In addition, certain KCNQ1 haplotypes were strongly associated with T2D.

Novel polymorphisms in the GCKR gene and their influence on glucose and insulin levels in a Danish twin population

The glucokinase regulatory protein gene is a candidate gene for Type 2 diabetes. This study reveals three new polymorphisms and examines the impact of one new and one known polymorphism on insulin secretion and parameters associated with the insulin resistance syndrome in Danish twins with different degrees of glucose tolerance. Single nucleotide polymorphism detection was performed in 20 healthy subjects and in 20 subjects with Type 2 diabetes. The effect of the polymorphisms on lipid, glucose and insulin measures was studied in 566 same-sex twins aged 55-74 years. The new nucleotide (nt) 363 polymorphism was found only in subjects with impaired glucose tolerance and Type 2 diabetes. The nt 11216 polymorphism influenced insulin measured at 120 min during an oral glucose tolerance test (OGTT). Subjects with genotype C11216C/T11216C had 21% higher insulin values (P<0.05) than subjects with genotype T11216T. In twins discordant for this genotype, the C-allele was associated with significantly higher plasma insulin levels at all time points during the OGTT, higher beta-cell function and lower plasma glucose levels during the OGTT. The C-allele of nt 11216 polymorphism was associated with increased insulin secretion, and may therefore exert a potentially protective effect against Type 2 diabetes. This remains to be shown in a larger study population.