Hyperinsulinemia promotes endothelial inflammation via increased expression and release of Angiopoietin-2.

BACKGROUND AND AIMS: Angiopoietin-2 (ANG-2) mediates endothelial inflammation to initiate atherosclerosis and angiogenesis. Here we determined the serum levels of ANG-2 in hyperinsulinemic subjects and whether insulin increases its expression and release. METHODS: Healthy male subjects were recruited from the D-CLIP and CURES studies and, based on their fasting insulin levels, were classified as normoinsulinemic (n = 228) and hyperinsulinemic (n = 32). Serum proteins were estimated by ELISA. Endothelial inflammation was scored as the number of THP-1 monocytes adhered to HUVEC monolayer. Gene expression was determined with promoter reporter assays and semi-quantitative RT-PCR. Western blotting was used to assess changes in protein expression and activation. Immunofluorescence imaging and ChIP assay were used for nuclear localization and promoter binding studies, respectively. RESULTS: ANG-2 and sTIE2 levels were higher in hyperinsulinemic subjects. Hyperinsulinemic serum elicited endothelial inflammation, which was abrogated by an ANG-2 blocker antibody. Insulin (100 nM) increased mRNA and protein expression of ANG-2, and its release from HUVECs. It induced activation of p38 MAPK and an increase in protein levels and nuclear localization of cFOS. Binding of cFOS to the -640 to -494 promoter region mediated insulin dependent ANG-2 transcription. p38 MAPK inhibitor (25 µM) blocked insulin-induced nuclear localization of cFOS, expression of ANG-2 and ICAM-1, and release of ANG-2 into the culture medium. Spent medium collected from insulin treated cells enhanced endothelial inflammation, which was lost upon ANG-2 knockdown as well as upon p38 MAPK inhibition. CONCLUSIONS: ANG-2 levels are high in hyperinsulinemic subjects and insulin induces expression and release of ANG-2 from HUVECs through p38 MAPK-cFOS pathway to elicit endothelial inflammation.

Cost-effectiveness of a Stepwise Approach vs Standard Care for Diabetes Prevention in India.

Importance: A stepwise approach that includes screening and lifestyle modification followed by the addition of metformin for individuals with high risk of diabetes is recommended to delay progression to diabetes; however, there is scant evidence regarding whether this approach is cost-effective. Objective: To estimate the cost-effectiveness of a stepwise approach in the Diabetes Community Lifestyle Improvement Program. Design, Setting, and Participants: This economic evaluation study included 578 adults with impaired glucose tolerance, impaired fasting glucose, or both. Participants were enrolled in the Diabetes Community Lifestyle Improvement Program, a randomized clinical trial with 3-year follow-up conducted at a diabetes care and research center in Chennai, India. Interventions: The intervention group underwent a 6-month lifestyle modification curriculum plus stepwise addition of metformin; the control group received standard lifestyle advice. Main Outcomes and Measures: Cost, health benefits, and incremental cost-effectiveness ratios (ICERs) were estimated from multipayer (including direct medical costs) and societal (including direct medical and nonmedical costs) perspectives. Costs and ICERs were reported in 2019 Indian rupees (INR) and purchasing power parity-adjusted international dollars (INT $). Results: The mean (SD) age of the 578 participants was 44.4 (9.3) years, and 364 (63.2%) were men. Mean (SD) body mass index was 27.9 (3.7), and the mean (SD) glycated hemoglobin level was 6.0% (0.5). Implementing lifestyle modification and metformin was associated with INR 10 549 (95% CI, INR 10 134-10 964) (INT $803 [95% CI, INT $771-834]) higher direct costs; INR 5194 (95% CI, INR 3187-INR 7201) (INT $395; 95% CI, INT $65-147) higher direct nonmedical costs, an absolute diabetes risk reduction of 10.2% (95% CI, 1.9% to 18.5%), and an incremental gain of 0.099 (95% CI, 0.018 to 0.179) quality-adjusted life-years per participant. From a multipayer perspective (including screening costs), mean ICERs were INR 1912 (INT $145) per 1 percentage point diabetes risk reduction, INR 191 090 (INT $14 539) per diabetes case prevented and/or delayed, and INR 196 960 (INT $14 986) per quality-adjusted life-year gained. In the scenario of a 50% increase or decrease in screening and intervention costs, the mean ICERs varied from INR 855 (INT $65) to INR 2968 (INT $226) per 1 percentage point diabetes risk reduction, from INR 85 495 (INT $6505) to INR 296 681 (INT $22 574) per diabetes case prevented, and from INR 88 121 (INT $6705) to INR 305 798 (INT $23 267) per quality-adjusted life-year gained. Conclusions and Relevance: The findings of this study suggest that a stepwise approach for diabetes prevention is likely to be cost-effective, even if screening costs for identifying high-risk individuals are added.

Dietary changes in a diabetes prevention intervention among people with prediabetes: the Diabetes Community Lifestyle Improvement Program trial.

AIMS: Diabetes prevention interventions have been less successful in Asian Indians compared to other populations, which may be due in part to dietary differences. The objective of this study was to determine the impact of a diabetes prevention intervention on diet and risk of diabetes in Asian Indians at high risk. METHODS: Data were included from the Diabetes Community Lifestyle Improvement Program (D-CLIP), a randomized control trial to prevent diabetes in overweight/obese Asian Indian adults (20-65 years) with prediabetes. Respondents received standard treatment (control; n = 283) or a 6-month intervention (n = 295) that included education and support to reduce intakes of fat and total calories (kilocalories; kcal). Diet was ascertained using a food frequency questionnaire, and incident diabetes was determined from annual 2-h plasma glucose post-oral glucose tolerance test or biannual fasting plasma glucose. RESULTS: There were 485 (control 240; intervention 245) respondents with complete diet data at baseline. At 6 months, the intervention was associated with decreased intake of total energy (- 185.6 kcal/day; 95% CI - 353.6, - 17.5 kcal/day) and refined cereals (- 7.2 g/1000 kcal; 95% CI - 12.7, - 1.7 g/1000 kcal), and increased intakes of fruits and vegetables (33.4 g/1000 kcal; 95% CI 16.0, 50.8 g/1000 kcal). The intervention group was half (HR 0.49; 95% CI 0.25, 0.94) as likely to develop diabetes at 1 year, and the hazard was significantly attenuated (12.2%; P = 0.015) with adjustment for fruits and vegetable intake. CONCLUSION: The D-CLIP decreased the total energy intake and increased the intakes of fruits and vegetables, and reduced the 1-year incidence of diabetes by half. TRIAL REGISTRATION: Clinicaltrails.gov # NCT01283308.

Elevated glycated hemoglobin predicts macrosomia among Asian Indian pregnant women (WINGS-9).

AIM: The aim of this study was to determine the optimal glycated hemoglobin (HbA1c) cut point for diagnosis of gestational diabetes mellitus (GDM) and to evaluate the usefulness of HbA1c as a prognostic indicator for adverse pregnancy outcomes. METHODS: HbA1c estimations were carried out in 1459 pregnant women attending antenatal care centers in urban and rural Tamil Nadu in South India. An oral glucose tolerance test was carried out using 75 g anhydrous glucose, and GDM was diagnosed using the International Association of the Diabetes and Pregnancy Study Groups criteria. RESULTS: GDM was diagnosed in 195 women. Receiver operating curves showed a HbA1c cut point of ≥ 5.0% (≥31 mmol/mol) have a sensitivity of 66.2% and specificity of 56.2% for identifying GDM (area under the curve 0.679, confidence interval [CI]: 0.655-0.703). Women with HbA1c ≥ 5.0% (≥31 mmol/mol) were significantly older and had higher body mass index, greater history of previous GDM, and a higher prevalence of macrosomia compared to women with HbA1c < 5.0% (<31 mmol/mol). The adjusted odds ratio for macrosomia in those with HbA1c ≥ 5.0% (≥31 mmol/mol) was 1.92 (CI: 1.24-2.97, P = 0.003). However, other pregnancy outcomes were not significantly different. CONCLUSION: In Asian Indian pregnant women, a HbA1c of 5.0% (31 mmol/mol) or greater is associated with increased risk of macrosomia.

Impaired glucose tolerance alters functional ability of peripheral blood-derived mononuclear cells in Asian Indian men.

AIM: To compare the adhesion, migration and endothelial differentiation potential of peripheral blood-derived mononuclear cells (PBMCs) obtained from drug-naive normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) Asian Indian men. METHODS: Based on the 75-g oral glucose tolerance test, 30 NGT and 31 IGT subjects were recruited into the study. PBMCs were isolated from fasting blood using histopaque density gradient centrifugation. Isolated PBMCs were analysed for their ability to adhere to extracellular matrices, incorporation into tubular structures formed by matured endothelial cells and differentiation into endothelial cells upon 7-day culture in endothelial-specific growth medium. RESULTS: PBMCs obtained from IGT subjects exhibit poor adherence to fibronectin and reduced incorporation into tubular structures. Migration towards stromal cell-derived factor-1α (SDF-1α) in a trans-well filter assembly was also reduced for these cells. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis revealed decreased expression of CXCR4 and ß2 integrin and increased expression of arginase II in IGT subjects. No differences were observed with regard to endothelial differentiation; however, cultured PBMCs of IGT subjects had decreased intracellular nitric oxide (NO) production. CONCLUSION: In pre-diabetic, Asian Indian men, PBMCs exhibit defective migration and homing potential.

Prevalence of overweight and obesity among school children and adolescents in Chennai.

OBJECTIVE: To determine the prevalence of overweight and obesity among children and adolescents in Chennai, India, using national and international age- and sex- specific body mass index (BMI) cut-off points. METHODS: The Obesity Reduction and Awareness and Screening of Non communicable diseases through Group Education in Children and Adolescents (ORANGE) project is a cross-sectional study carried out on 18,955 children (age 6-11 years) and adolescents (age 12-17 years) across 51 schools (31 private and 20 government) of Chennai. Overweight and obesity was classified by the International Obesity Task Force (IOTF 2000) and Khadilkars criteria (2012), and Hypertension by the IDF criteria (in children ≥10 years and adolescents). RESULTS: The prevalence of overweight/obesity was significantly higher in private compared to government schools both by the IOTF criteria [private schools: 21.4%, government schools: 3.6%, (OR: 7.4, 95% CI:6.3-8.6; P<0.001) and by Khadilkar criteria (private school: 26.4%, government schools: 4.6% OR: 6.9, 95% CI:6.2-7.8; P<0.001). Overweight/obesity was higher among girls (IOTF: 18%, Khadilkar: 21.3%) compared to boys (IOTF: 16.2%, Khadilkar: 20.7%) and higher among adolescents (IOTF: 18.1%, Khadilkar: 21.2%) compared to children (IOTF: 15.5%, Khadilkar: 20.7%). Prevalence of hypertension was 20.4% among obese/overweight and 5.2% among non-obese (OR 4.7, 95%CI: 4.2-5.3, P<0.001). CONCLUSIONS: The prevalence of overweight and obesity is high among private schools in Chennai, and hypertension is also common.