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Item Changes in insulin sensitivity over time and associated factors in HIV-infected adolescents(Lippincott, Williams & Wilkins, 2018-03-13) Geffner, Mitchell E.; Patel, Kunjal; Jacobson, Denise L.; Wu, Julia; Miller, Tracie L.; Hazra, Rohan; Gerschenson, Mariana; Sharma, Tanvi; Silio, Margarita; Jao, Jennifer; Takemoto, Jody K.; Van Dyke, Russell B.; Dimeglio, Linda A.; Pediatric HIV/AIDS Cohort Study (PHACS); Pediatrics, School of MedicineOBJECTIVE: To compare prevalence of insulin resistance between perinatally HIV-infected (PHIV+) and perinatally HIV-exposed, but uninfected adolescents (PHEU), determine incidence of and contributory factors to new and resolved cases of insulin resistance in PHIV+, and evaluate glucose metabolism. DESIGN: Cross-sectional design for comparison of prevalence among PHIV+ and PHEU. Longitudinal design for incidence and resolution of insulin resistance among PHIV+ at risk for these outcomes. METHODS: The source population was adolescents from pediatric HIV clinics in the United States and Puerto Rico participating in the Pediatric HIV/AIDS Cohort Study, an ongoing prospective cohort study designed to evaluate impact of HIV infection and its treatment on multiple domains in preadolescents and adolescents. Insulin resistance was assessed by homeostatic model assessment of insulin resistance. Those with incident insulin resistance underwent 2-h oral glucose tolerance test and HbA1c. Baseline demographic, metabolic, and HIV-specific variables were evaluated for association with incident or resolved insulin resistance. RESULTS: Unadjusted prevalence of insulin resistance in PHIV+ was 27.3 versus 34.1% in PHEU. After adjustment for Tanner stage, age, sex, and race/ethnicity, there was no significant difference between groups. Factors positively associated with developing insulin resistance included female sex, higher BMI z score, and higher waist circumference; those associated with resolving insulin resistance included male sex and lower BMI z score. CONCLUSION: Prevalence of insulin resistance in PHIV+ and PHEU was substantially higher than that reported in HIV-uninfected nonoverweight youth, but similar to that in HIV-uninfected obese youth. Factors associated with incident or resolved insulin resistance among PHIV+ were similar to those reported in HIV-negative obese youth. However, a contributory role of HIV infection and/or its treatment to the incident risk of insulin resistance cannot be excluded.Item Dysglycemia and Index60 as Prediagnostic End Points for Type 1 Diabetes Prevention Trials(American Diabetes Association, 2017-11) Nathan, Brandon M.; Boulware, David; Geyer, Susan; Atkinson, Mark A.; Colman, Peter; Goland, Robin; Russell, William; Wentworth, John M.; Wilson, Darrell M.; Evans-Molina, Carmella; Wherrett, Diane; Skyler, Jay S.; Moran, Antoinette; Sosenko, Jay M.; Type 1 Diabetes TrialNet and Diabetes Prevention Trial–Type 1 Study Groups; Medicine, School of MedicineOBJECTIVE: We assessed dysglycemia and a T1D Diagnostic Index60 (Index60) ≥1.00 (on the basis of fasting C-peptide, 60-min glucose, and 60-min C-peptide levels) as prediagnostic end points for type 1 diabetes among Type 1 Diabetes TrialNet Pathway to Prevention Study participants. RESEARCH DESIGN AND METHODS: Two cohorts were analyzed: 1) baseline normoglycemic oral glucose tolerance tests (OGTTs) with an incident dysglycemic OGTT and 2) baseline Index60 <1.00 OGTTs with an incident Index60 ≥1.00 OGTT. Incident dysglycemic OGTTs were divided into those with (DYS/IND+) and without (DYS/IND-) concomitant Index60 ≥1.00. Incident Index60 ≥1.00 OGTTs were divided into those with (IND/DYS+) and without (IND/DYS-) concomitant dysglycemia. RESULTS: The cumulative incidence for type 1 diabetes was greater after IND/DYS- than after DYS/IND- (P < 0.01). Within the normoglycemic cohort, the cumulative incidence of type 1 diabetes was higher after DYS/IND+ than after DYS/IND- (P < 0.001), whereas within the Index60 <1.00 cohort, the cumulative incidence after IND/DYS+ and after IND/DYS- did not differ significantly. Among nonprogressors, type 1 diabetes risk at the last OGTT was greater for IND/DYS- than for DYS/IND- (P < 0.001). Hazard ratios (HRs) of DYS/IND- with age and 30- to 0-min C-peptide were positive (P < 0.001 for both), whereas HRs of type 1 diabetes with these variables were inverse (P < 0.001 for both). In contrast, HRs of IND/DYS- and type 1 diabetes with age and 30- to 0-min C-peptide were consistent (all inverse [P < 0.01 for all]). CONCLUSIONS: The findings suggest that incident dysglycemia without Index60 ≥1.00 is a suboptimal prediagnostic end point for type 1 diabetes. Measures that include both glucose and C-peptide levels, such as Index60 ≥1.00, appear better suited as prediagnostic end points.Item Syntaxin 4 Overexpression Ameliorates Effects of Aging and High-Fat Diet on Glucose Control and Extends Lifespan(Elsevier, 2015-09-01) Oh, Eunjin; Miller, Richard A.; Thurmond, Debbie C.; Department of Pediatrics, IU School of MedicineIndirect evidence suggests that improved insulin sensitivity may contribute to improved lifespan of mice in which aging has been slowed by mutations, drugs, or dietary means, even in stocks of mice that do not show signs of late-life diabetes. Peripheral responses to insulin can be augmented by overexpression of Syntaxin 4 (Syn4), a plasma-membrane-localized SNARE protein. We show here that Syn4 transgenic (Tg) mice with high level expression of Syn4 had a significant extension of lifespan (33% increase in median) and showed increased peripheral insulin sensitivity, even at ages where controls exhibited age-related insulin resistance. Moreover, skeletal muscle GLUT4 and islet insulin granule exocytosis processes were fully protected in Syn4 Tg mice challenged with a high-fat diet. Hence, high-level expressing Syn4 Tg mice may exert better glycemic control, which slows multiple aspects of aging and extends lifespan, even in non-diabetic mice.