Disruption of fasting and post-load glucose homeostasis are largely independent and sustained by distinct and early major beta-cell function defects: a cross-sectional and longitudinal analysis of the Relationship between Insulin Sensitivity and Cardiovascular risk (RISC) study cohort

Abstract Objective To investigate the prospective associations of life-course perfluoroalkyl substances (PFASs) exposure with glucose homeostasis at adulthood. Methods We calculated insulin sensitivity and beta-cell function indices based on 2-h oral glucose tolerance tests at age 28 in 699 Faroese born in 1986-1987. Five major PFASs were measured in cord whole blood and in serum from ages 7, 14, 22 and 28 years. We evaluated the associations with glucose homeostasis measures by PFAS exposures at different ages, using multiple informant models fitting generalized estimating equations, and by life-course PFAS exposures using structural equation models. Results Associations were stronger for perfluorooctane sulfonate (PFOS) and suggested decreased insulin sensitivity and increased beta-cell function, e.g., β (95% CI) for log-insulinogenic index per PFOS doubling = 0.12 (0.02,0.22) for prenatal exposures; 0.04 (-0.10,0.19) at age-7; 0.07 (-0.07,0.21) at age-14; 0.05 (-0.04,0.15) at age-22; 0.04 (-0.03,0.11) at age-28. Associations were consistent across ages (P for age-interaction >0.10 for all PFASs) and sex (P for sex-interaction >0.10 for all PFASs, except perfluorodecanoic acid). The overall life-course PFOS exposure was also associated with altered glucose homeostasis (P=0.04). Associations for other life-course PFAS exposures were non-significant. Conclusions Life-course PFAS exposure is associated with decreased insulin sensitivity and increased pancreatic beta-cell function in young adults.

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One-Hour Postload Hyperglycemia Is a Stronger Predictor of Type 2 Diabetes Than Impaired Fasting Glucose

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-2573 ◽

2015 ◽

Vol 100 (10) ◽

pp. 3744-3751 ◽

Cited By ~ 63

Author(s):

Teresa Vanessa Fiorentino ◽

Maria Adelaide Marini ◽

Francesco Andreozzi ◽

Franco Arturi ◽

Elena Succurro ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Beta Cell ◽

Impaired Fasting Glucose ◽

Longitudinal Analysis ◽

Beta Cell Function ◽

Cell Function ◽

Fasting Glucose

Context: Subjects with normal glucose tolerance (NGT) but 1-h postload glucose ≥ 155 mg/dL (NGT-1h-high) exhibit an intermediate cardiometabolic risk profile between individuals with NGT and impaired glucose tolerance (IGT). Objective: This study aimed to evaluate whether NGT-1h-high subjects have different cardiometabolic characteristics and an increased risk of type 2 diabetes compared with individuals with isolated impaired fasting glucose (IFG). Setting, Design, and Patients: A cross-sectional analysis was performed on 595 nondiabetic subjects who underwent an oral glucose tolerance test and an euglycemic hyperinsulinemic clamp in an ambulatory care setting. In addition, a longitudinal analysis was performed on 392 individuals, who were reexamined after a followup of 5.2 ± 0.9 y. Main Outcome Measures: Insulin sensitivity, beta-cell function, and risk of developing diabetes were measured. Results: Subjects with NGT-1h-high have a significant reduction of peripheral insulin sensitivity and beta-cell function, assessed by the disposition index, compared with either 1-h postload glucose < 155 mg/dL (NGT-1h-low) or IFG individuals, but not compared with IGT. Among the 392 subjects studied in the longitudinal analysis the incidence rate of type 2 diabetes over the follow-up period was 2.9, 16.7, 12.5, and 31.4% for subjects with NGT-1h-low, NGT-1h-high, IFG, and IGT, respectively. In a Cox proportional hazard regression analysis the risk of developing diabetes for NGT-1h-high subjects was 4.02 (95% confidence interval [CI] 1.06–15.26); an even higher risk (6.67; 95% CI, 2.09–21.24) was observed in subjects with IGT, but not in the isolated IFG group (1.91; 95% CI, 0.44–8.29). Conclusions: NGT-1h-high subjects exhibit a higher risk of developing diabetes than those with IFG or NGT-1h-low, likely due to decreased insulin sensitivity and beta-cell function.

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