American Diabetes Association
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Alterations in adipose tissue distribution, cell morphology and function mark primary insulin hypersecretion in youths with obesity

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posted on 2023-10-23, 15:12 authored by Domenico Tricò, Martina Chiriacò, Jessica Nouws, Alla Vash-Margita, Romy Kursawe, Elena Tarabra, Alfonso Galderisi, Andrea Natali, Cosimo Giannini, Marc Hellerstein, Ele Ferrannini, Sonia Caprio

Excessive insulin secretion independent of insulin resistance, defined as primary hypersecretion, is associated with obesity and an unfavorable metabolic phenotype. We examined the characteristics of the adipose tissue in youths with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of non-diabetic adolescents with obesity, primary insulin hypersecretors had enhanced model-derived β-cell glucose sensitivity and rate sensitivity, but worse glucose tolerance, despite similar demographics, adiposity, and insulin resistance measured by both OGTT and euglycemic-hyperinsulinemic clamp. Hypersecretors had greater intrahepatic and visceral fat depots at abdominal MRI, hypertrophic abdominal subcutaneous adipocytes, higher FFA and leptin serum levels per fat mass, and faster in vivo lipid turnover assessed by a long-term 2H2O labeling protocol. At 2-year follow up, hypersecretors had greater fat accrual and 3-fold higher risk for abnormal glucose tolerance, while individuals with hypertrophic adipocytes or higher leptin levels showed enhanced β-cell glucose sensitivity. Primary insulin hypersecretion is associated with marked alterations in adipose tissue distribution, cellularity, and lipid dynamics, independent of whole-body adiposity and insulin resistance. Pathogenetic insight into the metabolic crosstalk between β-cell and adipocyte may help identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance.


S.C. is funded by the National Institutes of Health (NIH) (grants R01-HD-40787, R01-HD-28016, R01DK111038 and K24-HD01464). This work was also made possible by DK-045735 to the Yale Diabetes Endocrinology Research Center and by Clinical and Translational Science Awards Grant UL1-RR-024139 from the National Center for Advancing Translational Sciences, a component of the NIH, and NIH Roadmap for Medical Research. The contents of this scientific contribution are solely the responsibility of the authors and do not necessarily represent the official view of the NIH.