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.