Alterations in Adipose Tissue Distribution, Cell Morphology, and Function Mark Primary Insulin Hypersecretion in Youth With Obesity

Abstract

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 adipose tissue of youth with primary insulin hypersecretion and the longitudinal metabolic alterations influenced by the complex adipo-insular interplay. In a multiethnic cohort of adolescents with obesity but without diabetes, 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 oral glucose tolerance test and euglycemic-hyperinsulinemic clamp. Hypersecretors had greater intrahepatic and visceral fat depots at abdominal MRI, hypertrophic abdominal subcutaneous adipocytes, higher free fatty acid 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 a threefold 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 to identify individuals at risk for chronic hyperinsulinemia, body weight gain, and glucose intolerance.

Graphical abstract

Figure 1

Glucose homeostatic mechanisms in participants with HyperS or NormS. A: Identification of participants with HyperS and NormS as the upper and middle-lower tertiles of the residuals’ distribution of the OGTT-derived insulin secretion/WBISI best-fit line. B–D: Plasma glucose, insulin, and C-peptide–derived ISR profiles during the OGTT. E and F: Fasting and total insulin secretion. G–J: Model-derived β-cell glucose sensitivity, ISR@5, β-cell rate sensitivity, and potentiation factor ratio. K and L: Insulin clearance and WBISI. In B–D, data are mean ± SEM, and the group (G) and group-by-time interaction (G × T) effects were tested by two-way repeated-measures ANOVA. In E–L, lines represent median (IQR), and group differences were tested by Mann-Whitney U test.

Figure 2

Adipose tissue distribution, morphology, and function in participants with HyperS or NormS. A–D: SAT, VAT, VAT proportion (VAT / [VAT + SAT]), and HFF by abdominal MRI. E and F: Peak diameter and nadir diameter of the large adipocyte population by curve-fitting analysis of SAT biopsies. G–I: Plasma leptin, adiponectin, and leptin-to-adiponectin ratio normalized by FM. J: Plasma FFAs normalized by FM. K and L: Newly synthesized TG-glycerol and TG-palmitate by ²H₂O labeling. Lines represent median (IQR). Group differences were tested using Mann-Whitney U test.

Figure 3

Longitudinal changes in FM, glucose tolerance, and β-cell function. A and B: Percent change in FM% and progression from NGT to IFG/IGT or persistence in the IFG/IGT phenotype of participants with HyperS or NormS. C: Percent change in model-derived β-cell glucose sensitivity in participants with adipocyte peak diameter above (>121.5 μm) or below (≤121.5 μm) the median. D: Percent change in model-derived β-cell glucose sensitivity in participants with plasma leptin levels above (>0.9 ng ⋅ mL⁻¹ ⋅ kg_FM⁻¹) or below (≤0.9 ng ⋅ mL⁻¹ ⋅ kg_FM⁻¹) the median. In A, C, and D, the lines represent the median (IQR), and group differences were tested using Mann-Whitney U test. In B, group differences were tested using Fisher exact test.