Obesity Is Associated With Increased Basal and Postprandial β-Cell Insulin Secretion Even in the Absence of Insulin Resistance

Abstract

We tested the hypothesis that obesity, independent of insulin resistance, is associated with increased insulin secretion. We compared insulin kinetics before and after glucose ingestion in lean healthy people and people with obesity who were matched on multiorgan insulin sensitivity (inhibition of adipose tissue lipolysis and glucose production and stimulation of muscle glucose uptake) as assessed by using a two-stage hyperinsulinemic-euglycemic pancreatic clamp procedure in conjunction with glucose and palmitate tracer infusions and positron emission tomography. We also evaluated the effect of diet-induced weight loss on insulin secretion in people with obesity who did not improve insulin sensitivity despite marked (∼20%) weight loss. Basal and postprandial insulin secretion rates were >50% greater in people with obesity than lean people even though insulin sensitivity was not different between groups. Weight loss in people with obesity decreased insulin secretion by 35% even though insulin sensitivity did not change. These results demonstrate that increased insulin secretion in people with obesity is associated with excess adiposity itself and is not simply a compensatory response to insulin resistance. These findings have important implications regarding the pathogenesis of diabetes because hyperinsulinemia causes insulin resistance and insulin hypersecretion is an independent risk factor for developing diabetes.

Trial registration: ClinicalTrials.gov NCT02994459 NCT03408613 NCT02207777 NCT01299519.

© 2020 by the American Diabetes Association.

Figures

Figure 1

Basal palmitate and glucose Ra in plasma (A and B) and plasma free fatty acid and glucose concentrations (C and D), insulin-stimulated muscle Rg determined by PET after intravenous injection of [18F]FDG (E), and the relationships between plasma insulin concentration during basal conditions and during the hyperinsulinemic-euglycemic clamp and endogenous glucose Ra in plasma relative to fat-free mass (FFM) (F), total palmitate Ra in plasma (G), and palmitate Ra in plasma relative to fat mass (H) in the lean (n = 8) and obese (n = 8) groups. Data in panels A–E are mean ± SEM. *P < 0.05 vs. the lean group. FFM, fat-free mass.

Figure 2

Basal insulin secretion rate (A) and concentration (B) and plasma glucose and insulin concentrations and insulin kinetics before and after glucose ingestion (C–J) in the lean (n = 8) and obese (n = 8) groups. Data are mean ± SEM. *P < 0.05 vs. the lean group. FFM, fat-free mass.

Figure 3

Effect of diet-induced weight loss on plasma glucose and insulin concentrations (A–D) and insulin secretion rate (E and F) before and after glucose ingestion in women with obesity (n = 6) who did not improve whole-body insulin sensitivity despite marked (∼20%) weight loss. Data are mean ± SEM. *P < 0.05 vs. before weight loss.