β Cell function and plasma insulin clearance in people with obesity and different glycemic status

BACKGROUND: It is unclear how excess adiposity and insulin resistance affect β cell function, insulin secretion, and insulin clearance in people with obesity. METHODS: We used a hyperinsulinemic-euglycemic clamp procedure and a modified oral glucose tolerance test to evaluate the interrelationships among obesity, insulin sensitivity, insulin kinetics, and glycemic status in 5 groups of individuals: normoglycemic lean and obese individuals with (a) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), (b) NFG and impaired glucose tolerance (Ob-NFG-IGT), (c) impaired fasting glucose and IGT (Ob-IFG-IGT), or (d) type 2 diabetes (Ob-T2D). RESULTS: Glucose-stimulated insulin secretion (GSIS), an assessment of β cell function, was greater in the Ob-NFG-NGT and Ob-NFG-IGT groups than in the lean group, even when insulin sensitivity was matched in the obese and lean groups. Insulin sensitivity, not GSIS, was decreased in the Ob-NFG-IGT group compared with the Ob-NFG-NGT group, whereas GSIS, not insulin sensitivity, was decreased in the Ob-IFG-IGT and Ob-T2D groups compared with the Ob-NFG-NGT and Ob-NFG-IGT groups. Insulin clearance was directly related to insulin sensitivity and inversely related to the postprandial increase in insulin secretion and plasma insulin concentration. CONCLUSION: Increased adiposity per se, not insulin resistance, enhanced insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raised the plasma insulin concentrations needed to maintain normoglycemia in individuals with moderate, but not severe, insulin resistance. A deterioration in β cell function, not a decrease in insulin sensitivity, was a determinant of IFG and ultimately leads to T2D. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT02706262, NCT04131166, and NCT01977560. FUNDING: NIH (P30 DK056341, P30 DK020579, and UL1 TR000448); American Diabetes Association (1-18-ICTS-119); Longer Life Foundation; Pershing Square Foundation; and Washington University-Centene ARCH Personalized Medicine Initiative (P19-00559).