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

BACKGROUND. It is unclear how excess adiposity and insulin resistance affect beta 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 beta 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 beta 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.

Automated summary

This study investigated the relationship between obesity, insulin sensitivity, insulin secretion, and clearance, revealing that increased adiposity enhances insulin secretion in people with obesity. The development of IFG is primarily determined by the deterioration in beta cell function rather than a decrease in insulin sensitivity.