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Beta-cell function and plasma insulin clearance in people with obesity and different glycemic status
Bettina Mittendorfer et al. J Clin Invest. 2021.

Abstract

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 five groups: normoglycemic lean and obese with: i) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), ii) NFG and impaired glucose tolerance (Ob-NFG-IGT), iii) impaired fasting glucose and IGT (Ob-IFG-IGT), and iv) 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, enhances insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raise plasma insulin concentrations needed to maintain normoglycemia in people with moderate, but not severe insulin resistance. A deterioration in β-cell function, not a decrease in insulin sensitivity, is a determinant of IFG and ultimately leads to T2D.