β Cell function and plasma insulin clearance in people with obesity and different glycemic status
Bettina Mittendorfer, … , Mihoko Yoshino, Samuel Klein
Bettina Mittendorfer, … , Mihoko Yoshino, Samuel Klein
Published December 14, 2021
Citation Information: J Clin Invest. 2022;132(3):e154068. https://doi.org/10.1172/JCI154068.
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Clinical Medicine Metabolism

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

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 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).

Authors

Bettina Mittendorfer, Bruce W. Patterson, Gordon I. Smith, Mihoko Yoshino, Samuel Klein

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Figure 1

Basal and postprandial plasma glucose and insulin concentrations and insulin kinetics in the lean group and the obese groups with different glycemic status (related to Table 1).

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Basal and postprandial plasma glucose and insulin concentrations and ins...
Basal and postprandial plasma glucose (A) and insulin (B) concentrations and insulin secretion (C) and insulin clearance (D) rates in healthy lean participants (lean, n = 19) and participants with obesity and either NFG and NGT (Ob-NFG-NGT, n = 33), NFG and IGT (Ob-NFG-IGT, n = 17), IFG and IGT (Ob-IFG-IGT, n = 19), or T2D (n = 18). Relationships between the plasma glucose concentration and the ISR (E), plasma glucose concentration and ISR in relation to m2 of body surface area (BSA) (F), plasma glucose concentration and plasma insulin concentration (G), and plasma insulin concentration and ICR (H) before and during the first 30 minutes after glucose ingestion in the same participants. The data in F do not include the Ob-T2D group to highlight the isolated effect of IFG on the relationship between the plasma glucose concentration and the ISR. IFG values: plasma glucose at 0 minutes ≥100 mg/dL and <126 mg/dL; IGT values: plasma glucose at 120 minutes ≥140 mg/dL and <200 mg/dL; NFG values: plasma glucose at 0 minutes <100 mg/dL; NGT values: plasma glucose at 120 minutes <140 mg/dL. Data are expressed as the mean ± SEM.