Abstract
BackgroundIt is unclear how excess adiposity and insulin resistance affect β cell function, insulin secretion, and insulin clearance in people with obesity.MethodsWe 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).ResultsGlucose-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.ConclusionIncreased 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 REGISTRATIONClinicalTrials.gov NCT02706262, NCT04131166, and NCT01977560.FUNDINGNIH (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).
Highlights
Obesity is often associated with insulin-resistant glucose metabolism [1]
By design, fasting plasma glucose concentration and the plasma glucose concentration at 2 hours after glucose ingestion increased from the Lean to the Ob-normal fasting plasma glucose (NFG)-normal glucose tolerance (NGT) to the Ob-NFG-IGT to the Ob-IFG-IGT to the ObT2D groups (Table 1)
Fasting plasma insulin concentration and basal insulin secretion rate (ISR) increased from the Lean to the Ob-NFG-NGT to the Ob-NFG-IGT to the Ob-IFG-IGT groups, but were not different between the Ob-T2D and the Ob-NFG-NGT groups (Table 1)
Summary
Obesity is often associated with insulin-resistant glucose metabolism (i.e., impaired insulinmediated suppression of hepatic glucose production and insulin-mediated stimulation of muscle glucose uptake) [1]. We have recently found that ISR is greater in people with obesity than in people who are lean, even when both groups are matched on basal plasma glucose concentration and hepatic and muscle insulin sensitivity [7]. This observation demonstrates that excessive body fat mass per se causes unique alterations in the relationship between plasma glucose and ISR that are independent of insulin sensitivity. A deterioration in β-cell function, not a decrease in insulin sensitivity, is a determinant of IFG and leads to T2D
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