β Cell function and plasma insulin clearance in people with obesity and different glycemic status
Bettina Mittendorfer, Bruce W Patterson, Gordon I Smith, Mihoko Yoshino, Samuel Klein, Bettina Mittendorfer, Bruce W Patterson, Gordon I Smith, Mihoko Yoshino, Samuel Klein
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).
Keywords: Beta cells; Insulin; Metabolism.
Conflict of interest statement
Conflict of interest: BM has served as a scientific advisor for Nestle. SK receives research funding from Janssen Pharmaceuticals Inc. and serves on scientific advisory boards for Altimmune and ProSciento.
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References
- Smith GI, et al. Metabolically healthy obesity: facts and fantasies. J Clin Invest. 2019;129(10):3978–3989. doi: 10.1172/JCI129186.
- Esser N, et al. Early beta cell dysfunction vs insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia. Diabetologia. 2020;63(10):2007–2021. doi: 10.1007/s00125-020-05245-x.
- Bergman RN, et al. Accurate assessment of beta-cell function: the hyperbolic correction. Diabetes. 2002;51 Suppl 1:S212–S220.
- Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017;23(7):804–814. doi: 10.1038/nm.4350.
- Piccinini F, Bergman RN. The measurement of insulin clearance. Diabetes Care. 2020;43(9):2296–2302. doi: 10.2337/dc20-0750.
- Gastaldelli A, et al. Adaptation of insulin clearance to metabolic demand is a key determinant of glucose tolerance. Diabetes. 2021;70(2):377–385. doi: 10.2337/db19-1152.
- van Vliet S, et al. Obesity is associated with increased basal and postprandial beta-cell insulin secretion even in the absence of insulin resistance. Diabetes. 2020;69(10):2112–2119. doi: 10.2337/db20-0377.
- Polidori DC, et al. Hepatic and extrahepatic insulin clearance are differentially regulated: results from a novel model-based analysis of intravenous glucose tolerance data. Diabetes. 2016;65(6):1556–1564. doi: 10.2337/db15-1373.
- Smith GI, et al. Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics. J Clin Invest. 2020;130(6):3305–3314. doi: 10.1172/JCI136756.
- Ferrannini E, et al. Splanchnic and renal metabolism of insulin in human subjects: a dose-response study. Am J Physiol. 1983;244(6):E517–E527.
- Tillil H, et al. Dose-dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans. Am J Physiol. 1988;254(3 pt 1):E349–E357.
- Tillil H, et al. Reduction of insulin clearance during hyperglycemic clamp. Dose-response study in normal humans. Diabetes. 1988;37(10):1351–1357.
- Henquin JC, et al. Nutrient control of insulin secretion in isolated normal human islets. Diabetes. 2006;55(12):3470–3477. doi: 10.2337/db06-0868.
- Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycaemia. Diabetologia. 2003;46 Suppl 1:M2–8.
- Caumo A, Luzi L. First-phase insulin secretion: does it exist in real life? Considerations on shape and function. Am J Physiol Endocrinol Metab. 2004;287(3):E371–E385. doi: 10.1152/ajpendo.00139.2003.
- Campbell JE, Newgard CB. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat Rev Mol Cell Biol. 2021;22(2):142–158. doi: 10.1038/s41580-020-00317-7.
- Brambilla P, et al. Normal fasting plasma glucose and risk of type 2 diabetes. Diabetes Care. 2011;34(6):1372–1374. doi: 10.2337/dc10-2263.
- Tirosh A, et al. Normal fasting plasma glucose levels and type 2 diabetes in young men. N Engl J Med. 2005;353(14):1454–1462. doi: 10.1056/NEJMoa050080.
- Nichols GA, et al. Normal fasting plasma glucose and risk of type 2 diabetes diagnosis. Am J Med. 2008;121(6):519–524. doi: 10.1016/j.amjmed.2008.02.026.
- Saisho Y, et al. beta-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care. 2013;36(1):111–117. doi: 10.2337/dc12-0421.
- Prentki M, et al. Nutrient-induced metabolic stress, adaptation, detoxification, and toxicity in the pancreatic β-cell. Diabetes. 2020;69(3):279–290. doi: 10.2337/dbi19-0014.
- Nichols CG, et al. Preferential Gq signaling in diabetes: an electrical switch in incretin action and in diabetes progression? J Clin Invest. 2020;130(12):6235–6237. doi: 10.1172/JCI143199.
- Huopio H, et al. K(ATP) channels and insulin secretion disorders. Am J Physiol Endocrinol Metab. 2002;283(2):E207–E216. doi: 10.1152/ajpendo.00047.2002.
- Meier JJ, et al. Pancreatic diabetes manifests when beta cell area declines by approximately 65% in humans. Diabetologia. 2012;55(5):1346–1354. doi: 10.1007/s00125-012-2466-8.
- Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016;4(6):525–536. doi: 10.1016/S2213-8587(15)00482-9.
- Holst JJ, Deacon CF. Is there a place for incretin therapies in obesity and prediabetes? Trends Endocrinol Metab. 2013;24(3):145–152. doi: 10.1016/j.tem.2013.01.004.
- Najjar SM, Perdomo G. Hepatic insulin clearance: mechanism and physiology. Physiology (Bethesda) 2019;34(3):198–215.
- Mondon CE, et al. Removal of insulin by perfused rat liver: effect of concentration. Metabolism. 1975;24(2):153–160. doi: 10.1016/0026-0495(75)90016-5.
- Sonne O, Simpson IA. Internalization of insulin and its receptor in the isolated rat adipose cell. Time-course and insulin concentration dependency. Biochim Biophys Acta. 1984;804(4):404–413.
- Gliemann J, et al. Time course of insulin-receptor binding and insulin-induced lipogenesis in isolated rat fat cells. J Biol Chem. 1975;250(9):3368–3374. doi: 10.1016/S0021-9258(19)41524-X.
- Caro JF, et al. Studies on the mechanism of insulin resistance in the liver from humans with noninsulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest. 1986;78(1):249–258. doi: 10.1172/JCI112558.
- Caro JF, et al. Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes. J Clin Invest. 1987;79(5):1330–1337. doi: 10.1172/JCI112958.
- Goodyear LJ, et al. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest. 1995;95(5):2195–2204. doi: 10.1172/JCI117909.
- Frank HJ, Davidson MB. Insulin binding and action in isolated rat hepatocytes: effect of obesity and fasting. Am J Physiol. 1982;243(3):E240–E245.
- Kolterman OG, et al. Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. J Clin Invest. 1980;65(6):1272–1284. doi: 10.1172/JCI109790.
- Unwin N, et al. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med. 2002;19(9):708–723. doi: 10.1046/j.1464-5491.2002.00835.x.
- Van Cauter E, et al. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes. 1992;41(3):368–377.
- Koh HE, et al. Heterogeneity in insulin-stimulated glucose uptake among different muscle groups in healthy lean people and people with obesity. Diabetologia. 2021;64(5):1158–1168. doi: 10.1007/s00125-021-05383-w.
- Ferrannini E, et al. beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab. 2005;90(1):493–500. doi: 10.1210/jc.2004-1133.
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