Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics
Open Access
- 1 June 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (6), 3305-3314
- https://doi.org/10.1172/jci136756
Abstract
BACKGROUND. Insulin is a key regulator of metabolic function. The effects of excess adiposity, insulin resistance, and hepatic steatosis on the complex integration of insulin secretion and hepatic and extrahepatic tissue extraction are not clear. METHODS. A hyperinsulinemic-euglycemic clamp and a 3-hour oral glucose tolerance test were performed to evaluate insulin sensitivity and insulin kinetics after glucose ingestion in 3 groups: (a) lean subjects with normal intrahepatic triglyceride (IHTG) and glucose tolerance (lean-NL; n = 14), (b) obese subjects with normal IHTG and glucose tolerance (obese-NL; n = 24), and (c) obese subjects with nonalcoholic fatty liver disease (NAFLD) and prediabetes (obese-NAFLD; n = 22). RESULTS. Insulin sensitivity progressively decreased and insulin secretion progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Fractional hepatic insulin extraction progressively decreased from the lean-NL to the obese-NL to the obese-NAFLD groups, whereas total hepatic insulin extraction (molar amount removed) was greater in the obese-NL and obese-NAFLD subjects than in the lean-NL subjects. Insulin appearance in the systemic circulation and extrahepatic insulin extraction progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Total hepatic insulin extraction plateaued at high rates of insulin delivery, whereas the relationship between systemic insulin appearance and total extrahepatic extraction was linear. CONCLUSION. Hyperinsulinemia after glucose ingestion in obese-NL and obese-NAFLD is due to an increase in insulin secretion, without a decrease in total hepatic or extrahepatic insulin extraction. However, the liver’s maximum capacity to remove insulin is limited because of a saturable extraction process. The increase in insulin delivery to the liver and extrahepatic tissues in obese-NAFLD is unable to compensate for the increase in insulin resistance, resulting in impaired glucose homeostasis. TRIAL REGISTRATION. ClinicalTrials.gov NCT02706262. FUNDING. NIH grants DK56341 (Nutrition Obesity Research Center), DK052574 (Digestive Disease Research Center), RR024992 (Clinical and Translational Science Award), and T32 DK007120 (a T32 Ruth L. Kirschstein National Research Service Award); the American Diabetes Foundation (1-18-ICTS-119); Janssen Research & Development; and the Pershing Square Foundation.Keywords
Funding Information
- National Center for Advancing Translational Sciences (RR024992)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56341,DK052574,T32 DK007120)
- American Diabetes Association Research Foundation (1-18-ICTS-119)
- Janssen Research & Development (None)
- Pershing Square Foundation (None)
This publication has 45 references indexed in Scilit:
- The Original Michaelis Constant: Translation of the 1913 Michaelis–Menten PaperBiochemistry, 2011
- Increased Whole‐Body Adiposity Without a Concomitant Increase in Liver Fat is Not Associated With Augmented Metabolic DysfunctionObesity, 2010
- Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implicationsJournal of Hepatology, 2009
- Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesityProceedings of the National Academy of Sciences of the United States of America, 2009
- The Use of Areas Under Curves in Diabetes ResearchDiabetes Care, 1995
- Splanchnic insulin metabolism in obesity. Influence of body fat distribution.JCI Insight, 1986
- Feedback Inhibition of Insulin Secretion by Insulin: Relation to the Hyperinsulinemia of ObesityThe New England Journal of Medicine, 1982
- Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose.JCI Insight, 1981
- IMPROVEMENT IN INSULIN SECRETION IN DIABETES AFTER DIAZOXIDEThe Lancet, 1976
- Removal of insulin by perfused rat liver: Effect of concentrationMetabolism, 1975