Cited by 78Liver Disease Diagnosis and TreatmentPancreatic function and diabetesDiabetes, Cardiovascular Risks, and Lipoproteins

Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics

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Smith, Gordon I., Polidori, David C., Yoshino, Mihoko, Kearney, Monica L., Patterson, Bruce W., Mittendorfer, Bettina, Klein, Samuel·2020·Journal of Clinical Investigation

Abstract

BACKGROUNDInsulin 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.METHODSA 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).RESULTSInsulin 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.CONCLUSIONHyperinsulinemia 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 REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGNIH 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.

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  • Insulin delivered into the portal vein is a major regulator of hepatic glucose production, and people with obesity, prediabetes, and type 2 diabetes have increased gluconeogenesis and impaired insulin suppression of hepatic glucose production.

    “Furthermore, insulin delivered into the portal vein is a major regulator of hepatic glucose production (HGP) and people with obesity, prediabetes, and type 2 diabetes have increased gluconeogenesis and an impairment in the capacity of insulin to suppress HGP 4, 5.”

    From Effect of exercise training on insulin-stimulated glucose disposal: A systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [5]

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  1. [16]16. Bril F, et al. Relationship between disease severi- ty, hyperinsulinemia, and impaired insulin clear- ance in patients with nonalcoholic steatohepati- tis. Hepatology. 2014;59(6):2178-2187.
  2. [35]35. Greenwood RH, Mahler RF, Hales CN. Improve- ment in insulin secretion in diabetes after diazox- ide. Lancet. 1976;1(7957):444-447.

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Authors
Smith, G. I., Polidori, D. C., Yoshino, M., Kearney, M. L., Patterson, B. W., Mittendorfer, B., & Klein, S.
Affiliations
  • Washington University in St. Louis (US)
  • Janssen Research & Development (United States) (US)
Corresponding author
Klein, Samuel
Venue
Journal of Clinical Investigation
Published
2020-05-18
Volume
130
Issue
6
Pages
3305-3314
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
OpenAlex
W3012365429
Cited by
78
References
45
Citations by year
2026: 8 · 2025: 6 · 2024: 13 · 2023: 12 · 2022: 13 · 2021: 17 · 2020: 9
FWCI
9.14
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Funders
  • 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)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
insulin kinetics, insulin resistance, intrahepatic triglyceride, hepatic insulin extraction, non-alcoholic fatty liver disease, prediabetes, obesity, insulin secretion, hyperinsulinemia, glucose tolerance, insulin sensitivity, glucose homeostasis, hyperinsulinemic-euglycemic clamp
MeSH terms
Insulin Secretion, Adult, Female, Humans, Insulin, Insulin Resistance, Kinetics, Liver, Male, Obesity, Triglycerides, Adiposity, Non-alcoholic Fatty Liver Disease

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