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. 2025 Apr 22;110(5):e1395-e1403.
doi: 10.1210/clinem/dgae572.

Liver Fat Accumulation Is Associated With Increased Insulin Secretion Independent of Total, Visceral, and Pancreatic Fat

Karoline Sandby  1 , Thure Krarup  1   2 , Elizaveta Chabanova  3 , Nina R W Geiker  1   4 , Faidon Magkos  1
Affiliations

Liver Fat Accumulation Is Associated With Increased Insulin Secretion Independent of Total, Visceral, and Pancreatic Fat

Karoline Sandby et al. J Clin Endocrinol Metab. .

Abstract

Context: Studies in heterogeneous groups of people with respect to sex, body mass index (BMI), and glycemic status (normoglycemia, impaired glucose tolerance, diabetes), indicate no relationship between liver fat accumulation and pancreatic insulin secretion.

Objective: This work aimed to better understand the association of liver fat with insulin secretion.

Methods: A cross-sectional analysis was conducted of 61 men with abdominal obesity who had high liver fat (HLF, ≥ 5.6% by magnetic resonance spectroscopy, n = 28) or low liver fat (LLF, n = 33), but were balanced on BMI, total body fat, visceral adipose tissue (VAT), and pancreatic fat. A frequently sampled 5-hour oral glucose tolerance test with 11 samples, in conjunction with mathematical modeling, was used to compute indices of insulin sensitivity and insulin secretion (oral minimal model).

Results: Compared to individuals with LLF, those with HLF had significantly greater fasting glucose, insulin, C-peptide, and triglycerides; lower high-density lipoprotein cholesterol; but similar glycated hemoglobin A1c. Areas under the 5-hour curve for glucose, insulin, and C-peptide were greater in the HLF group than the LLF group (by ∼10%, ∼38%, and ∼28%, respectively); fasting and total postprandial insulin secretion rates were approximately 37% and approximately 50% greater, respectively (all P < .05); whereas the insulinogenic index was not different. HLF participants had lower whole-body and hepatic insulin sensitivity, disposition index, and total insulin clearance than LLF participants (all P < .05).

Conclusion: Accumulation of liver fat is associated with increased insulin secretion independently of total adiposity, abdominal fat distribution, and pancreatic fat. Thereby, hyperinsulinemia in fatty liver disease is partly because of insulin hypersecretion and partly because of impaired insulin clearance.

Keywords: glucose homeostasis; intra-abdominal fat; intrahepatic triglyceride; steatosis.

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