Liver fat accumulation is associated with reduced hepatic insulin extraction and beta cell dysfunction in healthy older individuals

Francis M Finucane,Ema De Lucia Rolfe,Mensud Hatunic,Stephen J Sharp,Nicholas J Wareham,Cyrus Cooper,Alison Sleigh,Simon J Griffin,Avan Aihie Sayer

doi:10.1186/1758-5996-6-43

Abstract

BackgroundThere is a well-established association between type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) secondary to excess accumulation of intrahepatic lipid (IHL), but the mechanistic basis for this association is unclear. Emerging evidence suggests that in addition to being associated with insulin resistance, NAFLD may be associated with relative beta-cell dysfunction. We sought to determine the influence of liver fat on hepatic insulin extraction and indices of beta-cell function in a cohort of apparently healthy older white adults.MethodsWe performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial (39 males, age 71.3 ± 2.4 years) who underwent oral glucose tolerance testing with glucose, insulin and C-Peptide levels measured every 30 minutes over two hours. The areas under the concentration curve for glucose, insulin and C-Peptide were used to quantify hepatic insulin extraction (HIE), the insulinogenic index (IGI), the C-Peptide increment (CGI), the Disposition Index (DI) and Adaptation Index (AI). Visceral fat was quantified with magnetic resonance (MR) imaging and IHL with MR spectroscopy. Insulin sensitivity was measured with the Oral Glucose Insulin Sensitivity (OGIS) model.Results29 of 70 participants (41%) exceeded our arbitrary threshold for NAFLD, i.e. IHL >5.5%. Compared to those with normal IHL, those with NAFLD had higher weight, BMI, waist and MR visceral fat, with lower insulin sensitivity and hepatic insulin extraction. Alcohol consumption, age, HbA1c and alanine aminotransferase (ALT) levels were similar in both groups. Insulin and C-Peptide excursions after oral glucose loading were higher in the NAFLD group, but the CGI and AI were significantly lower, indicating a relative defect in beta-cell function that is only apparent when C-Peptide is measured and when dynamic changes in glucose levels and also insulin sensitivity are taken into account. There was no difference in IGI or DI between the groups.ConclusionsAlthough increased IHL was associated with greater insulin secretion, modelled parameters suggested relative beta-cell dysfunction with NAFLD in apparently healthy older adults, which may be obscured by reduced hepatic insulin extraction. Further studies quantifying pancreatic fat content directly and its influence on beta cell function are warranted.Trial registrationISRCTN60986572

Highlights

There is a well-established association between type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) secondary to excess accumulation of intrahepatic lipid (IHL), but the mechanistic basis for this association is unclear
Excess accumulation of intrahepatic lipid (IHL) leads to non-alcoholic fatty liver disease (NAFLD), an important component of the spectrum of metabolic abnormalities implicated in the pathogenesis of type 2 diabetes mellitus [1]
Previous studies have suggested that liver fat accumulation is associated with absolute increases in insulin secretion from the beta-cell, in order to compensate for insulin resistance and maintain euglycaemia [3]

Summary

Introduction

There is a well-established association between type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) secondary to excess accumulation of intrahepatic lipid (IHL), but the mechanistic basis for this association is unclear. Emerging evidence suggests that in addition to being associated with insulin resistance, NAFLD may be associated with relative beta-cell dysfunction. It is plausible that IHL accumulation could be associated with a relative beta-cell failure to adapt to increasing insulin resistance but that such a defect might not be apparent, because the concomitant reduction in HIE would lead to elevated circulating insulin levels. While a study of 64 overweight white adults with a family history of type 2 diabetes found an association between pancreatic fat content and glucose tolerance status, no such association was found for measures of beta cell function [8]. A direct association with liver fat content (measured with computerised tomography) and beta-cell dysfunction was not found [9]

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