The Role of Hepatic Fat Accumulation in Glucose and Insulin Homeostasis-Dysregulation by the Liver.

Amalie London,Bente Kiens,Kirstine Nyvold Bojsen-Møller,Anne-Marie Lundsgaard

doi:10.3390/jcm10030390

Abstract

Accumulation of hepatic triacylglycerol (TG) is associated with obesity and metabolic syndrome, which are important pathogenic factors in the development of type 2 diabetes. In this narrative review, we summarize the effects of hepatic TG accumulation on hepatic glucose and insulin metabolism and the underlying molecular regulation in order to highlight the importance of hepatic TG accumulation for whole-body glucose metabolism. We find that liver fat accumulation is closely linked to impaired insulin-mediated suppression of hepatic glucose production and reduced hepatic insulin clearance. The resulting systemic hyperinsulinemia has a major impact on whole-body glucose metabolism and may be an important pathogenic step in the development of type 2 diabetes.

Highlights

Accumulation in Glucose and InsulinObesity is a central component in the development of metabolic syndrome [1,2], which is characterized and defined by central obesity or body mass index (BMI, weight/height (m)2 ) > 30 combined with two of the following: elevated circulating triacylglycerol (TG), reduced high-density lipoprotein (HDL) cholesterol, hypertension and elevated fasting plasma glucose [3]
It has been shown that in severely obese individuals with steatosis, the hepatic content of diacylglycerol (DAG) correlated positively with liver TG content and negatively with insulin-mediated suppression of glucose production [47], and it was shown in obese individuals that lipid-droplet associated DAG in liver samples correlated with homeostasis model assessment of insulin resistance (HOMA-insulin receptor (IR)), and with protein kinase C ε (PKCε) activation, the main PKC isoform in human liver, which impairs insulin signaling [48]
In line with this, when oral glucose tolerance was assessed in 75 young overweight men with steatosis, HOMA-IR was the most important predictor (Odds Ratio of 3.4 compared with no steatosis) of impaired glucose tolerance, with the glucose-intolerant individuals characterized by 70% higher fasting insulin levels [84], likely related to reduced insulin clearance

Summary

Introduction

Obesity is a central component in the development of metabolic syndrome [1,2], which is characterized and defined by central obesity (i.e., increased waist circumference) or body mass index (BMI, weight (kg)/height (m)2 ) > 30 combined with two of the following: elevated circulating triacylglycerol (TG), reduced high-density lipoprotein (HDL) cholesterol, hypertension and elevated fasting plasma glucose [3]. Central obesity, determined by the waist to hip ratio or waist circumference, is closely associated with excess TG accumulation in the liver [4,5,6,7] and with increased visceral fat content [8,9]. Liver TG accumulation, rather than visceral fat, is suggested to be the primary driver for the above-mentioned metabolic derangements associated with central obesity and MS [10,11]. This is supported by studies of obese individuals where higher total body adiposity, including doubling of visceral fat mass, does not lead to additional metabolic derangements if hepatic TG content is constant [12]. We will summarize the effects of hepatic TG accumulation on hepatic glucose and insulin metabolism and the underlying molecular regulation in order to highlight the importance of hepatic TG accumulation for whole-body glucose metabolism

Liver TG Accumulation and Hepatic Glucose Production and Insulin Resistance

Mechanisms in Increased Hepatic Glucose Production

Liver TG Accumulation and Hepatic Insulin Signaling

Increased Gluconeogenic Flux

Findings

Conclusions