Authors
L. VONGHIA (1), F. CARLI (2), A. VERRIJKEN (3), J. WEYLER (1), E. DIRINCK (3), P. MICHIELSEN (1), T. VANWOLLEGHEM (1), A. DRIESSEN (4), L. VAN GAAL (3), A. GASTALDELLI (2), S. FRANCQUE (1) / [1] Antwerp University Hospital, Antwerp, Belgium, Edegem, Belgium, Department of Gastroenterology and Hepatology, [2] Institute of Clinical Physiology, CNR, Pisa, Italy, Pisa, Italy, Cardiometabolic Risk Unit, [3] Antwerp University Hospital, Antwerp, Belgium, Edegem, Belgium, Department of Endocrinology, Diabetology and Metabolism, [4] Antwerp University Hospital, Antwerp, Belgium, Edegem, Belgium, Department of Pathology
Introduction
Patients with non-alcoholic fatty liver disease (NAFLD) are at high risk to develop type 2 diabetes (T2DM). It is well established that ß-cell dysfunction, i.e. impairment in insulin secretion meant to overcome the muscle insulin resistance (IR), is a strong predictor of the development of postprandial hyperglycemia and T2DM. The liver plays a central role since it clears up to 80% of the secreted insulin. However, in conditions of liver disease and/or IR the insulin clearance (ClearIns) is reduced.
Aim
The goal of this study was to evaluate if insulin secretion rate (ISR) and ß-cell function were decreased in Non-alcoholic steatohepatitis (NASH) vs Non-alcohol Fatty Liver (NAFL) thus predisposing these subjects to T2DM.
Methods
We analyzed the glucose, insulin and c-peptide profiles (at 0,30,60,120,180min) during a 75gram oral glucose tolerance test (OGTT) in 402 non-diabetic NAFLD patients (BMI kg/m 25-69, age 18-74 years, 31.5/68.4% M/F). We assessed Matsuda insulin sensitivity index (ISI), ISR during OGTT (from deconvolution analysis of c-peptide), the insulin response to glucose (ΔAUC-I/ΔAUC-G) and ClearIns. We also determined ß-cell function as the insulin secretion/insulin resistance or disposition index (DI) (i.e. calculating the insulin response factored by the degree of IR: DI=ISI∙ΔAUC-I/ΔAUC-G). A low DI was used to indicate a predisposition to develop T2DM. Liver biopsy was scored according to NASH CRN. In this cohort n=224 patients had NASH.
Results
Subjects were grouped according to liver histologic phenotype as NAFL, NASH with low or high fibrosis (NASH-LF vs NASH-HF) and according to BMI as non-obese (BMI<30), obese (BMI 30-40) or morbid obese (BMI>40). Obesity was associated with increased IR, fasting and postprandial insulin secretion, but decreased ClearIns. Within each weight category, NAFLD severity was significantly associated with increased IR, ISR and decreased ClearIns. ß-cell function assessed by DI was significantly decreased with both severity of liver disease and obesity.
Conclusions
ß-cell dysfunction is more prevalent in non-diabetic obese subjects and is significantly aggravated by the concomitant presence and severity of NAFLD supporting an independent causative role of NAFLD in development of T2DM. Furthermore, insulin clearance is even so decreased in relation to the presence and severity of NAFLD.
