Metabolic Impact of Nonalcoholic Steatohepatitis in Obese Patients With Type 2 Diabetes

Abstract

OBJECTIVE Nonalcoholic steatohepatitis (NASH) is increasingly common in obese patients. However, its metabolic consequences in patients with type 2 diabetes mellitus (T2DM) are unknown. RESEARCH DESIGN AND METHODS We studied 154 obese patients divided in four groups: 1) control (no T2DM or NAFLD), 2) T2DM without NAFLD, 3) T2DM with isolated steatosis, and 4) T2DM with NASH. We evaluated intrahepatic triglycerides by proton MRS (1H-MRS) and assessed insulin secretion/resistance during an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp with glucose turnover measurements. RESULTS No significant differences among groups were observed in sex, BMI, or total body fat. Metabolic parameters worsened progressively with the presence of T2DM and the development of hepatic steatosis, with worse hyperinsulinemia, insulin resistance, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol) in those with NASH (P < 0.001). Compared with isolated steatosis, NASH was associated with more dysfunctional and insulin-resistant adipose tissue (either as insulin suppression of plasma FFA [33 ± 3 vs. 48 ± 6%] or adipose tissue insulin resistance index [9.8 ± 1.0 vs. 5.9 ± 0.8 mmol/L ⋅ µIU/mL]; both P < 0.03). Furthermore, insulin suppression of plasma FFA correlated well with hepatic steatosis (r = –0.62; P < 0.001) and severity of steatohepatitis (rs = −0.52; P < 0.001). Hepatic insulin sensitivity was also more significantly impaired among patients with T2DM and NASH, both fasting and with increasing insulin levels within the physiological range (10 to 140 µIU/mL), compared with other groups. CONCLUSIONS In obese patients with T2DM, the presence of NAFLD is associated with more severe hyperinsulinemia, dyslipidemia, and adipose tissue/hepatic insulin resistance compared with patients without NAFLD. The unfavorable metabolic profile linked to NAFLD should prompt strategies to identify and treat this population early on.