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

Romina Lomonaco, Fernando Bril, Paola Portillo-Sanchez, Carolina Ortiz-Lopez, Beverly Orsak, Diane Biernacki, Margaret Lo, Amitabh Suman, Michelle H Weber, Kenneth Cusi, Romina Lomonaco, Fernando Bril, Paola Portillo-Sanchez, Carolina Ortiz-Lopez, Beverly Orsak, Diane Biernacki, Margaret Lo, Amitabh Suman, Michelle H Weber, Kenneth Cusi

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 ((1)H-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.

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1
Figure 1
A: Adipo-IRi (FPI × fasting FFA concentration). B: Percentage suppression of plasma FFA concentration by low-dose insulin infusion. C: HIRi (FPI concentration × fasting endogenous [primarily hepatic] glucose production). Dotted lines represent mean values for nonobese healthy subjects from the group.
Figure 2
Figure 2
Changes in endogenous (primarily hepatic) glucose production and plasma insulin concentration during the low- and high-dose euglycemic-hyperinsulinemic clamp. Arrows represent progression from obese control subjects without NAFLD to obese patients with T2DM and NASH during fasting (top arrow) as well as low-dose (middle arrow) and high-dose (bottom-right arrow) insulin infusion.
Figure 3
Figure 3
A: Pearson correlation between suppression of plasma FFA levels by low-dose insulin during the euglycemic-hyperinsulinemic clamp and intrahepatic triglycerides measured by 1H-MRS. B: Spearman correlation between suppression of plasma FFA levels by low-dose insulin during the euglycemic-hyperinsulinemic clamp and histological severity of liver disease expressed as the NAFLD activity score.

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