Peripheral insulin resistance predicts liver damage in nondiabetic subjects with nonalcoholic fatty liver disease

Abstract

Surrogate indexes of insulin resistance and insulin sensitivity are widely used in nonalcoholic fatty liver disease (NAFLD), although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with the NAFLD fibrosis score. Surrogate indexes were validated by the tracer technique (6,6-D 2 -glucose and U-13 C-glucose) in the basal state and during an oral glucose tolerance test. The best-performing indexes were used in an independent cohort of 145 nondiabetic NAFLD subjects to identify liver damage (fibrosis and nonalcoholic steatohepatitis). In the validation NAFLD cohort, homeostasis model assessment of insulin resistance, insulin to glucose ratio, and insulin sensitivity index Stumvoll had the best association with hepatic insulin resistance, while peripheral insulin sensitivity was most significantly related to oral glucose insulin sensitivity index (OGIS), insulin sensitivity index Stumvoll, and metabolic clearance rate estimation without demographic parameters. In the independent cohort, only oral glucose tolerance test-derived indexes were associated with liver damage and OGIS was the best predictor of significant (F2) fibrosis (odds ratio 5 0.76, 95% confidence interval 0.61-0.96, P 5 0.0233) and of nonalcoholic steatohepatitis (odds ratio 5 0.75, 95% confidence interval 0.63-0.90, P 5 0.0021). Both OGIS and NAFLD fibrosis score identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NAFLD fibrosis score (odds ratio 5 0.57, 95% confidence interval 0.45-0.72, P < 0.001) and was also able to discriminate F2 from F3/F4 (P < 0.003). Conclusion: OGIS is associated with peripheral insulin sensitivity in NAFLD and inversely associated with an increased risk of significant/advanced liver damage in nondiabetic subjects with NAFLD. (HEPATOLOGY 2016;63:107-116)

Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study

“…We and others have shown that the cross‐talk between adipose tissue and liver is important in the development and progression of NAFLD, and that the presence of insulin resistance (IR) in liver, adipose tissue, and peripheral tissues is associated with hepatic dysfunction, that is, increased hepatic triglyceride re‐esterification, de novo lipogenesis and gluconeogenesis, and steatosis . Consistent with this, GLP‐1‐RAs have been shown to reduce body weight and hepatic steatosis in humans .…”

“…The beneficial effects of GLP‐1 RA treatment on IR have important implications for treatment of patients with diabetes and NAFLD. In fact, previous studies have shown that Adipo‐IR is associated with a worse hepatic profile (histology and enzymes) in patients with NAFLD/NASH, and that the increased Adipo‐IR was associated with the improved liver histology . We also quantitated ATGU ( 18 FDG incorporation into abdominal subcutaneous fat during OGTT), which is required for adipocyte TG synthesis.…”

Metabolic syndrome and severity of fibrosis in nonalcoholic fatty liver disease: An age‐dependent risk profiling study

“…This finding suggests that the assessment of a narrowly available parameter such as insulin does not offer a significant advantage in the prediction of fibrosis risk when used in combination with classical components of MS. However, the lack of oral glucose insulin sensitivity (an expression of peripheral IR that predicts severe fibrosis more accurately than HOMA) could affect the interpretation of these results.…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Nearly all nonalcoholic steatohepatitis (NASH) patients display insulin resistance independent of body weight (Chitturi et al 2002). In fact, peripheral insulin resistance is now considered a better predictor of hepatic injury in NAFLD than visceral adiposity or the commonly used fibrosis scoring system (Ercin et al 2015, Rosso et al 2016.…”