Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis

OBJECTIVES: The relationships between the adipokines tumor necrosis factor (TNF)-alpha and adiponectin and the parameters of glucose homeostasis and severity of liver disease were assessed in nonobese nondiabetic subjects with nonalcoholic steatohepatitis (NASH). METHODS: A frequently sampled intravenous glucose tolerance test, serum cytokine measurement, and 7-day alimentary record were performed in 20 biopsy-proven NASH patients and 45 age-, sex-, and BMI-matched controls (30 insulin sensitive and 15 insulin resistant). RESULTS: Patients with NASH had impaired pancreatic beta-cell function compared with both insulin-sensitive (adaptation index, AI: 97.7 +/- 17.7 vs 307.4 +/- 24.1 min(-2) mmol(-1) L; p= 0.00001) and insulin-resistant (adaptation index, AI: 97.7 +/- 17.7 vs 201.4 +/- 41.1 min(-2) mmol(-1) L; p= 0.001) controls. Serum adiponectin levels were also significantly lower in the NASH group than in the two control groups and correlated with adaptation index and with the severity of hepatic steatosis, necroinflammation, and fibrosis. When NASH patients were grouped according to the severity of histological liver damage, adiponectin was the only variable discriminating patients with higher necroinflammatory grade and fibrosis score from those with milder lesions. CONCLUSIONS: beta-cell secretory impairment is present in nonobese patients with NASH before glucose intolerance appears and may contribute to their increased risk for developing diabetes. Hypoadiponectinemia is a feature of NASH and may have a pathogenetic role in beta-cell dysfunction and in hepatic necroinflammation and fibrosis, independently of insulin resistance, visceral fat accumulation, TNF-alpha axis activity, and dietary habits. Our findings provide further rationale for therapeutic approaches aimed at increasing adiponectin levels together with restoring beta-cell function and insulin sensitivity.