359 SURROGATE MARKERS OF INSULIN SENSITIVITY / RESISTANCE IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASES AND CHRONIC HEPATITIS C

Abstract

Background and Aims: In obesity, excess fat accumulates in ectopic tissues which may lead to mitochondrial injury and result in insulin resistance (IR), the main risk factor for nonalcoholic fatty liver. We aimed to correlate intramyocellular fat, mitochondrial function, IR and hepatic injury, in morbid obesity. Methods: Prospective recruitment of morbidly obese patients undergoing bariatric surgery, with liver and deltoid muscle biopsies. A normal control group with muscle biopsies was also included. IR was considered if HOMA≥3. Liver biopsies were scored using NAFLD Activity Score. Muscle morphology and mitochondrial function (citrate sinthetase, respiratory chain I-IV complexes activities) were evaluated. Results: 35 patients (24 with simple steatosis – group 1; 11 with NASH/significant lobular inflammation – group 2), and 34 healthy controls were included. Group 2 was older (50±7 vs 40±11 years, p = 0.002), had more frequently IR (90% vs 65%, p = 0.044) and metabolic syndrome (82% vs 67%, p = 0.010) than group 1; sex distribution and BMI were similar. Muscle biopsies: no difference between proportions of type 1/2 fibers, size or variability was found between obese and controls. Interfascicular and intramyocellular fat were more frequent in obese than controls (36% vs 0%, p < 0.001 and 68% vs 9%, p < 0.001), furthermore intramyocellular fat was more frequent in group 2 vs 1 (60% vs 22%, p = 0.057). Obese had more frequently COX negative myocytes (40% vs 6%, p = 0.001), glycogen accumulation (37% vs 0%, p < 0.001) and less frequent mitochondrial aggregates (49% vs 79%, p = 0.012), but no such differences were found between obese groups. No differences between controls and obese in mitochondrial enzymes activity, however group 2 presented higher complex III (cytochrome c reductase) activity compared to group 1 (105±47 vs 68±33, p = 0.022). Citrate synthetase and complex III associated to IR (124±28 vs 90±30, p = 0.014 and 87±35 vs 61±29, p = 0.070). Conclusion: Obesity associates to lipid accumulation in the muscle, which if intracellular correlates to hepatic necroinflammation. A defect in muscle mitochondria was not apparent in obese regardless of liver histology. In fact, obese, particularly NASH patients, showed increase of mitochondria (citrate synthetase) and its activity (cytochrome c reductase), probably a compensatory response to fuel overload.