OBJECTIVE -To test the hypothesis that enzymes conventionally associated with liver dysfunction (aspartate aminotransferase, alanine aminotransferase, ␥-glutamyltransferase [GGT], and alkaline phosphatase) may predict diabetes. RESEARCH DESIGN AND METHODS-From a population-based diabetes survey, we selected 1,441 men and women in whom serum enzyme levels were Յ3 SDs of the mean population value, alcohol intake was Ͻ250 g/week, and hepatitis B and C virus testing was negative. At follow-up (7 years), 94 subjects developed diabetes and 93 impaired glucose tolerance (IGT).RESULTS -At baseline, all four enzymes were related to most of the features of the metabolic syndrome. After controlling for sex, age, adiposity/fat distribution, alcohol intake, serum lipids, and blood pressure, higher alanine aminotransferase and GGT values were significantly (P Ͻ 0.01) associated with both IGT and diabetes, whereas alkaline phosphatase was associated with diabetes only (P ϭ 0.0004) and aspartate aminotransferase with IGT only (P ϭ 0.0001). Raised GGT alone was associated with all the features of the metabolic syndrome. Raised GGT was a significant predictor of either IGT or diabetes (odds ratio 1.62 [95% CI 1.08 -2.42] top quartile vs. lower quartiles, P Ͻ 0.02) after controlling for sex, age, adiposity/fat distribution, alcohol consumption, fasting plasma insulin and proinsulin levels, and 2-h postglucose plasma glucose concentrations.CONCLUSIONS -Although mild elevations in liver enzymes are associated with features of the metabolic syndrome, only raised GGT is an independent predictor of deterioration of glucose tolerance to IGT or diabetes. As GGT signals oxidative stress, the association with diabetes may reflect both hepatic steatosis and enhanced oxidative stress. Diabetes Care 28:1757-1762, 2005A syndrome characterized by liver steatosis, lobular hepatitis, and chronically elevated serum alanine aminotransferase (ALT) concentrationstermed nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH), depending on the degree of parenchymal inflammation-has been identified in patients with negligible alcohol intake (1,2). These patients are often obese and dyslipidemic (3-6). In cross-sectional studies, NAFLD is associated with insulin resistance irrespective of BMI, fat distribution, and glucose tolerance (1,7,8). On these grounds, it has been suggested that hyperinsulinemia and insulin resistance may play a role in the pathogenesis of NAFLD (1) and that NAFLD is a feature of the metabolic syndrome (9).In a prospective study in Pima Indians, serum ALT concentrations were related to both hepatic insulin resistance and later decline in hepatic insulin sensitivity (10). In contrast, aspartate aminotransferase (AST) and ␥-glutamyltransferase (GGT) concentrations were unrelated to changes in hepatic insulin action (10). Based on previous findings (1,2), Vozarova et al. (10) suggested that a raised ALT reflects fatty changes in the liver and that this abnormality antedates the development of type 2 diabete...

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Insulin-elicited endothelin release in hypertriglyceridemic, hypertensive, hyperinsulinemic (HTG) rats was shown. Weanling male Wistar rats were given 30% sucrose in their drinking water for 20–24 wk. In vitro contractions of aorta and femoral arteries were elicited with 40 mM KCl. Endothelin release induced with KCl plus 50 μU/ml insulin resulted in increases in contractile responses: 41 ± 5.9 and 57 ± 6% for control and 65.5 ± 6 and 95 ± 9% for HTG aortas and femoral arteries, respectively. The endothelin ETB-receptor blocker BQ-788 decreased responses to KCl + insulin by 39 ± 8 and 53 ± 5% in control and 48 ± 13 and 79 ± 3.5% in HTG aortas and femoral arteries, respectively. The ETA-receptor antagonist PD-151242 inhibited these responses by 12 ± 10 and 1 ± 9% in control and by 51.5 ± 9 and 58.5 ± 1% in HTG aortas and femoral arteries, respectively. These results suggest that endothelin may contribute to the hypertension in this model.