Liver Enzymes, the Metabolic Syndrome, and Incident Diabetes

Abstract

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...

Plasma glucose levels as predictors of diabetes: the Mexico City diabetes study

“…Participants Data were collected as part of the Mexico City Diabetes Study [13], a population-based survey of diabetes and cardiovascular risk factors. Low-income neighbourhoods in Mexico City were selected and a complete enumeration of these was carried out from November 1989 to October 1992.…”

“…Participants with type 1 diabetes were excluded. Type 2 diabetes was classified as a fasting plasma glucose concentration ≥7.0 mmol/l or a 2 h plasma glucose concentration ≥11.1 mmol/l after a standard 75 g OGTT [13]. Participants who reported having a history of diabetes and who at the time of their clinical examination were taking oral glucose-lowering agents were also considered to have type 2 diabetes, regardless of their plasma glucose values.…”

“…Height, weight, waist and hip circumferences, and systolic and diastolic blood pressure were measured as described elsewhere [13].…”

“…Serum samples were centrifuged at 1,500×g, divided into aliquots and stored at −70°C until assayed. Fasting concentrations of serum insulin, proinsulin, plasma glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol and triacylglycerol, and plasma glucose and insulin concentrations 2 h after an oral glucose load were determined as described elsewhere [13] at baseline and follow-up.…”

“…The present work takes advantage of 7 year follow-up data from the Mexico City Diabetes Study [13], a population-based observational study in a population with a high prevalence of diabetes, to assess the value of categorisation of prediabetic states with respect to incident diabetes. Assessment was done by systematically analysing RR, population-attributable risk (PAR) and clinical phenotype of old and new definitions of IFG and IGT.…”