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Objective: Fluxes through mitochondrial pathways are defective in insulin-resistant skeletal muscle, but it is unclear whether similar mitochondrial defects play a role in the liver during insulin resistance and/or diabetes. The purpose of this study is to determine whether abnormal mitochondrial metabolism plays a role in the dysregulation of both hepatic fat and glucose metabolism during diabetes.Research Design and Methods: Mitochondrial fluxes were measured using (2)H/(13)C tracers and nuclear magnetic resonance spectroscopy in ZDF rats during early and advanced diabetes. To determine whether defects in hepatic fat oxidation can be corrected by peroxisome proliferator-activated receptor (PPAR-)-alpha activation, rats were treated with WY14,643 for 3 weeks before tracer administration.Results: Hepatic mitochondrial fat oxidation in the diabetic liver was impaired twofold secondary to decreased ketogenesis, but tricarboxylic acid (TCA) cycle activity and pyruvate carboxylase flux were normal in newly diabetic rats and elevated in older rats. Treatment of diabetic rats with a PPAR-alpha agonist induced hepatic fat oxidation via ketogenesis and hepatic TCA cycle activity but failed to lower fasting glycemia or endogenous glucose production. In fact, PPAR-alpha agonism overstimulated mitochondrial TCA cycle flux and induced pyruvate carboxylase flux and gluconeogenesis in lean rats.Conclusions: The impairment of certain mitochondrial fluxes, but preservation or induction of others, suggests a complex defect in mitochondrial metabolism in the diabetic liver. These data indicate an important codependence between hepatic fat oxidation and gluconeogenesis in the normal and diabetic state and potentially explain the sometimes equivocal effect of PPAR-alpha agonists on glycemia. [ABSTRACT FROM AUTHOR]

The Zucker diabetic fatty (ZDF) rat is a well studied model of obesity and Type 2 Diabetes Mellitus. These animals become insulin resistant early on and frankly diabetic by 12 weeks after birth. Adipocyte resistance to the antilipolytic activity of insulin, results in an elevated concentration of circulating free fatty acids in ZDF rats while hepatic insulin resistance leads to inappropriate rates of glucose production. Nonetheless, hepatocytes from these rats maintain elevated rates of de novo lipogenesis and a 3-fold decrease in fat oxidation and this has been implicated as a mechanism for the development of hepatic steatosis in the ZDF rat. However, it is not known 1) how these in vitro results translate to in vivo hepatic metabolism in the ZDF rat; 2) how abnormal hepatic fat oxidation progresses during the advancement of the phenotype or; 3) how obvious disruptions of hepatic energy metabolism integrate with the known disruption of hepatic glucose metabolism. To study these points we administered a stable isotope cocktail containing [sup 13]C-acetoacetate, [sup 13]C-β-hydroxybutyrate, [U-[sup 13]C]propionate and D[sub 2]O in conscious unrestrained ZDF[sup +/+] and their heterozygous littermate controls at 12 and 20 weeks of age. Isotopomer analysis of plasma metabolites by [sup 13]C and [sup 2]H NMR was used to determine in vivo hepatic ketone production, gluconeogenesis, glycogenolysis, pyruvate cycling and TCA cycle flux. The rate of in vivo ketone dilution was suppressed by 50% in the ZDF[sup +/+] rats compared to controls at 12 wks of age suggesting impaired hepatic fat oxidation. Surprisingly, after 20 weeks, the rate of ketone dilution returned to near normal levels despite an obvious worsening of the diabetic phenotype. These results indicate a clear role for impaired hepatic fat oxidation during the early phenotype of these animals, but suggest a more complex adaptation of hepatic fat oxidation during the progression of the diabetic phenotype. ADA-Funded Research [ABSTRACT FROM AUTHOR]