Intramuscular triglyceride content precedes impaired glucose metabolism without evidence for mitochondrial dysfunction during early development of a diabetic phenotype.

The incidence of type 2 diabetes is highly correlated with obesity; however, there is a lack of research elucidating the temporal progression. Transgenic FVB/N UCP-dta mice, which develop a diabetic phenotype, and their nontransgenic littermates were fed either a high-fat or normal-chow diet and were studied at 6, 9, 12, 15, 18, 21, and 24 weeks of age to test the hypothesis that increased lipid accumulation in skeletal muscle causes mitochondrial dysfunction, leading to the development of insulin resistance. Body composition, intramuscular triglyceride (IMTG) content, glucose metabolism, and mitochondrial function were measured to determine if IMTG drove mitochondrial dysfunction, leading to the development of type 2 diabetes. High-fat-fed transgenic mice had a significantly greater body mass, lipid mass, and IMTG content beginning early in the experiment. Glucose tolerance tests revealed that high-fat-fed transgenic mice developed a significantly insulin resistant response compared with the other 3 groups toward the end of the time course while plasma insulin was elevated very early in the time course. There was no significant difference in several measures of metabolic function throughout the time course. Long-term high-fat feeding in transgenic mice produced increases in IMTG, adiposity, body mass, and plasma insulin accompanied by decreases in glucose metabolism, but did not reveal any deficits in mitochondrial function or regulation during the early stage of the development of type 2 diabetes. It does not appear that lipotoxicity is driving defects in mitochondrial function prior to the onset of insulin resistance.