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1 Department of Pediatrics, Children's Hospital Philadelphia, Philadelphia, PA, USA; Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, USA
2 Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: rsimmons{at}mail.med.upenn.edu.
Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Early in life the animals are insulin resistant and by 6 months of age they develop diabetes. Glycogen content and insulin-stimulated glucose uptake were significantly decreased in muscle from IUGR rats. IUGR muscle mitochondria exhibited significantly decreased rates of state 3 oxygen consumption with pyruvate, glutamate, 
-ketoglutarate and succinate. Decreased pyruvate oxidation in IUGR mitochondria was associated with decreased ATP production, decreased pyruvate dehydrogenase activity and increased expression of pyruvate dehydrogenase kinase 4 (PDK4). Such a defect in IUGR mitochondria leads to a chronic reduction in the supply of ATP available from oxidative phosphorylation. Impaired ATP synthesis in muscle compromises energy-dependent GLUT4 recruitment to the cell surface, glucose transport and glycogen synthesis, which contributes to insulin resistance and hyperglycemia of type 2 diabetes.
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