Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats.
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 mo of age they develop diabetes. Glycogen content and insulin-stimulated 2-deoxyglucose uptake were significantly decreased in muscle from IUGR rats. IUGR muscle mitochondria exhibited significantly decreased rates of state 3 oxygen consumption with pyruvate, glutamate, alpha-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. 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 contribute to insulin resistance and hyperglycemia of type 2 diabetes.
Selak
Mary A
MA
Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania, 19104, USA.
Storey
Bayard T
BT
Peterside
Iyalla
I
Simmons
Rebecca A
RA
D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003580:Cytochromes / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D019344:Lactic Acid / Q000097:blood; D008854:Microscopy, Electron; D008931:Mitochondria, Muscle / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000196:embryology* / Q000378:metabolism* / Q000648:ultrastructure; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology; D011247:Pregnancy; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D003580:Cytochromes; D005230:Fatty Acids, Nonesterified; D009124:Muscle Proteins; D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D006003:Glycogen; D002950:Citrate (si)-Synthase; D000154:Aconitate Hydratase; D005947:Glucose