title: Effects of raising muscle glycogen synthesis rate on skeletal muscle ATP turnover rate in type 2 diabetes.
abstract: Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. We hypothesized that any impairment in insulin-stimulated muscle ATP production could merely reflect the lower rates of muscle glucose uptake and glycogen synthesis, rather than cause it. If this is correct, muscle ATP turnover rates in type 2 diabetes could be increased if glycogen synthesis rates were normalized by the mass-action effect of hyperglycemia. Isoglycemic- and hyperglycemic-hyperinsulinemic clamps were performed on type 2 diabetic subjects and matched controls, with muscle ATP turnover and glycogen synthesis rates measured using (31)P- and (13)C-magnetic resonance spectroscopy, respectively. In diabetic subjects, hyperglycemia increased muscle glycogen synthesis rates to the level observed in controls at isoglycemia [from 19 ± 9 to 41 ± 12 μmol·l(-1)·min(-1) (P = 0.012) vs. 40 ± 7 μmol·l(-1)·min(-1) in controls]. This was accompanied by a modest increase in muscle ATP turnover rates (7.1 ± 0.5 vs. 8.6 ± 0.7 μmol·l(-1)·min(-1), P = 0.04). In controls, hyperglycemia brought about a 2.5-fold increase in glycogen synthesis rates (100 ± 24 vs. 40 ± 7 μmol·l(-1)·min(-1), P = 0.028) and a 23% increase in ATP turnover rates (8.1 ± 0.9 vs. 10.0 ± 0.9 μmol·l(-1)·min(-1), P = 0.025) from basal state. Muscle ATP turnover rates correlated positively with glycogen synthesis rates (r(s) = 0.46, P = 0.005). Changing the rate of muscle glucose metabolism in type 2 diabetic subjects alters demand for ATP synthesis at rest. In type 2 diabetes, skeletal muscle ATP turnover rates reflect the rate of glucose uptake and glycogen synthesis, rather than any primary mitochondrial defect.
authors.affiliation: Institute of Cellular Medicine, Newcastle Magnetic Resonance Centre, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Ee L
authors.initials: EL
authors.lastname: Lim
authors.forename: Kieren G
authors.initials: KG
authors.lastname: Hollingsworth
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Smith
authors.forename: Peter E
authors.initials: PE
authors.lastname: Thelwall
authors.forename: Roy
authors.initials: R
authors.lastname: Taylor
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000465:Algorithms; D001786:Blood Glucose / Q000378:metabolism; D001944:Breath Tests; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D015309:Glucose Clamp Technique; D006003:Glycogen / Q000096:biosynthesis* / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000378:metabolism; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D000255:Adenosine Triphosphate; D006003:Glycogen