Prevailing hyperglycemia is critical in the regulation of glucose metabolism during exercise in poorly controlled alloxan-diabetic dogs.

The separate impacts of the chronic diabetic state and the prevailing hyperglycemia on plasma substrates and hormones, in vivo glucose turnover, and ex vivo skeletal muscle (SkM) during exercise were examined in the same six dogs before alloxan-induced diabetes (prealloxan) and after 4-5 wk of poorly controlled hyperglycemic diabetes (HGD) in the absence and presence of approximately 300-min phlorizin-induced (glycosuria mediated) normoglycemia (NGD). For each treatment state, the approximately 15-h-fasted dog underwent a primed continuous 150-min infusion of [3-(3)H]glucose, followed by a 30-min treadmill exercise test (approximately 65% maximal oxygen capacity), with SkM biopsies taken from the thigh (vastus lateralis) before and after exercise. In the HGD and NGD states, preexercise hepatic glucose production rose by 130 and 160%, and the metabolic clearance rate of glucose (MCRg) fell by 70 and 37%, respectively, compared with the corresponding prealloxan state, but the rates of glucose uptake into peripheral tissues (Rd(tissue)) and total glycolysis (GF) were unchanged, despite an increased availability of plasma free fatty acid in the NGD state. Exercise-induced increments in hepatic glucose production, Rd(tissue), and plasma-derived GF were severely blunted by approximately 30-50% in the NGD state, but increments in MCRg remained markedly reduced by approximately 70-75% in both diabetic states. SkM intracellular glucose concentrations were significantly elevated only in the HGD state. Although Rd(tissue) during exercise in the diabetic states correlated positively with preexercise plasma glucose and insulin and GF and negatively with preexercise plasma free fatty acid, stepwise regression analysis revealed that an individual's preexercise glucose and GF accounted for 88% of Rd(tissue) during exercise. In conclusion, the prevailing hyperglycemia in poorly controlled diabetes is critical in maintaining a sufficient supply of plasma glucose for SkM glucose uptake during exercise. During phlorizin-induced NGD, increments in both Rd(tissue) and GF are impaired due to a diminished fuel supply from plasma glucose and a sustained reduction in increments of MCRg.