Hypoxemic Stimulation of Heart Glycogen Synthase and Synthesis: Effects of Insulin and Diabetes Mellitus

With radiotracer and ¹³C nuclear magnetic resonance (¹³C-NMR) methods, we studied the time course of glycogen resynthesis after three 90-s episodes of hypoxemia in both control and diabetic rats in vivo. Glycogen synthesis was measured in the presence and absence of infused insulin and compared with the changes in glycogen synthase (GS) and phosphorylase activities. We observed in ¹³C-NMR spectra the expected mobilization of glycogen during hypoxia in vivo. In control rats with or without exogenous insulin, this was followed by a rapid resynthesis of glycogen during a 40-min recovery period. A marked activation of GS was observed by 10 min (glucose-6-phosphate–independent form of GS [GS_l] = 0.65 μmol · min⁻¹ · g⁻¹ or 92% of total GS), and activation persisted up to 40 min in both groups. Glycogen synthesis during the recovery period averaged 0.51 and 0.45 μmol · min⁻¹ · g⁻¹ in the saline- and insulin-treated rats, respectively. In the diabetic rats by 10 min after hypoxemia, GS_l increased only modestly in both saline-treated (0.16 μmol · min⁻¹· g⁻¹) and insulin-treated (0.21 μmol · min⁻¹ · g⁻¹) rats, and activation persisted up to 40 min only with insulin treatment. Glycogen synthesis was slower in the diabetic rats given insulin (0.28 μmol · min⁻¹ · g⁻¹) and essentially absent in the saline-treated rats (0.03 μmol · min⁻¹ · g⁻¹) compared with controls. We conclude that recovery from hypoxemia is accompanied by a marked activation of GS_l and rapid rates of glycogen synthesis in nondiabetic rats, and diabetes markedly blunts this response. Acute insulin infusion only partially overcomes this block. This impairment in glycogen storage may impact on the ability of the diabetic myocardium to withstand repeated hypoxemic or ischemic stresses.