Hypoxemic Stimulation of Heart Glycogen Synthase and Synthesis Effects of Insulin and Diabetes Mellitus MAREN R. LAUGHLIN, CHERYL MORGAN, AND EUGENE J. BARRETT With radiotracer and 13 C nuclear magnetic resonance ( 13 C-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 13 C-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,] = 0.65 (xmol • 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 fxmol • m i n 1 • g~ 1 in the saline- and insulin- treated rats, respectively. In the diabetic rats by 10 min after hypoxemia, GS, increased only modestly in both saline-treated (0.16 jxmol • min 1 • g~ 1 ) and insulin-treated (0.21 (xmol • 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 ixmol • min 1 • g~ 1 ) and essentially absent in the saline-treated rats (0.03 fxmol • min 1 • g~ 1 ) compared with controls. We conclude that recovery from hypoxemia is accompanied by a marked activation of GS, 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. Diabetes 40:385-90, 1991 From the Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut. Address correspondence and reprint requests to Dr. Eugene J. Barrett, Division of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, Fitkin 108, PO Box 3333, New Haven, CT 06510. Received for publication 28 November 1989 and accepted in revised form 1 November 1990. N ormally, the myocardium primarily oxidizes fatty acid to generate ATP. Glycolysis becomes an im- portant source of ATP during periods of relative oxygen deprivation that occur with ischemia, hy- poxemia, or very high work loads. Heart glycogen is mobi- lized quickly after the onset of absolute or relative oxygen deficiency, both in vitro and in vivo (1-3). This may occur both through phosphorylation of glycogen phosphorylase b (GPfc>) to the more active GPa form and by direct activation of GPfc> via increases in cellular AMP concentrations from ATP breakdown (3-5). Presumably, if the episode of oxygen deprivation is short-lived, the heart will replete the glycogen stores, although little is known regarding the time course of this process or how the activities of GP and glycogen syn- thase (GS) are regulated during this time. During periods of heart glycogen synthesis induced by insulin infusion, we have observed a quantitative correspon- dence between the activity of the glucose-6-phosphate (G6P)-independent form of GS (GS,) present in heart muscle and the rate of in vivo glycogen synthesis (6). This relation- ship appears to hold in the hearts of diabetic and fasted rats, which have depressed GS, activity, and nondiabetic rats (7) and supports the hypothesis that the activity of GS, is rate limiting for the process of glycogen synthesis in vivo. In studies of the effects of hypoxia on glycogen mobilization by heart, we observed an unexpected striking activation of GS during recovery from transient hypoxemic episodes. In this study, we report the time course for this activation of GS, its relationship to glycogen synthesis, and the effects of diabetes and insulin on the activation of GS in the posthy- poxic heart. RESEARCH DESIGN AND METHODS Male Sprague-Dawley rats (250-350 g) were kept on a 12- h light-dark cycle and fed standard lab chow and water ad libitum. Diabetes was induced by injection of alloxan (60- 70 mg/kg body wt) into a femoral vein 2-3 days before the DIABETES, VOL. 40, MARCH 1991 385 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/40/3/385/358298/40-3-385.pdf by guest on 04 November 2022