COUNTERREGULATION OF HYPOGLYCEMIA - SKELETAL-MUSCLE GLYCOGEN-METABOLISM DURING 3 HOURS OF PHYSIOLOGICAL HYPERINSULINEMIA IN HUMANS

We examined the role of skeletal muscle in counterregulation of hypoglycemia (3.4 +/- 0.1 mmol/l) in 12 nondiabetic individuals (age 26 +/- 1 years, body mass index 24.2 +/- 0.7 kg/m(2)) during physiological hyperinsulinemia (280 +/- 25 pmol/l compared with euglycemia (4.8 +/- 0.1 mmol/l). During hypoglycemia, hepatic glucose output (3-[H-3]-glucose) was greater (7.72 +/- 2.72 mu mol . kg(-1). min(-1), P < 0.01), glucose uptake was similar to 49% lower (21.20 +/- 3.55 mu mol . kg(-1) . min(-1),P < 0.005), and glucose clearance was reduced (P < 0.002) compared with euglycemia. Rates of flux of plasma-derived glucosyl units through glycolysis were similar in the two experiments, while glycogen synthetic rates were significantly reduced during hypoglycemia (P < 0.01) and accounted entirely for the reduction in glucose disposal. The insulin-induced activation of skeletal muscle glycogen synthase (reflected by K-m decline by similar to 50% from 0.408 +/- 0.056 mmol/l and fractional velocity increase by approximately twofold from 21.8 +/- 2.7%) was completely abolished in hypoglycemia. In concert, glycogen phosphorylase activity increased during hypoglycemia by similar to 40% (P = 0,0001). Hypoglycemia resulted in seven- to eightfold increments in plasma epinephrine (P < 0.0001) and growth hormone (P < 0.001) and 40-60% increments in plasma glucagon (P < 0.005) and cortisol (P < 0.05). We conclude that, in this model of mild hypoglycemia of moderate duration, the majority of the glucose made available during the counterregulatory process (similar to 60-70%) is due to the limitation of glucose disposal, mostly via decreased glycogen synthetic activity in skeletal muscle.