Counterregulation of Hypoglycemia: Skeletal Muscle Glycogen Metabolism During Three 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/m²) during physiological hyperinsulinemia (280 ± 25 pmol/l) compared with euglycemia (4.8 ± 0.1 mmol/l). During hypoglycemia, hepatic glucose output (3-[3H]-glucose) was greater (7.72 ± 2.72 mumol.kg⁻¹ · min⁻¹, P < 0.01), glucose uptake was ∼ 49% lower (21.20 ± 3.55 mumol.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 Km decline by ∼ 50% from 0.408 ± 0.056 mmol/l and fractional velocity increase by ∼ twofold from 21.8 ± 2.7%) was completely abolished in hypoglycemia. In concert, glycogen phosphorylase activity increased during hypoglycemia by ∼ 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 (∼ 60-70%) is due to the limitation of glucose disposal, mostly via decreased glycogen synthetic activity in skeletal muscle.