Counterregulation of Hypoglycemia: Skeletal Muscle Glycogen Metabolism During Three Hours of Physiological Hyperinsulinemia in Humans

Abstract

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 approximately 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 approximately 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 approximately 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 (approximately 60-70%) is due to the limitation of glucose disposal, mostly via decreased glycogen synthetic activity in skeletal muscle.

Inhibition of muscle glycogen synthase activity and non-oxidative glucose disposal during hypoglycaemia in normal man

“…This apparent discrepancy between both our results is probably explained by the presence of higher insulin levels in the study by Shamoon et al [56] and also it cannot be excluded that some suppression of glycogen synthase activity would have been unmasked if a constant euglycaemic control situation had been present. Our results are in agreement with those of a very recent study by Cohen et al [20], demonstrating decreased glycogen synthesis in skeletal muscle during mild hypoglycaemia and physiological hyperinsulinaemia in healthy subjects.…”

“…In recent studies we and others -= have demonstrated that muscle glucose uptake is dra-_~ 5-matically reduced during hypoglycaemia in healthy man [18][19][20]. However, the specific cellular events in-~ 4-volved in this phenomenon require further examination.…”

Opposite effects of acute hypoglycemia and acute hyperglycemia on glucose transport and glucose transporters in perfused rat skeletal muscle.

“…Indeed, the restraint on glucose disposal was found to be entirely due to a decrease in glycogen synthesis (44), primarily in nonoxidative skeletal muscle (45). Results from such studies are complicated by the fact that large doses of insulin are used to induce hypoglycemia in vivo, and that systemic hypoglycemia inevitably invokes a surge of counterregulatory hormones, especially catecholamines, which are known to impair muscle glucose uptake and glycogen synthesis.…”

“…Some studies have reported a marked decrease in muscle glucose disposal during insulin-induced hypoglycemia in humans relative to euglycemia (44)(45)(46). Indeed, the restraint on glucose disposal was found to be entirely due to a decrease in glycogen synthesis (44), primarily in nonoxidative skeletal muscle (45).…”

α- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog

“…Because the arterial plasma glucagon level and glucagon secretion decreased so little (if at all) in response to hyperglycemia, it is evident that hyperglycemia per se, even in the presence of modestly increased plasma insulin, had little effect on basal glucagon secretion. On the other hand, a decrease in plasma glucose from 5.8 to 5.2 mmol/l triggered a significant increase in arterial glucagon and glucagon secretion (>200% of basal) at a plasma glucose value well above the well-recognized threshold of 3.8 mmol/l observed in the presence of insulin-induced hypoglycemia in humans (1,12,25,32,33) and dogs (2)(3)(4)15). However, because basal plasma glucose levels in overnight-fasted humans (~4.7 mmol/l) (1-6) are usually lower than those in overnightfasted dogs (~5.8 mmol/l), the extent of the decrease in plasma glucose required to initiate an increase in glucagon secretion in the present study (0.6 mmol/l) was only about half (~1.2 mmol/l) of that reported to initiate glucagon release in response to insulin-induced hypoglycemia in humans (1,25).…”