SummaryThe purpose of the present study was to evaluate the role of muscle glycogen synthase activity in the reduction of glucose uptake during hypoglycaemia. Six healthy young men were examined twice; during 120 min of hyperinsulinaemic (1.5 mU 9 kg -1 9 min -1) euglycaemia followed by: 1) 240 min of graded hypoglycaemia (plasma glucose nadir 2.8 mmol/1) or 2) 240 min of euglycaemia. At 350-360 min a muscle biopsy was taken and indirect calorimetry was performed at 210-240 and 330-350 rain. Hypoglycaemia was associated with markedly increased levels of adrenaline, growth hormone and glucagon and also with less hyperinsulinaemia. During hypoglycaemia the fractional velocity for glycogen synthase was markedly reduced; from 29.8 + 2.3 to 6.4 + 0.9 %, p < 0.05. Total glucose disposal was decreased during hypoglycaemia (5.58 + 0.55 vs 11.01 + 0.75 mg. kg -1 9 min 1 (euglycaemia); p < 0.05); this was primarily due to a reduction of non-oxidative glucose disposal (2.43 + 0.41 vs 7.15 + 0.7 mg. kg -1 9 min -1 (euglycaemia); p < 0.05), whereas oxidative glucose disposal was only suppressed to a minor degree. In conclusion hypoglycaemia virtually abolishes the effect of insulin on muscle glycogen synthase activity. This is in keeping with the finding of a marked reduction of non-oxidative glucose metabolism. [Diabetologia (1996) 39: 226-234] Key words Hypoglycaemia, counter-regulation, glucose disposal, muscle glycogen synthase activity, glucose mass effect.Hypoglycaemic episodes represent a major treatment-induced problem [1][2][3][4][5]. Severe hypoglycaemia is more frequent in patients receiving intensive insulin treatment, and the recent results from the Diabetes Control and Complications trial (DCCT) [6], proving the benefit of strict metabolic control on late diabetic complications, may be anticipated to enhance this problem.

Growth hormone (GH) counteracts in general the effects of insulin on glucose and lipid metabolism, but shares protein anabolic properties with insulin. Under physiological circumstances GH does not affect total glucose turnover directly. There is however evidence that GH acutely decreases glucose oxidation (secondary to an increase in lipid oxidation) and suppresses muscle uptake of glucose, suggesting that GH redistributes glucose fluxes into a non-oxidative pathway, which could be a build up of glycogen depots through gluconeogenesis. Since GH secretion is inhibited in the fed state these actions are mainly important in the postprandial or fasting state. Under pathological conditions of GH excess (e.g. acromegaly, poorly controlled tp. 1 diabetes or high dose GH treatment) the diabetogenic actions of GH become apparent. In these patients increased endogenous glucose production, decreased muscle glucose uptake and rising blood glucose levels are observed. In patients with intact β-cell function these changes are counterbalanced by hyperinsulinemia – such hyperinsulinemia may in the long term induce increased cardiovascular morbidity and mortality (‘Reavens syndrome X’). When stimulated with insulin these patients exhibit insulin resistance at the liver, in adipose tissue and in muscle. Few elaborate studies on the effects of GH on glucose metabolism in GH deficient patients have been conducted. These patients are hypersensitive to the actions of insulin on glucose metabolism and there is some evidence that when GH initially is given to such patients in the GH deprived state, paradox insulin-like effects of GH may be observed. Whether this may relate to increased activity of insulin-like growth factors is unsettled.