INCREASED EPINEPHRINE AND SKELETAL-MUSCLE RESPONSES TO HYPOGLYCEMIA IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS

We evaluated skeletal muscle counterregulation during hypoglycemia in nine subjects with non-insulin-dependent diabetes mellitus (NIDDM) (Hb A(1c) 9.4 +/- 0.5%, nl < 6.2%) compared with six normal controls, matc hed for age (51 +/- 3 and 49 +/- 5 yr, respectively) and body mass ind ex(27.3 +/- 1.2 and 27.0 +/- 2.1 kg/ m(2)). After 60 min of euglycemia (plasma insulin similar to 140 mu U/ ml), plasma glucose was lowered to 62 +/- 2 mg/dl by 120 min. Hypoglycemia induced a 2.2-fold greater increase in plasma epinephrine in NIDDM (P < 0.001), while the plasma glucagon response was blunted (P < 0.01). Hepatic glucose output ([H-3 -3]glucose) suppressed similarly during euglycemia, but during hypogly cemia was greater in NIDDM(P < 0.001). Conversely, glucose uptake duri ng euglycemia was 150%; greater in controls (P < 0.01) and remained pe rsistently higher than in NIDDM during hypoglycemia. In NIDDM, plasma FFA concentrations were approximately fivefold greater (P < 0.001), an d plasma lactate levels were similar to 40% higher than in controls du ring hypoglycemia (P < 0.01); the rates of glycolysis from plasma gluc ose were similar in the two groups despite a 49% lower rate of glucose uptake in NIDDM (3.4 +/- 0.9 vs. 6.9 +/- 1.3 mg/kg per minute, P < 0. 001). Muscle glycogen synthase activity. fell by 42% with hypoglycemia (P < 0.01)in NIDDM but not in controls. In addition, glycogen phosphor ylase was activated by 56% during hypoglycemia in NIDDM only (P < 0.01 ). Muscle glucose-6-phosphate concentrations rose during hypoglycemia by a twofold greater increment in NIDDM (P < 0.01). Thus, skeletal mus cle participates in hypoglycemia counterregulation in NIDDM, directly by decreased removal of plasma glucose and, indirectly, by providing l actate for hepatic gluconeogenesis. Consequently, in addition to inher ent insulin resistance in NIDDM, the enhanced plasma epinephrine respo nse during hypoglycemia may partially offset impaired glucagon secreti on and counteract the effects of hyperinsulinemia on Liver, fat, and s keletal muscle.