Hormone-independent activation of EGP during hypoglycemia is absent in type 1 diabetes mellitus

It has been suggested that insulin-induced suppression of endogenous glucos e production (EGP) may be counteracted independently of increased epinephri ne (Epi) or glucagon during moderate hypoglycemia. We examined EGP in nondi abetic (n = 12) and type 1 diabetic (DM1, n = 8) subjects while lowering pl asma glucose (PG) from clamped euglycemia (5.6 mmol/l) to values just above the threshold for Epi and glucagon secretion (3.9 mmol/l). Individualized doses of insulin were infused to maintain euglycemia during pancreatic clam ps by use of somatostatin (250 mu g/h), glucagon (1.0 ng.kg(-1).min(-1)), a nd growth hormone (GH) (3.0 ng.kg(-1).min(-1)) infusions without need for e xogenons glucose. Then, to achieve physiological hyperinsulinemia (HIns), i nsulin infusions were fixed at 20% above the rate previously determined for each subject. In nondiabetic subjects, PG was reduced from 5.4 +/- 0.1 mmo l/l to 3.9 +/- 0.1 mmol/l in the experimental protocol, whereas it was held constant (5.3 +/- 0.2 mmol/l and 5.5 mmol/l) in control studies. In the la tter, EGP (estimated by [3-H-3]glucose) fell to values 40% of basal (P < 0. 01). In contrast, in the experimental protocol, at comparable HIns but with PG at 3.9 +/- 0.1 mmol/l, EGP was activated to values about twofold higher than in the euglycemic control (P < 0.01). In DM1 subjects, EGP failed to increase in the face of HIns and PG = 3.9 +/- 0.1 mmol/l. The decrease from basal EGP in DM1 subjects (4.4 +/- 1.0 mu mol.kg(-1).min(-1)) was nearly t wofold that in nondiabetics (2.5 +/- 0.8 mu mol.kg(-1).min(-1), P < 0.02). When PG was lowered further to frank hypoglycemia (similar to 3.1 mmol/l), the failure of EGP activation in DML subjects was even more profound but as sociated with a 50% lower plasma Epi response (P < 0.02) compared with nond iabetics. We conclude that glucagon- or epinephrine-independent activation of EGP may accompany other counterregulatory mechanisms during mild hypogly cemia in humans and is impaired or absent in DM1.