Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia intensively treated type 1 diabetes

Impairment of hypoglycemic counterregulation in intensively treated type 1 diabetes has been attributed to deficits in counterregulatory hormone secretion. However, because the liver plays a critical part in recovery of plasma glucose, abnormalities in hepatic glycogen metabolism per se could also play an important role. We quantified the contribution of net hepatic glycogenolysis during insulin-induced hypoglycemia in 10 nondiabetic subjects and 7 type 1 diabetic subjects (HbA1c 6.5 \ub1 0.2%) using 13C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma glucose 92 \ub1 4 mg/dl) or hypoglycemia (plasma glucose 58 \ub1 3 mg/dl). In nondiabetic subjects, hypoglycemia was associated with a brisk counterregulatory hormone response (plasma epinephrine 246 \ub1 38 vs. 2,785 \ub1 601 pmol/l during hypoglycemia, plasma norepinephrine 1.9 \ub1 0.2 vs. 2.5 \ub1 0.3 nmol/l, and glucagon 38 \ub1 7 vs. 92 \ub1 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous glucose production (EGP 0.83 \ub1 0.14 mg \ub7 kg\u961 \ub7 min\u961 during euglycemia yet 50% higher with hypoglycemia [1.30 \ub1 0.20 mg \ub7 kg\u961 \ub7 min\u961], P < 0.001). Net hepatic glycogen content declined progressively during hypoglycemia to 22 \ub1 3% below baseline (P < 0.024). By the final 30 min of hypoglycemia, hepatic glycogen fell from 301 \ub1 14 to 234 \ub1 10 mmol/l (P < 0.001) and accounted for 100% of EGP. In marked contrast, after an overnight fast, hepatic glycogen concentration in type 1 diabetic subjects (215 \ub1 23 mmol/l) was significantly lower than in nondiabetic subjects (316 \ub1 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to hypoglycemia was significantly reduced with small increments in plasma epinephrine and norepinephrine (126 \ub1 22 vs. 448 \ub1 16 pmol/l in hypoglycemia and 0.9 \ub1 0.3 vs. 1.6 \ub1 0.3 nmol/l, respectively, P < 0.05 for both) and no increase in plasma glucagon. EGP decreased during hypoglycemia with no recovery (1.3 \ub1 0.5 vs. 1.2 \ub1 0.3 mg \ub7 kg\u961 \ub7 min\u961 compared with euglycemia, P =3D NS), and hepatic glycogen concentration did not change significantly with hypoglycemia. We conclude that glycogenolysis accounts for the majority of EGP during the first 90 min of hypoglycemia in nondiabetic subjects. In intensively treated type 1 diabetes, despite some activation of counterregulation, hypoglycemia failed to stimulate hepatic glycogen breakdown or activation of EGP, factors that may contribute to the defective counterregulation seen in such patient