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 +/- 0.2%) using 13C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma
glucose 92 +/- 4 mg/dl) or
hypoglycemia (plasma
glucose 58 +/- 3 mg/dl). In nondiabetic subjects,
hypoglycemia was associated with a brisk counterregulatory
hormone response (plasma
epinephrine 246 +/- 38 vs. 2,785 +/- 601 pmol/l during
hypoglycemia, plasma
norepinephrine 1.9 +/- 0.2 vs. 2.5 +/- 0.3 nmol/l, and
glucagon 38 +/- 7 vs. 92 +/- 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous
glucose production (EGP 0.83 +/- 0.14 mg x kg(-1) x min(-1) during euglycemia yet approximately 50% higher with
hypoglycemia [1.30 +/- 0.20 mg x kg(-1) x min(-1)], P < 0.001). Net
hepatic glycogen content declined progressively during
hypoglycemia to 22 +/- 3% below baseline (P < 0.024). By the final 30 min of
hypoglycemia,
hepatic glycogen fell from 301 +/- 14 to 234 +/- 10 mmol/l (P < 0.001) and accounted for approximately 100% of EGP. In marked contrast, after an overnight fast,
hepatic glycogen concentration in type 1 diabetic subjects (215 +/- 23 mmol/l) was significantly lower than in nondiabetic subjects (316 +/- 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to
hypoglycemia was significantly reduced with small increments in plasma
epinephrine and
norepinephrine (126 +/- 22 vs. 448 +/- 16 pmol/l in
hypoglycemia and 0.9 +/- 0.3 vs. 1.6 +/- 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 +/- 0.5 vs. 1.2 +/- 0.3 mg x kg(-1) x min(-1) compared with euglycemia, P = 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 patients.