title: Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes.
abstract: 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.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. pkishore@aecom.yu.edu
authors.forename: Preeti
authors.initials: P
authors.lastname: Kishore
authors.forename: Ilan
authors.initials: I
authors.lastname: Gabriely
authors.forename: Min-Hui
authors.initials: MH
authors.lastname: Cui
authors.forename: Joseph
authors.initials: J
authors.lastname: Di Vito
authors.forename: Srikanth
authors.initials: S
authors.lastname: Gajavelli
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Hwang
authors.forename: Harry
authors.initials: H
authors.lastname: Shamoon
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005943:Gluconeogenesis; D005947:Glucose / Q000096:biosynthesis; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008112:Liver Glycogen; D005947:Glucose