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

Preeti Kishore, Ilan Gabriely, Min-Hui Cui, Joseph Di Vito, Srikanth Gajavelli, Jong Hee Hwang, Harry Shamoon

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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·kg -1·min-1 during euglycemia yet ∼50% higher with hypoglycemia [1.30 ± 0.20 mg·kg-1·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 ∼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·kg -1·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.

Original languageEnglish (US)
Pages (from-to)659-666
Number of pages8
JournalDiabetes
Volume55
Issue number3
StatePublished - Mar 2006

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Liver Glycogen
Type 1 Diabetes Mellitus
Hypoglycemia
Glycogenolysis
Glucose
Glucagon
Epinephrine
Norepinephrine
Hormones
Liver
Hypoglycemic Agents

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes. / Kishore, Preeti; Gabriely, Ilan; Cui, Min-Hui; Di Vito, Joseph; Gajavelli, Srikanth; Hwang, Jong Hee; Shamoon, Harry.

In: Diabetes, Vol. 55, No. 3, 03.2006, p. 659-666.

Research output: Contribution to journalArticle

Kishore, P, Gabriely, I, Cui, M-H, Di Vito, J, Gajavelli, S, Hwang, JH & Shamoon, H 2006, 'Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes', Diabetes, vol. 55, no. 3, pp. 659-666.
Kishore, Preeti ; Gabriely, Ilan ; Cui, Min-Hui ; Di Vito, Joseph ; Gajavelli, Srikanth ; Hwang, Jong Hee ; Shamoon, Harry. / Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes. In: Diabetes. 2006 ; Vol. 55, No. 3. pp. 659-666.
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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·kg -1·min-1 during euglycemia yet ∼50{\%} higher with hypoglycemia [1.30 ± 0.20 mg·kg-1·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 ∼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·kg -1·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.",
author = "Preeti Kishore and Ilan Gabriely and Min-Hui Cui and {Di Vito}, Joseph and Srikanth Gajavelli and Hwang, {Jong Hee} and Harry Shamoon",
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T1 - Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes

AU - Kishore, Preeti

AU - Gabriely, Ilan

AU - Cui, Min-Hui

AU - Di Vito, Joseph

AU - Gajavelli, Srikanth

AU - Hwang, Jong Hee

AU - Shamoon, Harry

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N2 - 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·kg -1·min-1 during euglycemia yet ∼50% higher with hypoglycemia [1.30 ± 0.20 mg·kg-1·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 ∼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·kg -1·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.

AB - 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·kg -1·min-1 during euglycemia yet ∼50% higher with hypoglycemia [1.30 ± 0.20 mg·kg-1·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 ∼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·kg -1·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.

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