TY - JOUR
T1 - Hypoglycemia-associated autonomic failure is prevented by opioid receptor blockade
AU - Leu, James
AU - Cui, Min Hui
AU - Shamoon, Harry
AU - Gabriely, Ilan
N1 - Funding Information:
This work was supported by National Institutes of Health Grants DK 079974 (to I.G.), RR017313 (to I.G.), DK 20541 (to I.G. and H.S.), and DK020541 , and the Clinical and Translational Science Awards ( 1UL1RR025750 ).
PY - 2009/9
Y1 - 2009/9
N2 - Context: Repeated hypoglycemia is associated with hypoglycemia-associated autonomic failure (HAAF), a syndrome of defective counterregulation. Objective: HAAF increases the risk of severe hypoglycemia in diabetes, although its mechanism remains unresolved. Because β-endorphin influences the autonomic response to hypoglycemia via opioid receptor activation, we hypothesized that it is also involved in the pathogenesis of HAAF. Research Design and Methods: We asked whether opioid receptor blockade during antecedent hypoglycemia (60 mg/dl) on d 1 would prevent development of HAAF on d 2 in eight nondiabetic subjects (five males, 3 females; age, 28 ± 3.5 yr; body mass index, 24.2 ± 2.1 kg/m2). On four occasions, d 1 was: 1) two 90-min hypoglycemic clamps (N-); 2) two 90-min hypoglycemic clamps plus naloxone (N+); 3) two euglycemic 90-min clamps (C); or 4) two euglycemic 90-min clamps plus naloxone (C+). Results: Day 1 hypoglycemia caused marked deterioration of d 2 hormonal responses to hypoglycemia, consistent with HAAF - i.e. decreased plasma epinephrine, norepinephrine, and glucagon compared to control (C) (374 ± 71 vs. 810 ± 94, 307 ± 65 vs. 686 ± 98, and 71 ± 9 vs. 93 ± 4 pg/ml, respectively, P < 0.01), as well as in endogenous glucose production (24 vs. 163%; P < 0.01). In contrast, naloxone on d 1 completely prevented the defective counterregulatory responses; epinephrine, norepinephrine, and glucagon (852 ± 82, 769 ± 77, and 98 ± 7 pg/ml) and endogenous glucose production recovery (167%) were identical to those after d 1 euglycemia (P < NS for all). Infusion of naloxone alone during euglycemia on d 1 (C+) had no effect on d 2 responses. Conclusions: These data suggest that the opioid signaling system is a promising target for further studies to prevent HAAF.
AB - Context: Repeated hypoglycemia is associated with hypoglycemia-associated autonomic failure (HAAF), a syndrome of defective counterregulation. Objective: HAAF increases the risk of severe hypoglycemia in diabetes, although its mechanism remains unresolved. Because β-endorphin influences the autonomic response to hypoglycemia via opioid receptor activation, we hypothesized that it is also involved in the pathogenesis of HAAF. Research Design and Methods: We asked whether opioid receptor blockade during antecedent hypoglycemia (60 mg/dl) on d 1 would prevent development of HAAF on d 2 in eight nondiabetic subjects (five males, 3 females; age, 28 ± 3.5 yr; body mass index, 24.2 ± 2.1 kg/m2). On four occasions, d 1 was: 1) two 90-min hypoglycemic clamps (N-); 2) two 90-min hypoglycemic clamps plus naloxone (N+); 3) two euglycemic 90-min clamps (C); or 4) two euglycemic 90-min clamps plus naloxone (C+). Results: Day 1 hypoglycemia caused marked deterioration of d 2 hormonal responses to hypoglycemia, consistent with HAAF - i.e. decreased plasma epinephrine, norepinephrine, and glucagon compared to control (C) (374 ± 71 vs. 810 ± 94, 307 ± 65 vs. 686 ± 98, and 71 ± 9 vs. 93 ± 4 pg/ml, respectively, P < 0.01), as well as in endogenous glucose production (24 vs. 163%; P < 0.01). In contrast, naloxone on d 1 completely prevented the defective counterregulatory responses; epinephrine, norepinephrine, and glucagon (852 ± 82, 769 ± 77, and 98 ± 7 pg/ml) and endogenous glucose production recovery (167%) were identical to those after d 1 euglycemia (P < NS for all). Infusion of naloxone alone during euglycemia on d 1 (C+) had no effect on d 2 responses. Conclusions: These data suggest that the opioid signaling system is a promising target for further studies to prevent HAAF.
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U2 - 10.1210/jc.2009-0882
DO - 10.1210/jc.2009-0882
M3 - Article
C2 - 19567512
AN - SCOPUS:69949109033
SN - 0021-972X
VL - 94
SP - 3372
EP - 3380
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 9
ER -