Abstract

Objective: Hypoglycemia commonly occurs in intensively treated patients with Diabetes. Repeated hypoglycemia blunts counterregulatory responses thereby increasing the risk for further hypoglycemic events. Currently, physiologic approaches to augment counterregulatory responses to hypoglycemia have not been established. Therefore the specific aim of this study was to test the hypothesis that 6 weeks administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine would amplify autonomic nervous system (ANS) and neuroendocrine counterregulatory mechanisms during hypoglycemia.

Research Design and Methods: Twenty healthy (10M/10F) subjects participated in an initial single step hyperinsulinemic (9pmol/kg/min) hypoglycemic (2.9±0.1 mmol/l) clamp study and were then randomized to receive 6 weeks of fluoxetine (n=14) or identical placebo (n=6) in a double blind fashion. After 6 weeks, subjects returned for a second hypoglycemic clamp. Glucose kinetics were determined by 3-tritiated glucose, and muscle sympathetic nerve activity (MSNA) was measured by microneurography.

Results: Despite: identical hypoglycemia (2.9±0.1 mmol/l) and insulinemia during all clamp studies, key ANS (epinephrine, norepinephrine, MSNA but not symptoms), neuroendocrine (cortisol) and metabolic (endogenous glucose production, glycogenolysis, lipolysis) were increased (p<0.01) following fluoxetine.

Conclusion: This study has demonstrated that 6 weeks administration of the SSRI fluoxetine can amplify a wide spectrum of ANS and metabolic counterregulatory responses during hypoglycemia in healthy man. These data further suggest that serotonergic transmission may be an important mechanism in modulating sympathetic nervous system (SNS) drive during hypoglycemia in healthy man.