Effects of a Selective Serotonin Reuptake Inhibitor, Fluoxetine, on Counterregulatory Responses to Hypoglycemia in Healthy Individuals

Abstract

OBJECTIVE-Hypoglycemia commonly occurs in intensivelytreated diabetic patients. 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-A total of 20 healthy (10 male and 10 female) subjects participated in an initial single-step hyperinsulinemic (9 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 )-hypoglycemic (means Ϯ SE 2.9 Ϯ 0.1 mmol/l) clamp study and were then randomized to receive 6 weeks' administration of fluoxetine (n ϭ 14) or identical placebo (n ϭ 6) in a double-blind fashion. After 6 weeks, subjects returned for a second hypoglycemic clamp. Glucose kinetics were determined by three-tritiated glucose, and muscle sympathetic nerve activity (MSNA) was measured by microneurography.RESULTS-Despite identical hypoglycemia (2.9 Ϯ 0.1 mmol/l) and insulinemia during all clamp studies, key ANS (epinephrine, norepinephrine, and MSNA but not symptoms), neuroendocrine (cortisol), and metabolic (endogenous glucose production, glycogenolysis, and lipolysis) responses were increased (P Ͻ 0.01) following fluoxetine.CONCLUSIONS-This study demonstrated that 6 weeks' administration of the SSRI fluoxetine can amplify a wide spectrum of ANS and metabolic counterregulatory responses during hypoglycemia in healthy individuals. These data further suggest that serotonergic transmission may be an important mechanism in modulating sympathetic nervous system drive during hypoglycemia in healthy individuals. Diabetes 57:2453-2460, 2008 S everal reports have indicated that fluoxetine could have metabolic effects and influence carbohydrate metabolism (1-3). In fact, there have been three case studies reporting the occurrence of hypoglycemia related to the use of selective serotonin reuptake inhibitors (SSRIs) in depressed patients with and without diabetes (4 -6). However, although SSRIs are potent inhibitors of neuronal serotonin uptake, they also have the ability to block norepinephrine transport (7). This could increase sympathetic outflow activity (2,8). Baudrie and Chaouloff (9) have previously reported an increased hyperglycemic response to 2-deoxy-D-glycose in conscious rats following serotononergic receptor antagonists, implying increased counterregulation in these animals.A subsequent study by Perry and Fuller (2) demonstrated that systemic injection of the SSRI fluoxetine in rats resulted in threefold increases of hypothalamic norepinephrine release, thereby providing a mechanistic basis for SSRIs to modulate sympathetic nervous system activity. A later study by Bymaster et al. (3) examined the specificity of five different SSRIs (fluoxetine, citalopram, fluvoxamine, paroxe...

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Counterregulatory Responses to Hypoglycemia in Individuals With Type 1 Diabetes

“…We therefore hypothesize that fluoxetine exerted a relatively restraining effect on symptom generation while stimulating neurohumoral and cardiovascular sympathetic tone during hypoglycemia. Similar to our findings in nondiabetic individuals, despite the increased sympathetic nervous system drive and elevated epinephrine levels, fluoxetine had no effects on amplifying glucagon responses during hypoglycemia (9). This would add support to the hypothesis that there is an inherent B-cell defect restricting glucagon release during hypoglycemia in type 1 diabetes rather than simply just a loss of ANS input into the ␣-cells (37).…”

“…Somewhat surprisingly, there was not an increase in symptom scores despite the significant increases in central ANS drive and the respective target organ responses (i.e., liver, adipose tissue, and heart) following fluoxetine. This apparent dissociation between neutral symptom responses and increases in other components of the sympathetic nervous system following fluoxetine was also clearly demonstrated in the previous study with nondiabetic individuals (9). These data further suggest that serotonergic pathways are involved in the generation of symptom responses during hypoglycemia.…”

“…Hypoglycemia remains the major barrier to even near normalization of glucose in patients with type 1 diabetes. We have recently reported the beneficial effects of 6 weeks' fluoxetine administration on amplifying counterregulatory mechanisms during hypoglycemia in nondiabetic individuals (9). In this present study, we have tested the hypothesis that 6 weeks' administration of fluoxetine will enhance counterregulatory responses during hypoglycemia in type 1 diabetes.…”

“…Two recent studies in healthy humans (9) and conscious rats (10) have provided further insight into the effects of SSRIs on counterregulatory physiology during hypoglycemia. Briscoe et al (9) investigated the effects of 6 weeks of high-dose fluoxetine administration on physiological responses to hypoglycemia in a group of healthy, nondepressed humans.…”

“…Briscoe et al (9) investigated the effects of 6 weeks of high-dose fluoxetine administration on physiological responses to hypoglycemia in a group of healthy, nondepressed humans. Key sympathetic nervous system (epinephrine, norepinephrine, and muscle sympathetic nerve activity [MSNA]) and metabolic (glucose production and lipolysis) counterregulatory mechanisms were significantly amplified by the SSRI.…”