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

Abstract

OBJECTIVE-Previous work has demonstrated that chronic administration of the serotonin reuptake inhibitor (SSRI) fluoxetine augments counterregulatory responses to hypoglycemia in healthy humans. However, virtually no information exists regarding the effects of fluoxetine on integrated physiological counterregulatory responses during hypoglycemia in type 1 diabetes. Therefore, the specific aim of this study was to test the hypothesis that 6-week use of the SSRI fluoxetine would amplify autonomic nervous system (ANS) counterregulatory responses to hypoglycemia in individuals with type 1 diabetes. )-hypoglycemic clamp studies before and after 6 weeks of fluoxetine administration (n ϭ 8) or identical placebo (n ϭ 10). Glucose kinetics was determined by 3-tritiated glucose. Muscle sympathetic nerve activity (MSNA) was determined by microneurography. RESEARCH DESIGN AND METHODS-EighteenRESULTS-Hypoglycemia (2.8 Ϯ 0.1 mmol/l) and insulinemia (646 Ϯ 52 pmol/l) were similar during all clamp studies. ANS, neuroendocrine, and metabolic counterregulatory responses remained unchanged in the placebo group. However, fluoxetine administration significantly (P Ͻ 0.05) increased key ANS (epinephrine, norepinephrine, and MSNA), metabolic (endogenous glucose production and lipolysis), and cardiovascular (systolic blood pressure) counterregulatory responses during hypoglycemia.CONCLUSIONS-This study has demonstrated that 6-week administration of the SSRI fluoxetine can amplify ANS and metabolic counterregulatory mechanisms during moderate hypoglycemia in patients with type 1 diabetes. These data also suggest that the use of fluoxetine may be useful in increasing epinephrine responses during hypoglycemia in clinical practice. Diabetes 57:3315-3322, 2008 S elective serotonin reuptake inhibitors (SSRIs) are effective drugs for the treatment of depressive disorders associated with reduced serotonergic function. Serotonergic neurons play an important role in the regulation of neuroendocrine function carried out via both sympathoadrenal and hypothalamic-pituitaryadrenal (HPA) pathways.Two studies have reported increased hypoglycemia and loss of awareness to hypoglycemia related to the use of SSRIs in depressed patients with type 1 diabetes (1,2). Although SSRIs are potent inhibitors of neuronal serotonin uptake, they also have the ability to block norepinephrine transport (3,4). This would be predicted to increase sympathetic outflow activity (4 -7). Supporting this, previous studies by a number of investigators have demonstrated that SSRIs can modulate sympathetic nervous system activity and increase counterregulation in rats (8).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. Key sympathetic nervous system (epinephrine, norepinephrine,...

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