Submitted on December 12, 2007
Accepted on March 4, 2008
The Selective Serotonin Reuptake Inhibitor Sertraline Enhances Counterregulatory Responses to Hypoglycemia
Nicole M. Sanders1*, Charles W. Wilkinson2, Gerald J. Taborsky3, Salwa Al-Noori4, Wendi Daumen5, Aryana Zavosh5, and Dianne P. Figlewicz1
1 Metabolism & Endocrinology, VA Puget Sound Health Care System, Seattle, Washington, United States; Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, United States
2 Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington, United States; Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, United States
3 Metabolism & Endocrinology, VA Puget Sound Health Care System, Seattle, Washington, United States; Medicine, University of Washington, Seattle, Washington, United States
4 Seattle Institute for Biomedical and Clinical Research, Seattle, Washington, United States; Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, United States
5 Seattle Institute for Biomedical and Clinical Research, Seattle, Washington, United States
* To whom correspondence should be addressed. E-mail: sandersn{at}u.washington.edu.
Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for patients with co-morbid diabetes and depression. Clinical case studies in diabetic patients, however, suggest that SSRI therapy may exacerbate hypoglycemia. We hypothesized that SSRIs might increase the risk of hypoglycemia by impairing hormonal counterregulatory responses (CRR). We evaluated the effect of the SSRI sertraline on hormonal CRRs to single or recurrent hypoglycemia in non-diabetic rats. Since there are time dependent-effects of SSRIs on serotonin neurotransmission that correspond with therapeutic action, we evaluated the effect of 6 or 20d sertraline treatment on hypoglycemia CRRs. We found that 6d sertraline (SERT) treatment specifically enhanced the epinephrine response to a single bout of hypoglycemia vs. vehicle- (VEH) treated rats (t.120; VEH, 2,573±448 vs. SERT, 4,202±545, pg/ml; p<0.05). In response to recurrent hypoglycemia, VEH-treated rats exhibited the expected impairment in epinephrine secretion (t.60; 678±73, pg/ml) vs. VEH-treated rats experiencing first time hypoglycemia (t.60; 2,081±436, pg/ml; p<0.01). SERT treatment prevented the impaired epinephrine response in recurrent hypoglycemic rats (t.60; 1,794±276, pgl/ml). In 20d SERT-treated rats, epinephrine, norepinephrine and glucagon CRRs were all significantly elevated above VEH-treated controls in response to hypoglycemia. Similar to 6d sertraline treatment, 20d sertraline treatment rescued the impaired epinephrine response in recurrent hypoglycemic rats. Our data demonstrate that neither 6 nor 20d sertraline treatment impaired hormonal CRRs to hypoglycemia in non-diabetic rats. Instead, sertraline treatment resulted in an enhancement of hypoglycemia CRRs and prevented the impaired adrenomedullary response normally observed in recurrent hypoglycemic rats.
