ANTIDEPRESSANT THERAPY AND HYPOGLYCEMIA

描述（由申请人提供）：糖尿病控制和并发症试验的研究结果表明，通过强化胰岛素治疗实现严格的血糖控制，可以预防和减少与未控制的糖尿病相关的并发症的发生和进展。要实现这一目标，患者的高水平自我护理至关重要。然而，糖尿病患者患抑郁症的可能性是普通人群的两倍。对于合并抑郁症的糖尿病患者，勤奋的自我保健和糖尿病管理可能会严重受损，导致发生糖尿病相关并发症和发病率的风险显著增加。常用的抗抑郁药物选择性5 -羟色胺再摄取抑制剂（SSRIs）与低血糖的发生率显著相关。这背后的机制尚未阐明。拟议的研究将验证SSRIs可能通过降低后脑葡萄糖感应神经元的反应性来损害大脑检测低血糖的能力的假设，而后脑葡萄糖感应神经元对低血糖检测和反调节反应的激活至关重要。本文将检验以下假设：1)外周给药SSRIs可降低对低血糖的反调节反应；2)SSRIs直接递送至后脑葡萄糖感应神经元末端区可损害对低血糖的反调节反应。为了验证这些假设，我们将给非糖尿病Wistar大鼠注射舍曲林（急性或慢性），并测量其对低血糖发作的神经内分泌反调节反应。最后，糖尿病患者表现出严重低血糖发作的显著增加。因此，我们将验证假设III，即SSRIs对糖尿病大鼠的反调节更有害。这些研究的结果将提供新的知识，最终可能帮助初级医生确定对糖尿病抑郁症患者最有利的治疗方法。

DESCRIPTION (provided by applicant): Findings from the Diabetes Control and Complications Trial have shown that tight glycemic control, achieved through intensive insulin therapy, prevents and reduces the onset and progression of the complications associated with uncontrolled diabetes. To achieve this, a high level of patient self-care is critical. Patients with diabetes, however, are twice as likely to develop depression compared to the general population. For diabetic patients with co-morbid depression, diligent self-care and diabetes management can be profoundly impaired, resulting in a significantly greater risk of developing diabetes-related complications and morbidity. The commonly prescribed antidepressant class of selective serotonin reuptake inhibitors (SSRIs) has been associated with significant incidence of hypoglycemia. The mechanism(s) underlying this have not been elucidated. The proposed studies will test the hypothesis that the SSRIs may impair the ability of the brain to detect hypoglycemia by reducing the responsiveness of hindbrain glucose sensing neurons that are critical to hypoglycemia detection and activation of counterregulatory responses. The following hypotheses will be tested: I) Peripheral administration of SSRIs decrease the counterregulatory response to hypoglycemia and II) SSRIs delivered directly into the terminal fields of hindbrain glucose sensing neurons impair the counterregulatory response to hypoglycemia. To test these hypotheses we will administer sertraline, acutely or chronically, to non-diabetic Wistar rats and will measure the neuroendocrine counterregulatory response to a bout of hypoglycemia. Finally, patients with diabetes exhibit a significant increase in severe hypoglycemic episodes. Thus, we will test the hypothesis III) that SSRIs are more detrimental to counterregulation in diabetic vs. non-diabetic rats. The results of these studies will provide new knowledge that ultimately may assist primary physicians in determining the most advantageous treatment for their diabetic patients with depression.