ANTIDEPRESSANT THERAPY AND HYPOGLYCEMIA

描述(申请人提供)：糖尿病控制和并发症试验的结果表明，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发展。要做到这一点，高度的病人自我护理是至关重要的。然而，与普通人群相比，糖尿病患者患抑郁症的可能性是普通人的两倍。对于患有抑郁症的糖尿病患者，勤奋的自我护理和糖尿病管理可能会受到严重损害，导致发生糖尿病相关并发症和发病率的风险显著增加。常用的抗抑郁药类选择性5-羟色胺再摄取抑制剂(SSRIs)与显著的低血糖发生率有关。这背后的机制(S)尚未阐明。这项拟议的研究将检验这样一种假设，即SSRI可能通过降低后脑葡萄糖敏感神经元的反应性来削弱大脑检测低血糖的能力，而后脑葡萄糖敏感神经元是检测低血糖和激活反调节反应的关键。将检验以下假设：i)外周给药可降低对低血糖的反调节反应；ii)直接进入后脑葡萄糖感觉神经元的终末区域的SSRI会削弱对低血糖的反调节反应。为了验证这些假说，我们将急性或慢性地给非糖尿病Wistar大鼠服用舍曲林，并将测量神经内分泌对低血糖的反向调节反应。最后，糖尿病患者的严重低血糖发作显著增加。因此，我们将测试假设III)，即SSRI对糖尿病大鼠与非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患有抑郁症的糖尿病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.