Glucagon Secretion and Islet Neuropathy

描述(申请人提供)：我们对非糖尿病动物和人类的十年研究表明，胰升糖素对胰岛素诱导的低血糖(IIH)的反应在很大程度上是自主调节的。由于这种特殊的胰升糖素反应在1型糖尿病早期就丧失了，早期的自主神经缺陷可能是原因之一。事实上，我们在BB糖尿病大鼠、糖尿病NOD小鼠以及现在患有1型糖尿病的人类受试者中展示了早期交感神经胰岛神经病变(ESIN)。具体目标#1：确定人类1型糖尿病患者的胰岛交感神经缺失是否与其胰升糖素反应受损有关。我们将量化1型糖尿病人尸检样本中胰岛神经的丢失，并确定交感A细胞途径的损害是否与他们对IIH的胰高血糖素反应受损有关。具体目的#2：确定保护和维持胰岛交感神经的胰岛周围许旺细胞(PSC)的损伤是否是Esin发生的机制。首先，我们将在非肥胖糖尿病(NOD)小鼠中将不同程度的PSC损伤与胰岛神经丢失联系起来。其次，我们将使用神经胶质毒素来确定PSC的化学损伤是否会导致神经丢失。第三，我们将确定这种神经丢失是否足以损害交感A细胞通路的功能。最后，我们将通过在NOD小鼠的颌下腺中重复这些研究来确定这种机制是胰岛特异的还是自身免疫特异的。具体目标3：确定BB糖尿病大鼠胰岛神经的恢复是否纠正了它们受损的胰升糖素对IIH的反应。我们将通过使用编码神经生长因子的病毒载体来恢复胰岛的神经支配，同时抑制对胰岛及其嵌入神经的反复的自身免疫攻击。我们将测量胰岛神经再支配前后的高血糖素对IIH的反应。意义：证实Esin损害了胰升糖素对IIH的反应，而胰岛的重新神经支配恢复了这一反应，这将为1型糖尿病患者失去这种反应的机制提供新的见解。恢复对IIH的胰高血糖素反应将允许对1型糖尿病患者进行更密集的治疗，这反过来将有助于预防这种疾病的长期并发症。

DESCRIPTION (provided by applicant): Our ten-year study of nondiabetic animals and humans shows that the glucagon response to insulin-induced hypoglycemia (IIH) is largely autonomically mediated. Since this specific glucagon response is lost early in type 1 diabetes, an early autonomic defect may be responsible. Indeed, we demonstrated an early sympathetic islet neuropathy (eSIN) in BB diabetic rats, diabetic NOD mice and now in human subjects with type 1 diabetes. Specific Aim #1: Determine if the loss of islet sympathetic nerves in human type 1 diabetes relates to their impaired glucagon responses. We will quantify the loss of islet nerves in autopsy samples from type 1 diabetic humans and determine if an impairment in this sympathetic A-cell pathway relates to the impairment of their glucagon response to IIH. Specific Aim #2: Determine if injury to the peri-islet Schwann cells (pSC), which protect and sustain islet sympathetic nerves, is the mechanism by which eSIN occurs. First, we will relate differing degrees of pSC injury to islet nerve loss in non-obese diabetic (NOD) mice. Second, we will administer glial toxins to determine if chemical injury to pSC causes nerve loss. Third, we will determine if this nerve loss is sufficient to impair the function of the sympathetic A-cell pathway. Finally, we will determine if this mechanism is islet- specific or autoimmune-specific by repeating these studies in the submandibular gland of the NOD mouse Specific Aim #3: Determine if restoring the islet nerves in BB diabetic rats corrects their impaired glucagon response to IIH. We will restore islet innervation by use of viral vectors encoding nerve growth factor while suppressing recurrent autoimmune attack on the islets and their ingrowing nerves. We will measure glucagon responses to IIH both before and after the reinnervation of the islets. Significance: Establishing that eSIN impairs the glucagon response to IIH and that reinnervation of the islet restores this response will provide new insight into the mechanism by which this response is lost in type 1 diabetes. Restoring the glucagon response to IIH will allow more intensive treatment of patients with type 1 diabetes which will in turn help prevent the long-term complications of this disease.