Glucagon Secretion and Islet Neuropathy

描述（由申请人提供）：我们对非糖尿病动物和人类的十年研究表明，胰高血糖素对胰岛素诱导的低血糖（IIH）的反应主要是自主介导的。由于这种特定的胰高血糖素反应在1型糖尿病早期消失，早期的自主神经缺陷可能是原因。事实上，我们在BB型糖尿病大鼠、糖尿病NOD小鼠和现在的1型糖尿病人类受试者中证实了早期交感胰岛神经病变（eSIN）。具体目标#1：确定人类1型糖尿病患者胰岛交感神经的丧失是否与胰高血糖素反应受损有关。我们将量化1型糖尿病患者尸检样本中胰岛神经的损失，并确定这种交感a细胞通路的损伤是否与胰高血糖素对IIH的反应损伤有关。具体目标2：确定保护和维持胰岛交感神经的胰岛周围雪旺细胞（pSC）的损伤是否是eSIN发生的机制。首先，我们将不同程度的pSC损伤与非肥胖糖尿病（NOD）小鼠的胰岛神经丧失联系起来。其次，我们将使用神经胶质毒素来确定化学损伤pSC是否会导致神经丧失。第三，我们将确定这种神经损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小鼠颌下腺中重复这些研究来确定这种机制是胰岛特异性的还是自身免疫特异性的。特定目的3：确定恢复BB糖尿病大鼠的胰岛神经是否能纠正其对IIH的受损胰高血糖素反应。我们将利用编码神经生长因子的病毒载体恢复胰岛的神经支配，同时抑制对胰岛及其生长神经的复发性自身免疫攻击。我们将测量胰高血糖素在胰岛神经再生前后对IIH的反应。意义：确立eSIN损害胰高血糖素对IIH的反应，胰岛神经再生恢复这种反应，将为1型糖尿病中这种反应丧失的机制提供新的见解。恢复胰高血糖素对IIH的反应将允许对1型糖尿病患者进行更强化的治疗，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.