Neuroendocrine Control of Glucose Metabolism

描述（由申请人提供）：尽管胰岛素仍然是人类1型糖尿病治疗的基础，但最近的证据表明，诱导高瘦素血症可以完全改善链脲佐菌素（STZ）诱导的糖尿病大鼠的高血糖，我们最近的发现表明大脑参与了这种作用。我们新的初步数据表明，这种瘦素效应涉及一种新的、不依赖胰岛素的机制，其特征是肝糖生成（HGP）速率降低和组织葡萄糖摄取速率增加，并确定大脑具有使uDM血糖水平正常化的能力。这些观察结果不同于任何先前描述的中枢神经系统（CNS）瘦素作用，并支持本提案的总体目标，即描绘由瘦素激活的神经元回路和外周机制，介导其抗糖尿病作用。具体来说，我们假设瘦素抑制交感神经向肝脏和胰腺的流出降低了uDM中的HGP，并且这种作用涉及黑素皮质素途径。此外，我们假设瘦素诱导的室旁核（PVN）促甲状腺素释放激素（TRH）神经元亚群的激活刺激葡萄糖摄取，从而有助于瘦素在uDM中的降血糖作用。为了实现这些目标，我们将采用先进的示踪剂稀释技术，结合药物、手术和免疫组织化学方法，并使用Cre- loxP重组技术建立条件敲除小鼠模型。因此，本提案中产生的数据有望确定瘦素作用下游的特定神经元亚群，这些神经元亚群连接大脑和外周组织之间的通信，以控制HGP和葡萄糖摄取。这些研究的表现有可能促进糖尿病治疗新方法的发展。

DESCRIPTION (provided by applicant): Although insulin remains the cornerstone of therapy for type 1 diabetes in humans, recent evidence suggests that induction of hyperleptinemia fully ameliorates hyperglycemia in streptozotocin (STZ)-induced diabetic rats and our recent findings implicate the brain in this effect. Our new Preliminary Data show that this leptin effect involves a novel, insulin-independent mechanism characterized by reduced rates of hepatic glucose production (HGP) and increased rates of tissue glucose uptake and establishes that the brain has the capacity to normalize blood glucose levels in uDM. These observations are distinct from any previously described central nervous system (CNS) leptin action and support the overarching goal of this proposal to delineate the neuronal circuits and peripheral mechanisms activated by leptin that mediate its anti-diabetic effects. Specifically, we hypothesize that leptin inhibition of sympathetic outflow to the liver and pancreas reduces HGP in uDM, and that this effect involves the melanocortin pathway. Moreover, we hypothesize that leptin-induced activation of a subset of thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus (PVN) stimulates glucose uptake, and thereby contributes to the glucose-lowering effects of leptin in uDM. To accomplish these objectives, we will employ sophisticated tracer dilution techniques, in combination with pharmacological, surgical and immunohistochemical approaches and established conditional knockout mouse models using Cre- loxP recombination technology. The data generated in this proposal is therefore expected to identify specific neuronal subsets downstream of leptin action that link communication between the brain and peripheral tissues to control both HGP and glucose uptake. Performance of these studies has the potential to facilitate the development of new approaches to diabetes treatment. PUBLIC HEALTH RELEVANCE: While treatment of hyperglycemia in type 1 diabetes is generally held to require exogenous insulin, recent evidence suggests that pharmacological doses of leptin can also induce this effect. Our recent findings implicate the brain in this effect and demonstrate that leptin action in the brain normalizes diabetic hyperglycemia in a model of uncontrolled, insulin-deficient diabetes (uDM) by increasing glucose uptake and reducing glucose output by the liver. The overarching goal of this proposal is to determine how the brain communicates to peripheral tissues to mediate the anti-diabetic effects of leptin and the data generated is expected to facilitate the development of new approaches for the control of blood sugars.