Dissecting mechanisms of GLP-1 based therapies for Type II Diabetes

描述（由申请人提供）：肥胖和II型糖尿病的双重流行对我们的医疗保健系统构成了巨大的挑战。这些疾病所造成的惊人的人力和金钱成本，是既不能降低血糖水平又不能减轻体重的治疗选择不足的直接结果。在过去的十年中，针对GLP-1系统的新的药理学策略已经成为可能。胰高血糖素样肽-1 （GLP-1）是一种调节肽，在营养摄取和处置的调节中起着广泛的作用，在肠道和后脑的一小群神经元中产生。血浆GLP-1起源于肠道，但被普遍存在的蛋白酶DPP-4迅速灭活。GLP-1非常短的半衰期挑战了在正常情况下由肠道释放的内源性GLP-1作用于胰腺或大脑中的远端受体的教条。新兴的基于GLP-1的疗法使用两种不同的策略：1)长效GLP-1受体（GLP-1R）激动剂，对DPP-4的作用具有抗性；2)降低GLP-1失活的DPP-4抑制剂，有效延长内源性GLP-1的活性。假设这两类药物都能刺激GLP-1R信号，从而通过共同的作用机制控制高血糖。然而，情况并非如此，因为它们的影响范围存在临床上重要但仍无法解释的差异。最值得注意的是，虽然这两类化合物都能改善葡萄糖耐量，但GLP-1R激动剂会导致体重减轻，而DPP-4抑制剂则不会。鉴于基于glp - 1r的疗法的疗效和越来越多的患者接受治疗，了解内源性GLP-1及其与基于GLP-1的疗法的药理作用的关系具有直接的临床意义。这项研究的首要目标是确定这些新疗法对糖尿病患者的影响的潜在机制，并解释它们之间的重要差异。该研究将使用最先进的小鼠基因技术，选择性地灭活胰腺、内脏感觉神经和/或中枢神经系统中唯一鉴定的GLP-1受体。转基因小鼠将同时接受GLP-1R激动剂和DPP-4抑制剂治疗，以确定哪些GLP-1R群是这些药物在葡萄糖代谢和体重调节的多个方面的特定作用所必需的。因此，我们将能够确定介导这些基于glp -1的治疗的重要和不同效果的关键受体群体。我们部署第二代这些药物并使其临床效益最大化的能力取决于确定关键的潜在机制。该提案的结果将同时推动对内源性GLP-1系统作用的新见解，并改进和优化当前和未来基于GLP-1的疗法，以更好地治疗2型糖尿病患者。

DESCRIPTION (provided by applicant): The dual epidemics of obesity and type II diabetes represent an enormous challenge to our health care system. The staggering human and monetary costs of these disorders are the direct result of having inadequate treatment options that both lower glucose levels and reduce body weight. Over the last decade, novel pharmacological strategies have become available that target the GLP-1 system. Glucagon-like-peptide- 1 (GLP-1), a regulatory peptide with a broad role in the regulation of nutrient ingestion and disposition, is produced in the intestine as well as in a small cluster of neurons in the hindbrain. Plasma GLP-1 originates from the gut, but is rapidly inactivated by the ubiquitous protease DPP-4. GLP-1's very short half-life challenges the dogma that under normal circumstances endogenous GLP-1 released by the gut acts on distant receptors in the pancreas or brain. Emerging GLP-1-based therapies use two distinct strategies: 1) Long- acting GLP-1 receptor (GLP-1R) agonists that are resistant to the actions of DPP-4; and 2) Inhibitors of DPP-4 that reduce GLP-1 inactivation, effectively prolonging the activity of endogenous GLP-1. Both classes of medication are hypothesized to stimulate GLP-1R signaling, and consequently to control hyperglycemia via a common mechanism of action. However, this cannot be the case since there are clinically important yet still unexplained differences in their spectrum of effects. Most notably, while both classes of compounds improve glucose tolerance, GLP-1R agonists additionally cause weight loss while DPP-4 inhibitors do not. Given the efficacy of GLP-1R-based therapies and the growing numbers of patients being treated with them, understanding endogenous GLP-1 and how it relates to the pharmacological action(s) of GLP-1-based therapies has immediate clinical relevance. The overarching goal of the proposed research is to identify the underlying mechanisms that mediate the effects of these novel treatments for diabetic patients, and to explain their important differences. The research will use state-of-the-art mouse genetic technologies to inactivate the only identified GLP-1 receptor selectively in pancreas, visceral sensory nerves and/or the central nervous system. Genetically modified mice will be treated with both GLP-1R agonists and DPP-4 inhibitors to determine which populations of GLP-1R are necessary for specific actions of these drugs on multiple aspects of glucose metabolism and body weight regulation. We will thus be able to identify the key receptor populations that mediate the important and varied effects of these GLP-1-based therapies. Our ability to deploy second generations of these medicines and to maximize their clinical benefit depends on identifying the key underlying mechanisms. The result of the this proposal will be to simultaneously drive new insights on the role of the endogenous GLP-1 system AND to refine and optimize current and future GLP-1-based therapies to better treat patients with type 2 diabetes.