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

剖析基于 GLP-1 的 II 型糖尿病疗法的机制

• 批准号: 8888781
• 负责人: RANDY J SEELEY
• 金额: $ 27.52万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-05 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888781
• 关键词: Accounting; Address; Afferent Neurons; Agonist; Axon; Behavioral; Body Weight; Body Weight decreased; Brain; Cells; Clinical; Data; Development; Diabetes Mellitus; Disease; Distal; Distant; Drug effect disorder; Enteral Feeding; Epidemic; Euglycemic Clamping; Exhibits; Future; GLP-I receptor; Gastric Emptying; Gastroparesis; Generations; Genetic Models; Glucose; Glucose Clamp; Goals; Half-Life; Healthcare Systems; Hepatic; Hormones; Human; Hyperglycemia; Hypothalamic structure; Imaging Techniques; Individual; Ingestion; Intestines; Islets of Langerhans; Mediating; Medicine; Metabolic; Mus; Nausea; Neuraxis; Neurons; Neurosecretory Systems; Nodose Ganglion; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Pancreas; Patients; Peptide Hydrolases; Peptides; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Physiological; Plasma; Population; Portal vein structure; Receptor Activation; Receptor Signaling; Regulation; Research; Resistance; Role; Satiation; Sensory Receptors; Signal Transduction; System; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Visceral; afferent nerve; base; blood glucose regulation; clinically relevant; cost; diabetic patient; effective therapy; energy balance; genetic technology; glucagon-like peptide; glucagon-like peptide 1; glucose metabolism; glucose production; glucose tolerance; glycemic control; hindbrain; improved; inhibitor/antagonist; insight; insulin secretion; insulin tolerance; islet; knock-down; mouse model; novel; receptor; research study; response

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.

描述（由申请人提供）：肥胖和II型糖尿病的双重流行病是对我们的医疗保健系统的巨大挑战。这些疾病的人类和货币成本惊人的直接结果是无法降低葡萄糖水平和减轻体重的治疗选择不足。在过去的十年中，新型的药理学策略已成为针对GLP-1系统的新型药理策略。胰高血糖素样肽-1（GLP-1）是一种在肠道摄入和处置中具有广泛作用的调节肽，在肠道以及后脑中的一小部分神经元中产生。血浆GLP-1起源于肠道，但被无处不在的蛋白酶DPP-4迅速失活。 GLP-1非常短的半衰期挑战了教条，在正常情况下，肠道释放的内源性GLP-1作用于胰腺或大脑中的遥远受体。新兴GLP-1的疗法使用两种不同的策略：1）对DPP-4的作用有抵抗力的长作用GLP-1受体（GLP-1R）激动剂； 2）DPP-4的抑制剂减少GLP-1失活，有效地延长内源性GLP-1的活性。假设两种类型的药物都可以刺激GLP-1R信号传导，从而通过共同的作用机理来控制高​​血糖。但是，情况并非如此，因为在临床上仍然存在重要的效果差异，但仍无法解释。最值得注意的是，尽管两种化合物都提高了葡萄糖耐量，但GLP-1R激动剂还会导致体重减轻，而DPP-4抑制剂则不会。鉴于基于GLP-1R的疗法的功效以及与他们治疗的患者数量越来越多，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，具有立即的临床相关性。 拟议研究的总体目标是确定介导这些新型治疗对糖尿病患者的影响的潜在机制，并解释其重要差异。该研究将使用最先进的小鼠遗传技术使胰腺，内脏感觉神经和/或中枢神经系统中唯一鉴定出的GLP-1受体失活。基因修饰的小鼠将通过GLP-1R激动剂和DPP-4抑制剂治疗，以确定这些药物对葡萄糖代谢和体重调节多个方面的特定作用是必需的。因此，我们将能够识别介导这些基于GLP-1的疗法的重要和各种作用的关键受体群体。我们部署第二代药物并最大化其临床益处的能力取决于确定关键的潜在机制。该提案的结果将是同时提出有关内源性GLP-1系统作用的新见解，并完善和优化基于GLP-1的疗法，以更好地治疗2型糖尿病患者。