Test of catestatin (CST) and its mimetic as a new therapy for type 2 diabetes (T2D)

儿茶素 (CST) 及其模拟物作为 2 型糖尿病 (T2D) 新疗法的测试

• 批准号: 10823055
• 负责人: Shandy Shahabi
• 金额: $ 30.61万
• 依托单位: SIRAJ THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10823055
• 关键词: Adult; Agonist; American; Amino Acids; Angioneurotic Edema; Animal Experiments; Animals; Anti-Inflammatory Agents; Antidiabetic Drugs; Antihypertensive Agents; Biological Availability; Biology; Blood Glucose; COVID-19; Cardiovascular system; Chromogranin A; Clinical Research; Combined Modality Therapy; Data; Diabetes Mellitus; Diabetic mouse; Dipeptidyl Peptidases; Disease; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Eating; Effectiveness; Evaluation; Fasting; GLP-I receptor; Gluconeogenesis; Gluconeogenesis Inhibition; Glucose; Glycogenesis Induction; Glycogenolysis Induction; Goals; Grant; Half-Life; Hepatic; Hour; Hypoglycemia; Impairment; Individual; Infection; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intraperitoneal Injections; Investigation; Knockout Mice; LDL Cholesterol Lipoproteins; Laboratories; Life Style; Liver; Macrophage; Marketing; Medicine; Metformin; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oral; Oral Administration; Organ; Outsourcing; Overweight; Pancreatitis; Pathway interactions; Peptides; Persons; Pharmaceutical Preparations; Pharmacy Schools; Phase; Phase I Clinical Trials; Physiological; Plasma; Population; Positioning Attribute; Prediabetes syndrome; Predisposition; Property; Scientist; Sensitivity and Specificity; Signal Pathway; Small Business Innovation Research Grant; Sodium; Structural Biologist; Sulfonylurea Compounds; Testing; Therapeutic; Thiazolidinediones; Toxic effect; Toxicity Tests; Work; absorption; analog; cell growth regulation; chronic infection; cohort; cost effective treatment; cytokine; diabetes mellitus therapy; diabetic; diabetic patient; diet-induced obesity; efficacy testing; experimental study; fasting glucose; gastrointestinal; glucagon-like peptide 1; glucose metabolism; glucose production; glucose tolerance; glycogenesis; improved; in vivo; inhibitor; insulin secretion; insulin sensitivity; mimetics; novel therapeutics; pandemic disease; pharmacologic; polyurea; prevent; programs; prohormone; response; side effect; symporter; therapeutic effectiveness

Over 130 million Americans are either diabetic or pre-diabetic. A significant fraction of them is obese or overweight. There are seven classes of diabetic therapies against type II diabetes available including insulin therapy. But all these drugs are associated with some side effects including the danger of hypoglycemia. Therefore, more options to treat T2D are needed. We found that Catestatin (CST) and its analog, retro-inverso (RI)-CST have anti-diabetic properties. CST is a Chromogranin A-derived peptide that improves insulin sensitivity and reduces blood glucose levels in diet-induced obese (DIO) mouse model of diabetes by acting on multiple pathways including anti-inflammatory and glucose metabolism. Its anti-inflammatory activity prevents the infiltration of pro-inflammatory macrophages in the liver. It inhibits gluconeogenesis and glycogenolysis but induces glycogenesis. Also notable is that CST and RI-CST can be administered orally, and plasma CST appears within 15 min with a half-life of around 7 hrs. These remarkable properties position CST and RI-CST as highly potential diabetes therapies which we plan to investigate in this proposal. We further plan to investigate the therapeutic potential of CST and its mimic RI-CST as combination therapies. All currently used diabetes therapy is associated with side effects which include gastrointestinal, cardiovascular, pancreatitis, polyurea, angioedema, and LDL cholesterol. We hypothesize that toxic side effects of currently used diabetes medicine will be minimized if their doses can be lowered which can be accomplished by the addition of CST. Indeed, our preliminary results confirm our hypothesis where we found two-fold lower amounts of TZD are more effective when used in combination with CST than the regular dose of TZD alone. We propose two aims: in Aim 1, we plan to investigate the absorption and tissue distribution of RI-CST and determine the toxicity of both CST and RI-CST in mice. In aim 2, we plan to investigate the effectiveness of both mono and combination therapy of CST and RI-CST.

超过1.3亿美国人是糖尿病或糖尿病前期。其中很大一部分人肥胖， 超重有七类糖尿病治疗对II型糖尿病包括胰岛素 疗法但所有这些药物都有一些副作用，包括低血糖的危险。 因此，需要更多治疗T2 D的选择。我们发现，Catestatin（CST）及其类似物，反转录酶， （RI）-CST具有抗糖尿病特性。CST是一种嗜铬粒蛋白A衍生肽，可改善胰岛素敏感性 并通过作用于多种胰岛素来降低饮食诱导的肥胖（DIO）糖尿病小鼠模型中的血糖水平 包括抗炎和葡萄糖代谢的途径。它的抗炎活性可以防止 肝脏中促炎性巨噬细胞的浸润。它抑制糖原合成和糖原分解， 诱导糖原生成。还值得注意的是，CST和RI-CST可以口服给药，并且血浆CST出现 半衰期约为7小时。这些显著的特性使CST和RI-CST成为高度 我们计划在本提案中研究潜在的糖尿病治疗方法。我们计划进一步调查 CST及其模拟物RI-CST作为组合疗法的治疗潜力。所有目前使用的糖尿病治疗 与副作用有关，包括胃肠道、心血管、胰腺炎、聚脲， 血管性水肿和LDL胆固醇。我们假设目前使用的糖尿病药物的毒副作用 如果可以通过添加CST降低其剂量，则将最小化。的确，我们的 初步结果证实了我们的假设，我们发现TZD的两倍更有效 当与CST联合使用时，比常规剂量的TZD单独使用更有效。我们提出两个目标：在目标1中，我们 计划研究RI-CST的吸收和组织分布，并确定CST和 小鼠中的RI-CST。在目标2中，我们计划研究CST的单药和联合治疗的有效性 和RI-CST。