糖尿病新靶点

nullnullnullDiabetes Mellitus Traditional Management of DM New Paradigms for Treatment Selective 11β-HSD1 Inhibitor nullDiabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Symptoms hungry, thirst, polyuria, blurring of vision, weight loss. Complications : Stroke, Heart attack, Kidney disease, Eye Disease, Nerve Damage, Ketoacidosis, coma, death nullType 1 Diabetes Mellitus - cells that produce insulin are destroyed - results in insulin dependence - commonly detected before 30 Type 2 Diabetes Mellitus - blood glucose levels rise due to 1) Lack of insulin production 2) Insufficient insulin action - commonly detected after 40 - eventually leads to IR and β-cell failure Gestational Diabetes nullnullnullnormal fasting blood glucose concentration, 80～90 mg/dl, with very low levels of insulin secretion. Fasting Plasma Glucose Test 100-125 mg/dl signals pre-diabetes >126 mg/dl signals diabetes Oral Glucose Tolerance Test (OGTT) tested for 2 hrs after glucose-rich drink 140-199 mg/dl signals pre-diabetes >200 mg/dl signals diabetes Glycated Hemoglobin tests normal 4.99%～6.79% for monitoring, not for diagnosis. nullnullnullnullnull由肠道L细胞所产生的一种肠促胰岛素 GLP-1在血液中易被二肽基肽酶Ⅳ(DPP4)降解，其半衰期仅数分钟 促进胰岛β-细胞的胰岛素分泌 抑制胰岛α-细胞的胰高血糖素分泌 抑制胃动力，使胃排空延迟 通过中枢神经系统抑制食欲 2型糖尿病患者体内GLP-1分泌明显减少 药物开发策略：GLP-1类似物，DPP4抑制剂 nullnullnullGK激活剂在胰腺和肝脏的双重作用可能比现有药物在血糖控制上更有效 目前仍处于临床开发早期阶段 nullPPAR：过氧化物酶体增殖激活受体（核受体） 存在3种亚型：α，δ和γ。 PPARα 参与调节脂质分解酶的达 PPARγ参与碳水化合物的代谢 PPARγ激动剂已上市有吡格列酮、罗格列酮（胰岛素增敏剂） 开发热点：PPARα和PPARγ双重激动剂，不但能有效控制血糖的异常变化，还能降低血中TG、FFA和LDL的含量，同时升高血中HDL浓度，从而对2型糖尿病患者的心血管并发症具有防治作用nullEarly Insulin Signalling Enhancers Non-peptide early insulin signalling enhancers Non-peptide Insulin Receptor Activators and SensitizersnullBuccal spray insulin Oral Liposomes Coated microcapsules HIM2 conjugate: alkyl polyethyleneglycol-conjugated hexyl insulin Other Liver-sensitive wrapped insulin transdermal（经皮给药） sensitive wrapped insulinnullSGLT-1： small intestine for glucose absorption SGLT-2： nephron， for glucose reabsorption SGLT2 inhibition = 30-80g glucosuria = 120-320 kcal lossnull11β-HSD1：肝脏、脂肪、骨骼和中枢神经系统 11β-HSD2：盐皮质激素靶组织，如肾远曲小管、结肠上皮、汗腺、唾液腺、胎盘 11β-HSD1位于细胞内质网，为NADPH依赖性还原酶。null人类 啮齿类动物nullH6PDH 己糖-6-磷酸脱氢酶 G6P 6-磷酸葡萄糖 6-PG 6-磷酸葡糖酸内酯G6P浓度影响H6PDH活性 从而影响11β-HSD1催化方向 高浓度G6P增强H6PDH活性，较多生成皮质醇 低浓度G6P减弱H6PDH活性，较多生成可的松 糖尿病患者体内G6P浓度较高 局部组织细胞糖皮质激素浓度升高可引起胰岛素抵抗，且独立于循环中糖皮质激素水平nullHSD2抑制剂会导致钠滞留和高血压及干扰类固醇激素的代谢 甘草酸及其衍生物生胃酮是11β-HSD的非选择性抑制剂 Pfizer PF915275 Incyte INCB13739 Amgen AMG221(BVT2773) 胆酸：石胆酸、鹅去氧胆酸nullnullnullnull尿中代谢物： （5THF +5THF）/ THE, an indicator of HSD1 inhibition was decresed HSD2 biomarker: UFF/UFE slightly higher, not statistically significant Satety:　safe and well tolerated no clinically significant postdose differences from baseline in ACTH, free testosterone, DHEA-s, or 4 androstenedione at any dose level PK：well-absorption dose-dependent T1/2 30h variability was moderate renal excretion <1% PD：dose-dependent nullIn vitro Recombinase Cell Docking Study In vivo Knockout mice ob/ob mice prednisone in monkey nullnullThank You