کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10749451 | 1050290 | 2015 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models
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کلمات کلیدی
G protein-coupled receptor 40GSISDPP IVGLP-1GPR40OGTTT2DMNEFAPC3Oral glucose tolerance test - آزمون تحمل گلوکز خوراکیNon-esterified fatty acid - اسید چرب غیر استرادیلیinsulin - انسولینGlucose-stimulated insulin secretion - ترشح انسولین تحریک شده توسط گلوکزtriacylglycerol - تری آسیل گلیسرول Type 2 diabetes mellitus - دیابت نوع دوdipeptidyl peptidase IV - دیپپتیدیل پپتیداز IVglucagon-like peptide-1 - پپتید 1-گلوکاگون-مانندtotal cholesterol - کلسترول تام
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved β-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and β-cell function, suggesting its promising potential for the treatment of type 2 diabetes.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 466, Issue 4, 30 October 2015, Pages 740-747
Journal: Biochemical and Biophysical Research Communications - Volume 466, Issue 4, 30 October 2015, Pages 740-747
نویسندگان
Dan-yang Guo, De-wen Li, Meng-meng Ning, Xiang-yu Dang, Li-na Zhang, Li-min Zeng, You-hong Hu, Ying Leng,