مورد إلكتروني
Free fatty acids and insulin hypersecretion studied in human islets
| العنوان: | Free fatty acids and insulin hypersecretion studied in human islets |
|---|---|
| بيانات النشر: | Uppsala universitet, Institutionen för medicinsk cellbiologi Uppsala 2018 |
| تفاصيل مُضافة: | Cen, Jing |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Free fatty acid (FFA) levels are increased in many obese subjects. High FFA levels stimulate the pancreatic beta-cells but have negative long-term effects. In obese children with high FFA levels circulating insulin concentration is high early in life but decline with age precipitating the development of type 2 diabetes mellitus (T2DM). The present study aims at preventing this development of T2DM by defining underlying mechanisms of insulin hypersecretion. Such mechanisms will be identified by studying regulation of insulin secretion from human pancreatic islets and human EndoC-βH1 cells exposed to elevated FFA levels. We found that elevated concentrations of FFAs acutely stimulate insulin from human pancreatic islets at fasting blood glucose level, with mono-unsatured being more potent than saturated fatty acids. Enhanced secretion was associated with increased glycolytic flux and mitochondrial respiration. Continued exposure to elevated palmitate levels for up to 2 days accentuated insulin secretion, whereas 7 days’ exposure caused secretory decline. Metformin prevented insulin hypersecretion from human islets treated with palmitate for 2 days by decreasing mitochondrial metabolism. In islets exposed to palmitate for 7 days metformin improved insulin secretion by enhancing calcium binding protein sorcin levels and thereby reducing ER stress and apoptosis. Downregulation of sorcin had negative effects on insulin secretion, mitochondrial metabolism and ER stress in human islets and EndoC-βH1 cells. Specific cellular pathways involved in insulin hypersecretion and secretory decline were identified by microarray expression analysis and subsequent bioinformatics in human islets cultured with palmitate for 0, 4, 12 hours, 1, 2, and 7 days. In conclusion, beta-cells respond to elevated levels of FFAs by initially augmenting insulin release followed by declining secretory levels after prolonged exposure. Metformin normalizes these secretory aberrations. Specific signaling |
| مصطلحات الفهرس: | free fatty acids, palmitate, human islets, EndoC-βH1 cells, metformin, sorcin, insulin secretion, mitochondrial respiration, ER stress, human transcriptome array, Cell and Molecular Biology, Cell- och molekylärbiologi, Doctoral thesis, comprehensive summary, info:eu-repo/semantics/doctoralThesis, text |
| URL: | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1476 |
| الإتاحة: | Open access content. Open access content info:eu-repo/semantics/openAccess |
| ملاحظة: | application/pdf English |
| أرقام أخرى: | UPE oai:DiVA.org:uu-355090 urn:isbn:978-91-513-0380-2 1235188196 |
| المصدر المساهم: | UPPSALA UNIV LIBR From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1235188196 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |