title: GLP-1 analogue recovers impaired insulin secretion from human islets treated with palmitate via down-regulation of SOCS2.
abstract: Elevated circulating palmitate levels have been connected with type 2 diabetes mellitus. GLP-1 has favorable effects on beta-cells function. The aim was to identify mechanisms for decreased GSIS after long-term palmitate exposure and restoration by GLP-1 by analyzing changes in G-protein coupled receptor (GPCR) pathway signaling. Insulin secretory response to 20 mM glucose was attenuated after 7 days in islets exposed to palmitate but inclusion of exendin-4 restored secretion. Palmitate treatment altered genes of several GPCR signaling pathways including inflammatory pathways with up-regulated IL-1B, SOCS1 and SOCS2 transcript levels. Protein level of SOCS2 was also up-regulated by palmitate and accompanied by down-regulation of pAkt(T308), which was restored by exendin-4 treatment. When SOCS2 was knocked down, palmitate-induced down-regulation of IRS-1 and pAkt(T308) was prevented and GSIS, proinsulin to insulin ratio and apoptosis was restored. Long-term palmitate treatment up-regulates SOCS2 and reduces PI3K activity, thereby impairing GSIS. GLP-1 reverts the palmitate-induced effects.
authors: Department of Medical Cell Biology, Uppsala University, Box 571, SE-75123, Uppsala, Sweden. Electronic address: azazul.chowdhury@mcb.uu.se.
authors: Azazul Islam
authors: AI
authors: Chowdhury
authors: Department of Medical Cell Biology, Uppsala University, Box 571, SE-75123, Uppsala, Sweden.
authors: Peter
authors: P
authors: Bergsten
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D019308:Palmitic Acid / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology
chemical_list: D007328:Insulin; D010455:Peptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D014688:Venoms; D019308:Palmitic Acid; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D005947:Glucose
keywords: GLP-1; PI3kinase; Palmitate; SOCS2; Type 2 diabetes