GLP-1 analogue recovers impaired insulin secretion from human islets treated with palmitate via down-regulation of SOCS2

• Published in: Molecular and cellular endocrinology Vol. 439; no. C; pp. 194 - 202
• Main Authors: Chowdhury, Azazul Islam, Bergsten, Peter
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 05.01.2017
• Subjects: Animals; apoptosis; Apoptosis - drug effects; Caspase 3 - metabolism; Cells, Cultured; Down-Regulation - drug effects; Exenatide; G-protein coupled receptors; gene expression regulation; genes; GLP-1; glucagon-like peptide 1; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - metabolism; glucose; Glucose - pharmacology; Humans; Insulin - metabolism; Insulin Secretion; islets of Langerhans; Islets of Langerhans - metabolism; Mice; Palmitate; palmitates; Palmitic Acid - pharmacology; Peptides - pharmacology; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; PI3kinase; proinsulin; protein content; Proto-Oncogene Proteins c-akt - metabolism; Receptors, G-Protein-Coupled - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; signal transduction; Signal Transduction - drug effects; SOCS2; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Type 2 diabetes; Venoms - pharmacology; Type 2 diabetes; SOCS2; PI3kinase; GLP-1; Palmitate
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2016.08.034

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. •Long term palmitate treatment up-regulates SOCS2 protein level.•SOCS2 decreases PI3K activity by degrading IRS-1 protein.•SOCS2 impairs GSIS and increase apoptosis which are reversed by GLP-1 analogue.