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Glucagon-Like Pepti...
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Kong, Xiangchen
(författare)
Glucagon-Like Peptide 1 Stimulates Insulin Secretion via Inhibiting RhoA/ROCK Signaling and Disassembling Glucotoxicity-Induced Stress Fibers
- Artikel/kapitelEngelska2014
Förlag, utgivningsår, omfång ...
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The Endocrine Society,2014
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electronicrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:lup.lub.lu.se:6d78d4b5-9731-467f-b60b-2decbab1cfee
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https://lup.lub.lu.se/record/4941438URI
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https://doi.org/10.1210/en.2014-1314DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
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Ämneskategori:ref swepub-contenttype
Anmärkningar
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Chronic hyperglycemia leads to pancreatic beta-cell dysfunction characterized by diminished glucose-stimulated insulin secretion (GSIS), but the precise cellular processes involved are largely unknown. Here we show that pancreatic beta-cells chronically exposed to a high glucose level displayed substantially increased amounts of stress fibers compared with beta-cells cultured at a low glucose level. beta-Cells at high glucose were refractory to glucose-induced actin cytoskeleton remodeling and insulin secretion. Importantly, F-actin depolymerization by either cytochalasin B or latrunculin B restored glucotoxicity-diminished GSIS. The effects of glucotoxicity on increasing stress fibers and reducing GSIS were reversed by Y-27632, a Rho-associated kinase (ROCK)-specific inhibitor, which caused actin depolymerization and enhanced GSIS. Notably, glucagon-like peptide-1-(7-36) amide (GLP-1), a peptide hormone that stimulates GSIS at both normal and hyperglycemic conditions, also reversed glucotoxicity-induced increase of stress fibers and reduction of GSIS. In addition, GLP-1 inhibited glucotoxicity-induced activation of RhoA/ROCK and thereby resulted in actin depolymerization and potentiation of GSIS. Furthermore, this effect of GLP-1 was mimicked by cAMP-increasing agents forskolin and 3-isobutyl-1-methylxanthine as well as the protein kinase A agonist 6-Bnz-cAMP-AM whereas it was abolished by the protein kinase A inhibitor Rp-Adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt. To establish a clinical relevance of our findings, we examined the association of genetic variants of RhoA/ROCK with metabolic traits in homeostasis model assessment index of insulin resistance. Several single-nucleotide polymorphisms in and around RHOA were associated with elevated fasting insulin and homeostasis model assessment index of insulin resistance, suggesting a possible role in metabolic dysregulation. Collectively these findings unravel a novel mechanism whereby GLP-1 potentiates glucotoxicity-diminished GSIS by depolymerizing F-actin cytoskeleton via protein kinase A-mediated inhibition of the RhoA-ROCK signaling pathway.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Yan, Dan
(författare)
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Sun, JiangmingLund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Diabetes - Molecular Metabolism,Lund University Research Groups(Swepub:lu)med-js5
(författare)
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Wu, Xuerui
(författare)
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Mulder, HindrikLund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Diabetes - Molecular Metabolism,Lund University Research Groups(Swepub:lu)medk-hmu
(författare)
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Hua, Xianxin
(författare)
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Ma, Xiaosong
(författare)
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Diabetes - molekylär metabolismForskargrupper vid Lunds universitet
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Endocrinology: The Endocrine Society155:12, s. 4676-46850013-72271945-7170
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