Glucagon-Like Peptide 1 Stimulates Insulin Secretion via Inhibiting RhoA/ROCK Signaling and Disassembling Glucotoxicity-Induced Stress Fibers
Kong, Xiangchen ; Yan, Dan ; Sun, Jiangming LU
; Wu, Xuerui
; Mulder, Hindrik
LU
; Hua, Xianxin
and Ma, Xiaosong
(2014)
In Endocrinology
155(12).
p.4676-4685
- Abstract
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4941438
- author
- Kong, Xiangchen
; Yan, Dan
; Sun, Jiangming
LU
; Wu, Xuerui
; Mulder, Hindrik
LU
; Hua, Xianxin
and Ma, Xiaosong
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Endocrinology
- volume
- 155
- issue
- 12
- pages
- 4676 - 4685
- publisher
- Oxford University Press
- external identifiers
-
- wos:000346668000009
- scopus:84914181252
- pmid:25243854
- ISSN
- 0013-7227
- DOI
- 10.1210/en.2014-1314
- language
- English
- LU publication?
- yes
- id
- 6d78d4b5-9731-467f-b60b-2decbab1cfee (old id 4941438)
- date added to LUP
- 2016-04-01 10:28:01
- date last changed
- 2022-03-12 06:08:06
@article{6d78d4b5-9731-467f-b60b-2decbab1cfee,
abstract = {{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.}},
author = {{Kong, Xiangchen and Yan, Dan and Sun, Jiangming and Wu, Xuerui and Mulder, Hindrik and Hua, Xianxin and Ma, Xiaosong}},
issn = {{0013-7227}},
language = {{eng}},
number = {{12}},
pages = {{4676--4685}},
publisher = {{Oxford University Press}},
series = {{Endocrinology}},
title = {{Glucagon-Like Peptide 1 Stimulates Insulin Secretion via Inhibiting RhoA/ROCK Signaling and Disassembling Glucotoxicity-Induced Stress Fibers}},
url = {{https://lup.lub.lu.se/search/files/1868805/7695389}},
doi = {{10.1210/en.2014-1314}},
volume = {{155}},
year = {{2014}},
}