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Excessive islet NO generation in type 2 diabetic GK rats coincides with abnormal hormone secretion and is counteracted by GLP-1.

Salehi, S Albert LU orcid ; Meidute Abaraviciene, Sandra ; Jimenez, Javier LU ; Ostenson, Claes-Göran ; Efendic, Suad and Lundquist, Ingmar LU (2008) In PLoS ONE 3(5).
Abstract
BACKGROUND: A distinctive feature of type 2 diabetes is inability of insulin-secreting beta-cells to properly respond to elevated glucose eventually leading to beta-cell failure. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of beta-cell dysfunction. PRINCIPAL FINDINGS: We show now that islets of type 2 spontaneous diabetes in GK rats display excessive NO generation associated with abnormal iNOS expression in insulin and glucagon cells, increased ncNOS activity, impaired glucose-stimulated insulin release, glucagon hypersecretion, and impaired glucose-induced glucagon suppression. Pharmacological blockade of islet NO production by the NOS inhibitor... (More)
BACKGROUND: A distinctive feature of type 2 diabetes is inability of insulin-secreting beta-cells to properly respond to elevated glucose eventually leading to beta-cell failure. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of beta-cell dysfunction. PRINCIPAL FINDINGS: We show now that islets of type 2 spontaneous diabetes in GK rats display excessive NO generation associated with abnormal iNOS expression in insulin and glucagon cells, increased ncNOS activity, impaired glucose-stimulated insulin release, glucagon hypersecretion, and impaired glucose-induced glucagon suppression. Pharmacological blockade of islet NO production by the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) greatly improved hormone secretion from GK islets suggesting islet NOS activity being an important target to inactivate for amelioration of islet cell function. The incretin hormone GLP-1, which is used in clinical practice suppressed iNOS and ncNOS expression and activity with almost full restoration of insulin release and partial restoration of glucagon release. GLP-1 suppression of iNOS expression was reversed by PKA inhibition but unaffected by the proteasome inhibitor MG132. Injection of glucose plus GLP-1 in the diabetic rats showed that GLP-1 amplified the insulin response but induced a transient increase and then a poor depression of glucagon. CONCLUSION: The results suggest that abnormally increased NO production within islet cells is a significant player in the pathogenesis of type 2 diabetes being counteracted by GLP-1 through PKA-dependent, nonproteasomal mechanisms. (Less)
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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
islet hormone secretion, ncNOS, Diabetic GK rat, iNOS, NOS inhibition, GLP-1
in
PLoS ONE
volume
3
issue
5
article number
e2165
publisher
Public Library of Science (PLoS)
external identifiers
  • wos:000262172800030
  • pmid:18478125
  • scopus:47749085111
ISSN
1932-6203
DOI
10.1371/journal.pone.0002165
language
English
LU publication?
yes
id
002813cf-bc1f-49b1-9201-02e9fbebc4b2 (old id 1154188)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18478125?dopt=Abstract
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0002165
date added to LUP
2016-04-04 09:08:38
date last changed
2022-02-13 07:57:24
@article{002813cf-bc1f-49b1-9201-02e9fbebc4b2,
  abstract     = {{BACKGROUND: A distinctive feature of type 2 diabetes is inability of insulin-secreting beta-cells to properly respond to elevated glucose eventually leading to beta-cell failure. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of beta-cell dysfunction. PRINCIPAL FINDINGS: We show now that islets of type 2 spontaneous diabetes in GK rats display excessive NO generation associated with abnormal iNOS expression in insulin and glucagon cells, increased ncNOS activity, impaired glucose-stimulated insulin release, glucagon hypersecretion, and impaired glucose-induced glucagon suppression. Pharmacological blockade of islet NO production by the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) greatly improved hormone secretion from GK islets suggesting islet NOS activity being an important target to inactivate for amelioration of islet cell function. The incretin hormone GLP-1, which is used in clinical practice suppressed iNOS and ncNOS expression and activity with almost full restoration of insulin release and partial restoration of glucagon release. GLP-1 suppression of iNOS expression was reversed by PKA inhibition but unaffected by the proteasome inhibitor MG132. Injection of glucose plus GLP-1 in the diabetic rats showed that GLP-1 amplified the insulin response but induced a transient increase and then a poor depression of glucagon. CONCLUSION: The results suggest that abnormally increased NO production within islet cells is a significant player in the pathogenesis of type 2 diabetes being counteracted by GLP-1 through PKA-dependent, nonproteasomal mechanisms.}},
  author       = {{Salehi, S Albert and Meidute Abaraviciene, Sandra and Jimenez, Javier and Ostenson, Claes-Göran and Efendic, Suad and Lundquist, Ingmar}},
  issn         = {{1932-6203}},
  keywords     = {{islet hormone secretion; ncNOS; Diabetic GK rat; iNOS; NOS inhibition; GLP-1}},
  language     = {{eng}},
  number       = {{5}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{Excessive islet NO generation in type 2 diabetic GK rats coincides with abnormal hormone secretion and is counteracted by GLP-1.}},
  url          = {{http://dx.doi.org/10.1371/journal.pone.0002165}},
  doi          = {{10.1371/journal.pone.0002165}},
  volume       = {{3}},
  year         = {{2008}},
}