Metformin ameliorates dysfunctional traits of glibenclamide- and glucose-induced insulin secretion by suppression of imposed overactivity of the islet nitric oxide synthase-no system
Lundquist, Ingmar LU ; Mohammed, Israa LU ; Meidute, Sandra LU and Salehi, S Albert LU
(2016)
In PLoS ONE
11(11).
- Abstract
Metformin lowers diabetic blood glucose primarily by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. However, possible effects by metformin on beta-cell function are incompletely understood. We speculated that metformin might positively influence insulin secretion through impacting the beta-cell nitric oxide synthase (NOS)-NO system, a negative modulator of glucose-stimulated insulin release. In short-time incubations with isolated murine islets either glibenclamide or high glucose augmented insulin release associated with increased NO production from both neural and inducible NOS. Metformin addition suppressed the augmented NO generation coinciding with amplified insulin release. Islet culturing with... (More)
Metformin lowers diabetic blood glucose primarily by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. However, possible effects by metformin on beta-cell function are incompletely understood. We speculated that metformin might positively influence insulin secretion through impacting the beta-cell nitric oxide synthase (NOS)-NO system, a negative modulator of glucose-stimulated insulin release. In short-time incubations with isolated murine islets either glibenclamide or high glucose augmented insulin release associated with increased NO production from both neural and inducible NOS. Metformin addition suppressed the augmented NO generation coinciding with amplified insulin release. Islet culturing with glibenclamide or high glucose revealed pronounced fluorescence of inducible NOS in the beta-cells being abolished by metformin co-culturing. These findings were reflected in medium nitrite-nitrate levels. A glucose challenge following islet culturing with glibenclamide or high glucose revealed markedly impaired insulin response. Metformin coculturing restored this response. Culturing murine islets and human islets from controls and type 2 diabetics with high glucose or high glucose + glibenclamide induced a pronounced decrease of cell viability being remarkably restored by metformin co-culturing. We show here, that imposed overactivity of the beta-cell NOS-NO system by glibenclamide or high glucose leads to insulin secretory dysfunction and reduced cell viability and also, importantly, that these effects are relieved by metformin inhibiting beta-cell NO overproduction from both neural and inducible NOS thus ameliorating a concealed negative influence by NO induced by sulfonylurea treatment and/or high glucose levels. This double-edged effect of glibenclamide on the beta-cellsuggests sulfonylurea monotherapy in type 2 diabetes being avoided.
(Less)
- author
- Lundquist, Ingmar
LU
; Mohammed, Israa
LU
; Meidute, Sandra
LU
and Salehi, S Albert
LU
- organization
- publishing date
- 2016-11-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 11
- issue
- 11
- article number
- e0165668
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000387614800015
- scopus:84994645466
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0165668
- language
- English
- LU publication?
- yes
- id
- e729d939-7f1a-4e4b-baea-d4bca7c98b78
- date added to LUP
- 2016-12-05 11:03:22
- date last changed
- 2024-03-07 17:38:42
@article{e729d939-7f1a-4e4b-baea-d4bca7c98b78,
abstract = {{<p>Metformin lowers diabetic blood glucose primarily by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. However, possible effects by metformin on beta-cell function are incompletely understood. We speculated that metformin might positively influence insulin secretion through impacting the beta-cell nitric oxide synthase (NOS)-NO system, a negative modulator of glucose-stimulated insulin release. In short-time incubations with isolated murine islets either glibenclamide or high glucose augmented insulin release associated with increased NO production from both neural and inducible NOS. Metformin addition suppressed the augmented NO generation coinciding with amplified insulin release. Islet culturing with glibenclamide or high glucose revealed pronounced fluorescence of inducible NOS in the beta-cells being abolished by metformin co-culturing. These findings were reflected in medium nitrite-nitrate levels. A glucose challenge following islet culturing with glibenclamide or high glucose revealed markedly impaired insulin response. Metformin coculturing restored this response. Culturing murine islets and human islets from controls and type 2 diabetics with high glucose or high glucose + glibenclamide induced a pronounced decrease of cell viability being remarkably restored by metformin co-culturing. We show here, that imposed overactivity of the beta-cell NOS-NO system by glibenclamide or high glucose leads to insulin secretory dysfunction and reduced cell viability and also, importantly, that these effects are relieved by metformin inhibiting beta-cell NO overproduction from both neural and inducible NOS thus ameliorating a concealed negative influence by NO induced by sulfonylurea treatment and/or high glucose levels. This double-edged effect of glibenclamide on the beta-cellsuggests sulfonylurea monotherapy in type 2 diabetes being avoided.</p>}},
author = {{Lundquist, Ingmar and Mohammed, Israa and Meidute, Sandra and Salehi, S Albert}},
issn = {{1932-6203}},
language = {{eng}},
month = {{11}},
number = {{11}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{Metformin ameliorates dysfunctional traits of glibenclamide- and glucose-induced insulin secretion by suppression of imposed overactivity of the islet nitric oxide synthase-no system}},
url = {{http://dx.doi.org/10.1371/journal.pone.0165668}},
doi = {{10.1371/journal.pone.0165668}},
volume = {{11}},
year = {{2016}},
}