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 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 co-culturing 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.
Highlights
The biguanide metformin is presently recommended as a first-line drug in the treatment of impaired glucose tolerance and manifest type 2 diabetes [1]
Our results strongly suggest that imposed overactivity of the islet nitric oxide synthase (NOS)-nitric oxide (NO) system induced by glibenclamide and/or high glucose could markedly contribute to a progressive dysfunction of the insulin secretory mechanisms being counteracted by a beneficial action of metformin, an effect which in large part is due to a strong suppressive effect by the biguanide on the upregulated activity of the NOS-NO system in the beta-cell
It was shown several years ago that iNOS-derived NO, primarily produced from macrophages and invasive cells, with the resulting formation of reactive nitrogen species (RNS) and reactive oxygen species (ROS), has an important impact on the immunogenic and inflammatory destruction of islet beta-cells in type 1 diabetes [13,14,15]
Summary
The biguanide metformin is presently recommended as a first-line drug in the treatment of impaired glucose tolerance and manifest type 2 diabetes [1]. It has been reported that metformin may modestly augment glucose-stimulated insulin release in isolated human islets [3,4]. The mechanisms underlying this effect on the pancreatic beta-cell are presently still unclear. In current clinical praxis, when treating type 2 diabetes, metformin is often used together with sulfonylurea drugs such as e.g. glibenclamide. It seemed of great importance to elucidate what unexplained mechanisms could underlie the less understood effects of metformin on beta-cell function both after exposure to sulfonylurea treatment and to elevated glucose levels
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