Metformin Ameliorates Dysfunctional Traits of Glibenclamide- and Glucose-Induced Insulin Secretion by Suppression of Imposed Overactivity of the Islet Nitric Oxide Synthase-NO System.
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.
Department of Clinical Science, SUS, Division of Islet Cell Physiology University of Lund, Malmö, Sweden.|Department of Experimental Medical Science, University of Lund, Lund, Sweden.
Ingmar
I
Lundquist
Department of Clinical Science, SUS, Division of Islet Cell Physiology University of Lund, Malmö, Sweden.
Israa
I
Mohammed Al-Amily
Department of Clinical Science, SUS, Division of Islet Cell Physiology University of Lund, Malmö, Sweden.|Dept. of Physiology, Biochemistry, Microbiology and Laboratory Medicine Vilnius University, and Dep. of Regenerative Medicine, State Research Institute Center for Innovative Medicine, Vilnius, Lithuania.
Sandra
S
Meidute Abaraviciene
Department of Clinical Science, SUS, Division of Islet Cell Physiology University of Lund, Malmö, Sweden.|Department of Neuroscience and Physiology, Metabolic Research Unit, University of Gothenburg, Gothenburg, Sweden.
Albert
http://orcid.org/0000-0001-6120-3539
A
Salehi
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D007328:Insulin; D009569:Nitric Oxide; D008687:Metformin; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D005947:Glucose; D005905:Glyburide