Metformin Ameliorates Dysfunctional Traits of Glibenclamide- and Glucose-Induced Insulin Secretion by Suppression of Imposed Overactivity of the Islet Nitric Oxide Synthase-NO System
| Autor: | Sandra Meidute Abaraviciene, Ingmar Lundquist, Israa Mohammed Al-Amily, Albert Salehi |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
endocrine system diseases Physiology Glucose uptake medicine.medical_treatment Nitric Oxide Synthase Type II lcsh:Medicine Nitric Oxide Synthase Type I Type 2 diabetes Biochemistry Glibenclamide Mice Endocrinology 0302 clinical medicine Glyburide Insulin Secretion Medicine and Health Sciences Insulin lcsh:Science Multidisciplinary Organic Compounds Monosaccharides pancreatic beta-cells type-2 diabetes-mellitus protein s-nitrosylation chronic exposure hormone-release rat islets expression glp-1 rosiglitazone langerhans Neurochemistry Metformin Up-Regulation Type 2 Diabetes Insulin oscillation Chemistry Physical Sciences Female Neurochemicals Research Article medicine.drug medicine.medical_specialty Endocrine Disorders medicine.drug_class Carbohydrates 030209 endocrinology & metabolism Biology Nitric Oxide Islets of Langerhans 03 medical and health sciences Internal medicine Diabetes mellitus Diabetes Mellitus medicine Animals Humans Nitrites Diabetic Endocrinology Nitrates Dose-Response Relationship Drug Endocrine Physiology Organic Chemistry lcsh:R Chemical Compounds Biology and Life Sciences medicine.disease Sulfonylurea Hormones Glucose 030104 developmental biology Metabolic Disorders lcsh:Q Nitric Oxide Synthase Neuroscience |
| Zdroj: | PLoS ONE, Vol 11, Iss 11, p e0165668 (2016) PLoS One, San Francisco, Ca : Public Library of Science, 2016, Vol. 11, Iss. 11, Art. No. e0165668 PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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