Excessive islet NO generation in type 2 diabetic GK rats coincides with abnormal hormone secretion and is counteracted by GLP-1 |
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Authors: | Salehi Albert Meidute Abaraviciene Sandra Jimenez-Feltstrom Javier Ostenson Claes-Göran Efendic Suad Lundquist Ingmar |
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Institution: | 1. Department of Clinical Science, Universitetssjukhuset Malmö Allmäna Sjukhus (UMAS), Division of Endocrine Pharmacology, Karolinska Institute, Stockholm, Sweden.; 2. University of Lund, Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.; 3. Department of Experimental Medical Science, Karolinska Institute, Stockholm, Sweden.;Mayo Clinic College of Medicine, United States of America |
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Abstract: | BackgroundA distinctive feature of type 2 diabetes is inability of insulin-secreting β-cells to properly respond to elevated glucose eventually leading to β-cell failure. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of β-cell dysfunction.Principal FindingsWe 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 NG-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.ConclusionThe 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. |
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