Excessive Islet NO Generation in Type 2 Diabetic GK Rats Coincides with Abnormal Hormone Secretion and Is Counteracted by GLP-1

Autor: Claes-Göran Östenson, Suad Efendic, Javier Jimenez-Feltstrom, Sandra Meidute Abaraviciene, Albert Salehi, Ingmar Lundquist
Rok vydání: 2008
Předmět:
Male
medicine.medical_treatment
Nitric Oxide Synthase Type II
lcsh:Medicine
Nitric Oxide Synthase Type I
Type 2 diabetes
Rats
Sprague-Dawley
Glucagon-Like Peptide 1
Insulin Secretion
Insulin
Medicine
Enzyme Inhibitors
lcsh:Science
Microscopy
Confocal
geography.geographical_feature_category
Multidisciplinary
Islet
Insulin oscillation
Diabetes and Endocrinology
NG-Nitroarginine Methyl Ester
medicine.anatomical_structure
Research Article
endocrine system
medicine.medical_specialty
Science
Carbohydrate metabolism
Nitric Oxide
Glucagon
Diabetes Mellitus
Experimental
Islets of Langerhans
Diabetes mellitus
Internal medicine
Animals
Diabetes and Endocrinology/Type 2 Diabetes
Rats
Wistar
Pharmacology
geography
Physiology/Endocrinology
business.industry
Pancreatic islets
lcsh:R
Correction
medicine.disease
Rats
Glucose
Endocrinology
Diabetes Mellitus
Type 2
lcsh:Q
business
Zdroj: PLoS ONE, Vol 3, Iss 6 (2008)
PLoS ONE
PLoS ONE, Vol 3, Iss 5, p e2165 (2008)
ISSN: 1932-6203
Popis: BACKGROUND: A distinctive feature of type 2 diabetes is inability of insulin-secreting beta-cells to properly respond to elevated glucose eventually leading to beta-cell failure. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of beta-cell dysfunction. PRINCIPAL FINDINGS: We 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 N(G)-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. CONCLUSION: The 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. (Less)
Databáze: OpenAIRE
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