Increased neuronal nitric oxide synthase dimerisation is involved in rat and human pancreatic beta cell hyperactivity in obesity

Autor: B Nadal, F. Castex, Pascal Pomiès, K. Mezghenna, Pierre Petit, René Gross, J. Leroy, Linda Cambier, Nadja Niclauss, Anne-Dominique Lajoix, Ramon Gomis, C Cazevieille, Thierry Berney, A Chalançon
Rok vydání: 2011
Předmět:
Male
medicine.medical_specialty
Insulin-Secreting Cells/drug effects/metabolism/secretion/ultrastructure
Endocrinology
Diabetes and Metabolism
RNA
Messenger/metabolism
Type 2 diabetes
Nitric Oxide Synthase Type I
Gene Expression Regulation
Enzymologic
Rats
Mutant Strains
Tissue Culture Techniques
Islets of Langerhans
Insulin resistance
Internal medicine
Insulin-Secreting Cells
Obesity/metabolism
Insulin Secretion
Internal Medicine
medicine
Animals
Humans
Insulin
Obesity
RNA
Messenger
Cells
Cultured
Regulation of gene expression
ddc:617
business.industry
Pancreatic islets
Nitric Oxide Synthase Type I/antagonists & inhibitors/genetics/metabolism
Middle Aged
medicine.disease
Transport protein
Mitochondria
Rats
Rats
Zucker
Protein Transport
Endocrinology
medicine.anatomical_structure
Insulin/metabolism/secretion
Islets of Langerhans/drug effects/metabolism/secretion/ultrastructure
Female
Beta cell
Insulin Resistance
Mitochondria/drug effects/metabolism/ultrastructure
business
Dimerization
Function (biology)
Zdroj: Diabetologia, Vol. 54, No 11 (2011) pp. 2856-66
ISSN: 1432-0428
0012-186X
Popis: Pancreatic beta cell hyperactivity is known to occur in obesity, particularly in insulin-resistant states. Our aim was to investigate whether changes in neuronal nitric oxide synthase (nNOS) function affect beta cell compensation in two relevant models: the Zucker fa/fa rats and pancreatic islets from obese humans.Glucose-induced insulin response was evaluated in the isolated perfused rat pancreas and in human pancreatic islets from obese individuals. Expression of nNOS (also known as NOS1) and subcellular localisation of nNOS were studied by quantitative RT-PCR, immunoblotting, immunofluorescence and electron microscopy.Pancreatic beta cells from Zucker fa/fa rats and obese individuals were found to be hyper-responsive to glucose. Pharmacological blockade of nNOS was unable to modify beta cell response to glucose in fa/fa rats and in islets from obese individuals, suggesting an abnormal control of insulin secretion by the enzyme. In both cases, nNOS activity in islet cell extracts remained unchanged, despite a drastic increase in nNOS protein and an enhancement in the dimer/monomer ratio, pointing to the presence of high amounts of catalytically inactive enzyme. This relative decrease in activity could be mainly related to increases in islet asymmetric dimethyl-arginine content, an endogenous inhibitor of nNOS activity. In addition, mitochondrial nNOS level was decreased, which contrasts with a strongly increased association with insulin granules.Increased nNOS production and dimerisation, together with a relative decrease in catalytic activity and relocalisation, are involved in beta cell hyperactivity in insulin-resistant rats but also in human islets isolated from obese individuals.
Databáze: OpenAIRE
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