title: Abnormally decreased NO and augmented CO production in islets of the leptin-deficient ob/ob mouse might contribute to explain hyperinsulinemia and islet survival in leptin-resistant type 2 obese diabetes.
abstract: The role of the gaseous messengers NO and CO for β-cell function and survival is controversial. We examined this issue in the hyperglycemic-hyperinsulinemic ob/ob mouse, an animal model of type 2 obese diabetes, by studying islets from obese vs lean mice regarding glucose-stimulated insulin release in relation to islet NO and CO production and the influence of modulating peptide hormones. Glucose-stimulated increase in ncNOS-activity in incubated lean islets was converted to a decrease in ob/ob islets associated with markedly increased insulin release. Both types of islets displayed iNOS activity appearing after ~60 min in high-glucose. In ob/ob islets the insulinotropic peptides glucagon, GLP-1 and GIP suppressed NOS activities and amplified glucose-stimulated insulin release. The insulinostatic peptide leptin induced the opposite effects. Suppression of islet CO production inhibited, while stimulation amplified glucose-stimulated insulin release. Nonincubated isolated islets from young and adult obese mice displayed very low ncNOS and negligible iNOS activity. In contrast, production of CO, a NOS inhibitor, was impressively raised. Glucose injections induced strong activities of islet NOS isoforms in lean but not in obese mice and confocal microscopy revealed iNOS expression only in lean islets. Islets from ob/ob mice existing in a hyperglycemic in vivo milieu maintain elevated insulin secretion and protection from glucotoxicity through a general suppression of islet NOS activities achieved by leptin deficiency, high CO production and insulinotropic cyclic-AMP-generating hormones. Such a beneficial effect on islet function and survival might have its clinical counterpart in human leptin-resistant type 2 obese diabetes with hyperinsulinemia.
authors.affiliation: Department of Clinical Sciences, Islet Cell Physiology, SUS, University of Lund, SE-20502 Malmö, Sweden.
authors.forename: Javier
authors.initials: J
authors.lastname: Jimenez-Feltstrom
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.forename: Sandra
authors.initials: S
authors.lastname: Meidute Abaraviciene
authors.forename: Ragnar
authors.initials: R
authors.lastname: Henningsson
authors.forename: Ingmar
authors.initials: I
authors.lastname: Lundquist
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002248:Carbon Monoxide / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D057075:Enzyme Assays; D005260:Female; D005934:Glucagon / Q000097:blood / Q000494:pharmacology / Q000502:physiology; D005947:Glucose / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology*; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D009569:Nitric Oxide; D002248:Carbon Monoxide; D005934:Glucagon; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; D005947:Glucose