title: Impaired glucose-stimulated insulin secretion in the GK rat is associated with abnormalities in islet nitric oxide production.
abstract: We investigated implications of nitric oxide (NO) derived from islet neuronal constitutive NO synthase (ncNOS) and inducible NOS (iNOS) on insulin secretory mechanisms in the mildly diabetic GK rat. Islets from GK rats and Wistar controls were analysed for ncNOS and iNOS by HPLC, immunoblotting and immunocytochemistry in relation to insulin secretion stimulated by glucose or l-arginine in vitro and in vivo. No obvious difference in ncNOS fluorescence in GK vs control islets was seen but freshly isolated GK islets displayed a marked iNOS expression and activity. After incubation at low glucose GK islets showed an abnormal increase in both iNOS and ncNOS activities. At high glucose the impaired glucose-stimulated insulin release was associated with an increased iNOS expression and activity and NOS inhibition dose-dependently amplified insulin secretion in both GK and control islets. This effect by NOS inhibition was also evident in depolarized islets at low glucose, where forskolin had a further amplifying effect in GK but not in control islets. NOS inhibition increased basal insulin release in perfused GK pancreata and amplified insulin release after glucose stimulation in both GK and control pancreata, almost abrogating the nadir separating first and second phase in controls. A defective insulin response to l-arginine was seen in GK rats in vitro and in vivo, being partially restored by NOS inhibition. The results suggest that increased islet NOS activities might contribute to the defective insulin response to glucose and l-arginine in the GK rat. Excessive iNOS expression and activity might be deleterious for the beta-cells over time.
authors.affiliation: Department of Clinical Science, Malmö, Lund University, Sweden. henrik.mosen@med.lu.se
authors.forename: Henrik
authors.initials: H
authors.lastname: Mosén
authors.forename: Claes-Göran
authors.initials: CG
authors.lastname: Ostenson
authors.forename: Ingmar
authors.initials: I
authors.lastname: Lundquist
authors.forename: Per
authors.initials: P
authors.lastname: Alm
authors.forename: Ragnar
authors.initials: R
authors.lastname: Henningsson
authors.forename: Javier
authors.initials: J
authors.lastname: Jimenez-Feltström
authors.forename: Amel
authors.initials: A
authors.lastname: Guenifi
authors.forename: Suad
authors.initials: S
authors.lastname: Efendic
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D005576:Colforsin; D009569:Nitric Oxide; D001120:Arginine; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester