Acute pancreatitis, expression of inducible nitric oxide synthase and defective insulin secretion

Abstract

A high level of nitric oxide (NO) produced by inducible NO synthase (iNOS) is involved in pancreatic beta-cell dysfunction and apoptosis. In the present study, we examined whether iNOS is also expressed in beta cells after induction of acute pancreatitis (AP) in the rat. Pancreatic islets taken from AP animals and incubated for 60 min in the presence of 20.0 mmol/l glucose showed a decreased insulin secretory response to glucose. The basal insulin release at 1.0 mmol/l glucose was also moderately reduced. Experiments on the dynamics of insulin secretion from perfused pancreas revealed an impairment of both first and second phase of glucose-stimulated insulin release after the induction of AP. Confocal microscopy demonstrated that most of the beta cells in pancreas of rat with AP expressed strong immunoreactivity for iNOS. This was further confirmed by biochemical and Western blot analysis that showed a marked increase in iNOS protein expression and enzyme activity concomitant with a modest reduction in the cNOS protein and activity. Although the mechanisms underlying the defective insulin secretory response of beta cells seen during the early stage of AP are complex, the present finding suggests that the expression of iNOS and a marked iNOS-derived NO production in the beta cells may play at least a contributory role in the impairment of beta-cell function.

Effect of Quercetin on the Endocrine Pancreas of the Experimentally Induced Diabetes in Male Albino Rats: A Histological and Immunohistochemical Study

“…However, other findings suggest that iNOS isoform may play a role in the destruction of β cells during the development of DM2 [9].…”

Free radicals and the pancreatic acinar cells: role in physiology and pathology

“…Meanwhile, another study on the same model of AP implied that neuronal secretion of NO may cause significant protection (Dembinski et al 1996). It is also worth noting that, unlike iNOS, constitutive NOS activity becomes progressively depleted during AP (Takacs et al 2002;Qader et al 2003). This may explain adaptation to non-selective NOS inhibition over time (Kolaja et al 2004).…”

“…The role of NO produced by either constitutive or inducible NOS in experimental models of AP is controversial. Generally, NO generated by iNOS, which during AP is induced in infiltrating neutrophils and macrophages (Satoh et al 1998) and also in the other cells of pancreatic tissue (Al Mufti et al 1998;Rau et al 2001;Vaquero et al 2001;Qader et al 2003;Um et al 2003), has injurious effects (Lomis et al 1995;Ayub et al 2001;Simsek et al 2001;Cuzzocrea et al 2002;Ozturk et al 2003;Um et al 2003;Chen et al 2004;Isik et al 2004;Sandstrom et al 2005). The inducible form of cyclooxygenase, producing CO in a manner similar to NO production by iNOS, also exacerbates the severity of pancreatitis (Song et al 2002).…”

Inducible nitric oxide synthase immunoreactivity in healthy rat pancreas.

“…However, NO production in cells, exceeding the amount necessary for normal biological activities, results in cell death by apoptosis and tissue damage [2][3][4]. NO is produced by enzyme nitric oxide synthase (NOS), which is a short-lived mediator that can be produced in various cell types.…”

“…It is also believed that in insulin-dependent diabetes mellitus (IDDM), possible mediator of pancreatic beta-cell damage is radical NO and iNOS is the most involved of NOS isoforms in immune mediated beta-cell damage [8]. High level of NO produced by iNOS is related to pancreatic beta-cell disfunction and apoptosis [2,3]. IDDM is characterized by inflammatory reaction in and around Langerhans islets followed by selective destruction of insulin producing betacells.…”