Abstract
Dysfunction of the pancreatic β cells leads to several chronic disorders including diabetes mellitus. Several mediators and mechanisms are known to be involved in the regulation of β cell secretory function. In this study, we propose that cytokine-induced nitric oxide (NO) production interacts with cholinergic mechanisms to modulate insulin secretion from pancreatic β cells. Using a rat insulinoma cell line INS-1, we demonstrated that β cell viability decreases significantly in the presence of SNAP (NO donor) in a concentration- and time-dependent manner. Cell viability was also found to be decreased in the presence of a combined treatment of SNAP with SMN (muscarinic receptor antagonist). We then investigated the impact of these findings on insulin secretion and found a significant reduction in glucose uptake by INS-1 cells in the presence of SNAP and SMN as compared with control. Nitric oxide synthase 3 gene expression was found to be significantly reduced in response to combined treatment with SNAP and SMN suggesting an interaction between the cholinergic and nitrergic systems. The analysis of gene and protein expression further pin-pointed the involvement of M3 muscarinic receptors in the cholinergic pathway. Upon treatment with cytokines, reduced cell viability was observed in the presence of TNF-α and IFN-γ. A significant reduction in insulin secretion was also noted after treatment with TNF-α and IFN-γ and IL1-β. The findings of the present study have shown for the first time that the inhibition of the excitatory effects of cholinergic pathways on glucose-induced insulin secretion may cause β cell injury and dysfunction of insulin secretion in response to cytokine-induced NO production.
Highlights
Pathophysiology of diabetes mellitus (DM) is highly complex, and multiple factors and pathways are involved. β cell dysfunction is considered to be the main pathological feature of DM, and previous studies have identified several mediators of β cell injury that are associated with DM
An intact survival was observed in control cells which did not receive any treatment with significant increase in the expression of M3 (SNAP)
The findings of the present study have shown that a nitric oxide (NO) donor, muscarinic acetylcholine receptor blockade, and cytokines produced adverse effects on survival rate of β cells and insulin secretion
Summary
Pathophysiology of diabetes mellitus (DM) is highly complex, and multiple factors and pathways are involved. β cell dysfunction is considered to be the main pathological feature of DM, and previous studies have identified several mediators of β cell injury that are associated with DM. It is noteworthy that the mechanisms that underpin β cell failure in the progression of type 1 and type 2 DM differ considerably. In the former, the main process that leads to destruction of the β cell is based on autoimmune-mediated apoptosis, whereas in type 2 DM, the dysfunction of β cells mainly involves circulating cytokines (interleukin 1 beta, IL1β; tumor necrosis factor alpha, TNF-α; and interferon-γ, IFN-γ) which indirectly promote apoptosis through excessive production of nitric oxide (NO) [39]. NO is a free radical molecule which has several physiological and pathological functions It is generated by the oxidation of the amino acid L-arginine by a family of enzymes known as nitric oxide synthases (NOS). The constitutively expressed isoforms release low levels of NO that exert physiological functions, whereas iNOS releases a high output of NO production in response to immunogenic and inflammatory stimuli [38, 43]
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