Apoptosis of Beta Cells in Diabetes Mellitus

Abstract

Diabetes mellitus is a multifactorial metabolic disorder characterized by hyperglycemia. Apoptosis in beta cells has been observed in response to diverse stimuli, such as glucose, cytokines, free fatty acids, leptin, and sulfonylureas, leading to the activation of polyol, hexosamine, and diacylglycerol/protein kinase-C (DAG/PKC) pathways that mediate oxidative and nitrosative stress causing the release of different cytokines. Cytokines induce the expression of Fas and tumor necrosis factor-alpha (TNF-α) by activating the transcription factor, nuclear factor-κb, and signal transducer and activator of transcription 1 (STAT-1) in the β cells in the extrinsic pathway of apoptosis. Cytokines produced in beta cells also induce proapoptotic members of the intrinsic pathway of apoptosis. The genetic alterations in apoptosis signaling machinery and the pathogenesis of diabetes include Fas, FasL, Akt, caspases, calpain-10, and phosphatase and tensin homolog (Pten). The other gene products that are involved in diabetes are nitric oxide synthase-2 (NOS2), small ubiquitin-like modifier (SUMO), apolipoprotein CIII (ApoCIII), forkhead box protein O1 (FOXO1), and Kruppel-like zinc finger protein Gli-similar 3 (GLIS3). The gene products having antiapoptotic nature are Bcl-2 and Bcl-XL. Epigenetic mechanisms play an important role in type I and type II diabetes. Further studies on the apoptotic genes and gene products in diabetics may be helpful in pharmacogenomics and individualized treatment along with antioxidants targeting apoptosis in diabetes.

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

“…The advanced and terminal phases of T2DM are characterized with reduced beta cell mass and function due to cumulative cell damage and apoptosis. Beta cell apoptosis and demise at these stages, which result in severe hypoinsulinemia, often require parenteral insulin replacement therapy in these patients (Anuradha et al, 2014;Campbell, 2009;Johnson and Luciani, 2010;Montane et al, 2014;Oh, 2015;Shao et al, 2013;Thomas et al, 2009).…”

“…However, these protective interactions may turn detrimental as the disease progresses and mitochondrial oxidative and endoplasmic reticulum stress progress to apoptotic cell death (Janikiewicz et al, 2015;Kim et al, 2014;Martino et al, 2012). Indeed, diabetes-induced apoptosis cell death has been observed and investigated in pancreatic beta cells, vascular endothelial cells, cardiomyocytes, neural cells or renal cells (Anil Anuradha et al, 2014;Barber et al, 2011;Cnop et al, 2012;Ouyang et al, 2014;Rask-Madsen and King, 2013;Santin and Eizirik, 2013).…”

Islet inflammation in human type 1 diabetes mellitus

“…This relates to the mechanism by which b-cell loss occurs in T1DM and what subsequently happens to the associated debris. It has been widely supposed that the primary mechanism of b-cell death is by apoptosis (27)(28)(29) and that residual b-cell components are cleared rapidly by macrophages which normally patrol and monitor the islet milieu (30). Such hypotheses are based mainly on evidence arising from in vitro studies which show that pro-inflammatory cytokines (e.g., interleukin-1b, interferon-c and tumour necrosis factor-a) can promote b-cell apoptosis (31)(32)(33)(34)(35).…”

Butyrolactone‐I, an efficient α‐glucosidase inhibitor, improves type 2 diabetes with potent TNF‐α–lowering properties through modulating gut microbiota in db/db mice

“…Ideal anti-T2D drugs should aim at multiple therapeutic targets and play multiple roles in glycemic control, decreasing plasma lipid levels, losing weight, and improving systemic inflammation. Clinical studies have shown that T2D is often accompanied by an increase in the concentration of various inflammatory cytokines, among which TNF-a is an important indicator of systemic inflammation (5). Ghada et al found that the expression of cytokine TNF-a was significantly increased in the infected diabetic mice compared with the infected normal mice, and the inflammatory response time to pathogens was significantly prolonged, which may be the reason why patients with diabetes are prone to infection (6).…”