Treatment With Recombinant Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Alleviates the Severity of Streptozotocin-Induced Diabetes

Abstract

OBJECTIVETo evaluate the potential therapeutic effect of recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) treatment in a model of type 1 diabetes.RESEARCH DESIGN AND METHODSRecombinant TRAIL was added in vitro to primary human and mouse peripheral blood mononuclear cells (PBMCs) and isolated human islets to evaluate the expression of the immunoregulatory gene SOCS1. Diabetes was induced by five consecutive daily injections of low-concentration (50 mg/kg) streptozotocin (STZ) in C57 black mice (n = 24). A group of these mice (n = 12) was co-injected with recombinant TRAIL (20 μg/day) for 5 days, and the diabetic status (glycemia and body weight) was followed over time. After 6 weeks, circulating levels of insulin, TNF-α, and osteoprotegerin (OPG) were measured, and animals were killed to perform the histological analysis of the pancreas.RESULTSThe in vitro exposure of both PBMCs and human islets to recombinant TRAIL significantly upregulated the expression of SOCS1. With respect to STZ-treated animals, mice co-injected with STZ+TRAIL were characterized by 1) lower levels of hyperglycemia, 2) higher levels of body weight and insulinemia, 3) a partial preservation of pancreatic islets with normal morphology, and 4) a lower expression of both systemic (TNF-α and OPG) and pancreatic (vascular cell adhesion molecule [VCAM]-1) inflammatory markers.CONCLUSIONSOverall, these data demonstrate that the administration of recombinant TRAIL ameliorates the severity of STZ-induced type 1 diabetes, and this effect was accompanied by the upregulation of SOCS1 expression.

TNF-related apoptosis-inducing ligand (TRAIL) protects against diabetes and atherosclerosis in Apoe −/− mice

“…In keeping with this, overabundance of TRAIL in pancreatic islets prolonged normoglycaemia and reduced severity of insulitis in a rat model of diabetes [33]; TRAIL injection also improved islet damage in a mouse model of diabetes [34]. Apoe −/− mice had significantly higher macrophage numbers and caspase-3-positive cells than parental strains (Fig.…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…Cai et al (2011) reported that it increases TNF and IL-1␤ in rat hippocampus. This activity of SZT to induce TNF has been exploited to help understand the consequent pathologic features of diabetes (Sagara et al, 1994;Holstad and Sandler, 2001;Zauli et al, 2010;Devaraj et al, 2011). Specific examples include diabetic cardiomyopathy (Westermann et al, 2007) and diabetic nephropathy (Mensah-Brown et al, 2005;Navarro et al, 2005).…”

Association between the TRAIL single nucleotide polymorphism rs1131580 and type 2 diabetes mellitus in a Han Chinese population

“…Emerging evidence shows that TRAIL plays critical roles in T1DM. TRAIL deficiency accelerates the development of autoimmune diabetes, while treatment with recombinant TRAIL ameliorates the severity of streptozotocininduced T1DM (Lamhamedi-Cherradi et al, 2003;Zauli et al, 2010). In T2DM patients, the serum levels of TRAIL showed a tendency to decrease after insulin treatment, suggesting that TRAIL might be involved in diabetic vascular abnormalities by acting as an endogenous regulator of the vascular tone (Corallini et al, 2007).…”