Deletion of Fas in the pancreatic β-cells leads to enhanced insulin secretion

Abstract

Fas/Fas ligand belongs to the tumor necrosis factor superfamily of receptors/ligands and is best known for its role in apoptosis. However, recent evidence supports its role in other cellular responses, including proliferation and survival. Although Fas has been implicated as an essential mediator of β-cell death in the pathogenesis of type 1 diabetes, the essential role of Fas specifically in pancreatic β-cells has been found to be controversial. Moreover, the role of Fas on β-cell homeostasis and function is not clear. The objective of this study is to determine the role of Fas specifically in β-cells under both physiological and diabetes models. Mice with Fas deletion specifically in the β-cells were generated using the Cre-loxP system. Cre-mediated Fas deletion was under the control of the rat insulin promoter. Absence of Fas in β-cells leads to complete protection against FasL-induced cell death. However, Fas is not essential in determining β-cell mass or susceptibility to streptozotocin- or HFD-induced diabetes. Importantly, Fas deletion in β-cells leads to increased p65 expression, enhanced glucose tolerance, and glucose-stimulated insulin secretion, with increased exocytosis as manifested by increased changes in membrane capacitance and increased expression of Syntaxin1A, VAMP2, and munc18a. Together, our study shows that Fas in the β-cells indeed plays an essential role in the canonical death receptor-mediated apoptosis but is not essential in regulating β-cell mass or diabetes development. However, β-cell Fas is critical in the regulation of glucose homeostasis through regulation of the exocytosis machinery.

Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action

“…Exendin-4 (Sigma, St Louis, MO, USA) in PBS was administrated i.p. at 09:00 hours and 17:00 hours for 3 days at a dose of 24 nmol/kg [20]. Glucose tolerance tests (GTT), insulin tolerance tests (ITT) and glucose-stimulated insulin secretion (GSIS) were performed as previously described [21].…”

Downregulation of Fas activity rescues early onset of diabetes inc-KitWv/+mice

“…A previous study has reported that Fas is essential for ␤-cell insulin-secretory function but not in the regulation of ␤-cell mass (42). Another study has shown that islet-specific Fas deletion is protective against FasL-and ceramide-induced apoptosis ex vivo and enhances ␤-cell insulin secretion in vivo (8). These discrepancies may be linked to differences in genetic backgrounds of the mouse strains used in these two studies.…”

“…Previous ex vivo studies with human pancreatic ␤-cells have shown that glucotoxicity-induced ␤-cell apoptosis occurs via upregulation of the Fas-mediated apoptotic pathway, which could be rescued by downregulation of Fas (25,36). Furthermore, deletion of Fas in rodent pancreatic ␤-cells has shown protection against FasL-induced apoptosis and increased in vivo insulin secretion (8). While much evidence has pointed to Fas as an important mediator of ␤-cell apoptosis, downstream caspase-8 and -3 are also well known for their roles as the principal executioners of ␤-cells.…”

“…In addition, cytokine-induced upregulation of the Fas apoptotic pathway is also involved in glucotoxicity and subsequent increases in ␤-cell death (25); meanwhile, deletion of Fas protects human islet amyloid polypeptide deposition-mediated ␤-cell apoptosis (36). In vivo studies have demonstrated that nonobese diabetic mice with nonfunctional Fas (global lpr/lpr mutation) show protection against diabetes (10,40), and transgenic mice with ␤-cell-specific knockout of Fas exhibit increased ␤-cell insulin secretion function (8).…”

Mechanisms of non-apoptotic programmed cell death in diabetes and heart failure

“…11 Both forms of diabetes are causally linked to (absolute or relative) β-cell deficiency, 12 and in many instances attributed to increased β-cell apoptosis. [13][14][15] However, targeting β-cell apoptosis has either been incompletely successful in preventing diabetes, 16 or has unmasked latent oncogenic potential. 17 These results point to a parallel programmed death pathway in pancreatic β-cells.…”