Glucose Induces β-Cell Apoptosis Via Upregulation of the Fas Receptor in Human Islets

Abstract

In autoimmune type 1 diabetes, Fas-to-Fas-ligand (FasL) interaction may represent one of the essential proapoptotic pathways leading to a loss of pancreatic ␤-cells. In the advanced stages of type 2 diabetes, a decline in ␤-cell mass is also observed, but its mechanism is not known. Human islets normally express FasL but not the Fas receptor. We observed upregulation of Fas in ␤-cells of type 2 diabetic patients relative to nondiabetic control subjects. In vitro exposure of islets from nondiabetic organ donors to high glucose levels induced Fas expression, caspase-8 and -3 activation, and ␤-cell apoptosis. The effect of glucose was blocked by an antagonistic anti-Fas antibody, indicating that glucose-induced apoptosis is due to interaction between the constitutively expressed FasL and the upregulated Fas. These results support a new role for glucose in regulating Fas expression in human ␤-cells. Upregulation of the Fas receptor by elevated glucose levels may contribute to ␤-cell destruction by the constitutively expressed FasL independent of an autoimmune reaction, thus providing a link between type 1 and type 2 diabetes.

Adenoviral overexpression of interleukin-1 receptor antagonist protein increases β-cell replication in rat pancreatic islets

“…The susceptibility to the deleterious effects of cytokines is different among species, with rodent islets showing a higher sensitivity than human islets. 28 However, similar to our results in rat islets, a very strong reduction in b-cell replication has been recently observed in human islets cultured for 5 days in low and high glucose in the presence of IL-1b, 20 suggesting that the very high sensitivity of b-cell replication to IL-1b may be common to rodent and human islets.…”

“…[14][15][16] The effects of IL-1b on b-cell replication have been less studied, but available data indicate that IL-1b decreased DNA synthesis in fetal 17 and in adult islet cells. [18][19][20] It is basically unknown whether a negative effect of IL-1b on b-cell replication could reduce the capability of b-cells to compensate the increased b-cell loss that takes place in type I diabetes, and contribute to the development of diabetes.…”

Cluster analysis of rat pancreatic islet gene mRNA levels after culture in low-, intermediate- and high-glucose concentrations

“…Interestingly, the latter two genes are part of the integrated stress response (ISR), which is activated by oxidative stress, DNA damage, nutrient deprivation, viral infection and endoplasmic reticulum (ER) stress [27]. Surprisingly, Fas, a pro-apoptotic gene previously shown to be upregulated by prolonged exposure to high glucose [28], was highly expressed at low glucose and minimally expressed in G10 and G30. Together with other genes displaying a similar mRNA profile, these genes may play a role in the pro-apoptotic effect of prolonged culture in G2 and G5 instead of in G10 [12][13][14]26].…”

An immune origin of type 2 diabetes?

“…Metabolic stress resulting from a high-caloric diet and the concomitant detrimental effects of increased glucose or NEFA concentrations on beta cells are considered major contributors to beta cell loss [74,122,[124][125][126][127], which occurs mainly by apoptosis [128,129]. The question at issue is whether beta cell damage and apoptosis are direct consequences of the increased mitochondrial generation of oxygen radicals or whether immune/inflammatory mediators are responsible (Fig.…”