Connexins protect mouse pancreatic β cells against apoptosis

Abstract

Type 1 diabetes develops when most insulin-producing β cells of the pancreas are killed by an autoimmune attack. The in vivo conditions modulating the sensitivity and resistance of β cells to this attack remain largely obscure. Here, we show that connexin 36 (Cx36), a trans-membrane protein that forms gap junctions between β cells in the pancreatic islets, protects mouse β cells against both cytotoxic drugs and cytokines that prevail in the islet environment at the onset of type 1 diabetes. We documented that this protection was at least partially dependent on intercellular communication, which Cx36 and other types of connexin channels establish within pancreatic islets. We further found that proinflammatory cytokines decreased expression of Cx36 and that experimental reduction or augmentation of Cx36 levels increased or decreased β cell apoptosis, respectively. Thus, we conclude that Cx36 is central to β cell protection from toxic insults.

Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity

“…47 Therefore, it is plausible that, by allowing the intercellular diffusion of Ca 2 þ and/or IP3, Cx36 channels achieve a sufficient dilution of harmful signals across the population of coupled cells, thus preventing the activation of mitochondrial apoptosis. 4 Consistent with this hypothesis, Cx36 specifically hampers the intrinsic mitochondrial pathway of apoptosis by modulating the effect of cytokines on the Ca 2 þ stores of the ER and on the expression of the CHOP, Bcl-2 and Mcl-1 proteins. These data further confirm our previous findings that CHOP has an important role in cytokine-induced apoptosis of insulin-producing cells by altering the stability of the Bcl-2 and Mcl-1 proteins.…”

“…Here, we observe that Cx36 overexpression decreases the cytokineinduced production of ROS, but that neither the knockdown nor the overexpression of Cx36 influences the basal and the cytokine-induced production of NO (data not shown). 4 This indicates that the effect of Cx36 on ROS-RNS production occurs downstream the generation of NO. Furthermore, since Cx36 overexpression protects INS-1E cells against the thapsigargin-induced apoptosis, the cytokine-induced ROS Figure 8 Cx36 has a central role in cytokine-induced ER stress, AMPK regulation and apoptosis.…”

“…4 Cx36 also protects pancreatic b-cells in vitro against apoptosis induced by lipids 22,25 and cytokines. 4 Although these studies suggest a common pathway for Cx36-mediated protection against various cytotoxic insults both in vitro and in vivo, the molecular mechanisms activating this pathway remain to be unraveled. The aim of this study was to identify these mechanisms, specifically those contributing to the b-cell apoptosis induced by the pro-inflammatory cytokines involved in the pathophysiology of type 1 diabetes.…”

“…3 We recently reported that mice lacking Connexin36 (Cx36), the sole connexin expressed in b-cells, 1,2 are sensitized to cytotoxic drugs and cytokines, whereas mice overexpressing Cx36 in b-cells are more resistant to these insults. 4 However, the molecular mechanism of this protection remains to be established.…”

Low Level Pro-inflammatory Cytokines Decrease Connexin36 Gap Junction Coupling in Mouse and Human Islets through Nitric Oxide-mediated Protein Kinase Cδ

“…Changes in Cx36 gap junction coupling have been shown to be protective against cytokine-induced damage in INS-1E cells (30) and against apoptosis in mouse islets (31). Despite this protective mechanism and the importance of Cx36 in regulating insulin release, the regulation of Cx36 gap junction coupling in the islet is poorly understood (32).…”