Connexins protect mouse pancreatic β cells against apoptosis
Philippe Klee, … , Jacques-Antoine Haefliger, Paolo Meda
Philippe Klee, … , Jacques-Antoine Haefliger, Paolo Meda
Published November 7, 2011
Citation Information: J Clin Invest. 2011;121(12):4870-4879. https://doi.org/10.1172/JCI40509.
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Research Article Metabolism

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.

Authors

Philippe Klee, Florent Allagnat, Helena Pontes, Manon Cederroth, Anne Charollais, Dorothée Caille, Aurore Britan, Jacques-Antoine Haefliger, Paolo Meda

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Figure 3

Cx36 protects β cells from Th1 cytokines.

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Cx36 protects β cells from Th1 cytokines. (A) Islets isolated from C57BL...
(A) Islets isolated from C57BL/6 mice showed much more healthy cells (calcein stain; green) than dead cells (EB stain; red). The proportion of dead cells substantially increased after 24 hours exposure to STZ. (B) In islets of Cx36–/– mice, STZ (black) increased the volume density (Vv) of dead cells over that in untreated islets (white) and in islets exposed to citrate buffer (gray). The volume density of dead β cells was lower in the islets of STZ-treated Cx36+/+ mice than in those of Cx36+/– and Cx36–/– littermates. (C) Dead cell volume density was significantly higher in STZ-treated RIP-Cx36–/– islets than in islets of RIP-Cx36+/– and RIP-Cx36+/+ littermates. (D) TUNEL labeling showed that Cx36+/+ islets contained rare apoptotic cells (green). The number of apoptotic cells increased after 24 hours exposure to IL-1β, IFN-γ, and TNF-α. (E) Exposure of Cx36–/– islets to either IL-1β and IFN-γ (gray) or IL-1β, IFN-γ, and TNF-α (black) increased the volume density of apoptotic cells over that in untreated mice (white). Apoptosis was lower in the islets of cytokine-treated Cx36+/+ mice than in those of Cx36+/– and Cx36–/– littermates. (F) The volume density of apoptotic cells was higher in RIP-Cx36–/– islets than in islets of RIP-Cx36+/– littermates exposed to the 3 cytokines. Values are medians of the indicated number of experiments. *P < 0.05, **P < 0.01, ***P < 0.001 versus respective cognate control (Cx36+/+ or RIP-Cx36–/–).