Connexin Implication in the Control of the Murine Beta-Cell Mass

Abstract

Diabetes develops when the insulin needs of peripheral cells exceed the availability or action of the hormone. This situation results from the death of most beta-cells in type 1 diabetes, and from an inability of the beta-cell mass to adapt to increasing insulin needs in type 2 and gestational diabetes. We analyzed several lines of transgenic mice and showed that connexins (Cxs), the transmembrane proteins that form gap junctions, are implicated in the modulation of the beta-cell mass. Specifically, we found that the native Cx36 does not alter islet size or insulin content, whereas the Cx43 isoform increases both parameters, and Cx32 has a similar effect only when combined with GH. These findings open interesting perspectives for the in vitro and in vivo regulation of the beta-cell mass. and/or abnormal sensitivity of peripheral cells to the hormone (1). Type 1 diabetes results from a massive autoimmune destruction of the insulin-producing pancreatic betacells (2). Type 2 diabetes results from a combination of increased insulin resistance of peripheral cells and failure of the beta-cell mass to adapt to the increased needs of insulin (3). Increased needs of insulin are also seen during pregnancy and result in gestational diabetes when beta-cells fail to adequately increase their secretion or mass. In view of the high prevalence of diabetes worldwide, and of the economic burden of current treatments, strategies aimed at increasing the betacell mass could represent a valuable alternative to current approaches. Increasing the beta-cell mass could help to overcome the peripheral resistance to insulin observed in type 2 and gestational diabetes and to improve the effect of cell replacement therapies. Indeed, islet transplantation can normalize blood glucose levels and may prevent the devastating complications of diabetes. However, beta-cells from cadaver pancreases are in such short supply that transplants can be provided only to a limited number of patients, especially because multiple donors are usually necessary to achieve insulin independence of one recipient. The in vitro expansion of isolated islets/islet cells could markedly improve this therapeutic option.The beta-cell mass adapts to the changing needs of the body throughout life. Thus, the beta-cell population grows postnatally, at least until adolescence (4 -6). Thereafter, the increase in beta-cell mass continues to an advanced age and is linearly correlated with body weight (7). However, when a critical threshold is reached, insulin secretion can no longer meet the needs of the body, leading to glucose intolerance or diabetes. Obesity and pregnancy increase the insulin needs and failure to sufficiently increase the beta-cell mass results in type 2 diabetes and gestational diabetes, respectively. Several factors are implicated in the regulation of the beta-cell mass in rodents (8), including glucose (9 -11), insulin, IGF-I and -II (12-16), hepatocyte growth factor (HGF) (17), PTH-related protein (PTHrP) (18), GH, prolactin (PRL), placental lactog...

Connexins protect mouse pancreatic β cells against apoptosis

“…The RIP-directed lines were generated by microinjecting a Cx32 (12), Cx36, or Cx43 (14) transgene into zygotic pronuclei (Supplemental Figures 2 and 5 and Supplemental Methods). Genotype of littermates was determined by PCR amplification of tail DNA (7,9,(12)(13)(14). 3-to 6-monthold mice backcrossed with C57BL/6 controls were used in all experiments.…”

“…11) or Cx43 (RIP-Cx43 +/-, RIP-Cx43 +/+ ; ref. 14), whose de novo β cell-specific expression was also directed by RIP. The control mice of all lines expressed Cx36, even though the native levels of this Cx were higher in Cx36 +/+ mice than in RIP-Cx36 -/-, RIP-Cx32 -/-, and RIP-Cx43 -/-mice (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI40509DS1).…”

“…Here, we have investigated whether this protein also controls β cell survival. We tested the effects of streptozotocin (STZ) and alloxan (AX), 2 drugs that mimic in laboratory rodents the selective and massive death of β cells observed in type 1 diabetes (11), on a series of null and transgenic mice whose β cells feature various Cx and coupling patterns (7,8,(12)(13)(14). We further tested the in vitro resistance of islets isolated from these mice to 3 Th1 cytokines that are implicated at the onset of type 1 diabetes (15,16).…”

The β-Cell/EC Axis: How Do Islet Cells Talk to Each Other?

“…Cx36 junctions allow the passage of ions [in particular, Ca 2+ and cAMP (32) Cx43 and Cx45 have also been identified in pancreatic islets and are specifically expressed on intraislet endothelium rather than on b-cells (35). Interestingly, isletspecific overexpression of Cx43 increases islet size and insulin content (36) (38) and kidney (39). Alternatively, recent evidence that uncoupled hemichannels sample small molecules (e.g., ATP) from the extracellular environment (31) suggests that the role of connexins within the islet may not be limited to physical cellular contact, as they may also participate in paracrine signaling.…”

Connexins: Key Mediators of Endocrine Function

“…Present data show that it is partially explained by the extent of ␤-cell coupling and that it can be sustained by different connexin species (5,265). Given that apoptosis is a major determinant of ␤-cell life (127), and that ␤-cell coupling is enhanced in rodent pregnancy (354,484), a condition associated with a marked increase in ␤-cell proliferation and reduced ␤-cell apoptosis (161,500), the data suggest that Cx36 may also contribute to the regulation of the ␤-cell mass (266). There is presently no evidence that Cx36 forms "hemi-channels" in insulin-producing ␤-cells (455), as it does for example in degenerating neurons (384,385).…”