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.
The emergence of pancreatic islets has necessitated the development of a signalling system for the intra-and inter-islet coordination of b cells. With evolution, this system has evolved into a complex regulatory network of partially crosstalking pathways, whereby individual cells sense the state of activity of their neighbours and, accordingly, regulate their own level of functioning. A consistent feature of this network in vertebrates is the expression of connexin (Cx)-36-made cell-to-cell channels, which cluster at gap junction domains of the cell membrane, and which adjacent b cells use to share cytoplasmic ions and small metabolites within individual islets. This chapter reviews what is known about Cx36, and the mechanism whereby this b-cell connexin significantly regulates insulin secretion. It further outlines other less established functions of the protein and evaluates its potential relevance for the development of novel therapeutic approaches to diabetes.
Glands were the first type of tissues in which the permissive role of gap junctions in the cell-to-cell transfer of membrane-impermeant molecules was shown. During the 40 years that have followed this seminal finding, gap junctions have been documented in all types of multicellular secretory systems, whether of the exocrine, endocrine or pheromonal nature. Also, compelling evidence now indicates that gap junction-mediated coupling, and/or the connexin proteins per se, play significant regulatory roles in various aspects of gland functions, ranging from the biosynthesis, storage and release of a variety of secretory products, to the control of the growth and differentiation of secretory cells, and to the regulation of gland morphogenesis. This review summarizes this evidence in the light of recent reports.
Poor fetal growth, also known as intrauterine growth restriction (IUGR), is a worldwide health concern. IUGR is commonly associated with both an increased risk in perinatal mortality and a higher prevalence of developing chronic metabolic diseases later in life. Obesity, type 2 diabetes or metabolic syndrome could result from noxious “metabolic programming.” In order to better understand early alterations involved in metabolic programming, we modeled IUGR rat pups through either prenatal exposure to synthetic glucocorticoid (dams infused with dexamethasone 100 µg/kg/day, DEX) or prenatal undernutrition (dams feeding restricted to 30% of ad libitum intake, UN). Physiological (glucose and insulin tolerance), morphometric (automated tissue image analysis) and transcriptomic (quantitative PCR) approaches were combined during early life of these IUGR pups with a special focus on their endocrine pancreas and adipose tissue development. In the absence of catch-up growth before weaning, DEX and UN IUGR pups both presented basal hyperglycaemia, decreased glucose tolerance, and pancreatic islet atrophy. Other early metabolic defects were model-specific: DEX pups presented decreased insulin sensitivity whereas UN pups exhibited lowered glucose-induced insulin secretion and more marked alterations in gene expression of pancreatic islet and adipose tissue development regulators. In conclusion, these results show that before any catch-up growth, IUGR rats present early physiologic, morphologic and transcriptomic defects, which can be considered as initial mechanistic basis of metabolic programming.
Cell-to-cell communication mediated by gap junctions made of Connexin36 (Cx36) contributes to pancreatic b-cell function. We have recently demonstrated that Cx36 also supports b-cell survival by a still unclear mechanism. Using specific Cx36 siRNAs or adenoviral vectors, we now show that Cx36 downregulation promotes apoptosis in INS-1E cells exposed to the pro-inflammatory cytokines (IL-1b, TNF-a and IFN-c) involved at the onset of type 1 diabetes, whereas Cx36 overexpression protects against this effect. Cx36 overexpression also protects INS-1E cells against endoplasmic reticulum (ER) stress-mediated apoptosis, and alleviates the cytokine-induced production of reactive oxygen species, the depletion of the ER Ca 2 þ stores, the CHOP overexpression and the degradation of the anti-apoptotic protein Bcl-2 and Mcl-1. We further show that cytokines activate the AMP-dependent protein kinase (AMPK) in a NO-dependent and ER-stress-dependent manner and that AMPK inhibits Cx36 expression. Altogether, the data suggest that Cx36 is involved in Ca 2 þ homeostasis within the ER and that Cx36 expression is downregulated following ER stress and subsequent AMPK activation. As a result, cytokine-induced Cx36 downregulation elicits a positive feedback loop that amplifies ER stress and AMPK activation, leading to further Cx36 downregulation. The data reveal that Cx36 plays a central role in the oxidative stress and ER stress induced by cytokines and the subsequent regulation of AMPK activity, which in turn controls Cx36 expression and mitochondria-dependent apoptosis of insulin-producing cells.
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...
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