18 Current Protein and Peptide Science, 2009, 10, 18-29 1389-2037/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Connexins, Diabetes and the Metabolic Syndrome Romain Hamelin 1 , Florent Allagnat 2 , Jacques - Antoine Haefliger 2 and Paolo Meda 1,* 1 Department of Cell Physiology and Metabolism, University of Geneva, School of Medicine, 1211 Genève 4, Switzer- land, 2 Department of Medicine, University Hospital, CHUV-1011 Lausanne, Switzerland Abstract: Diabetes and the related metabolic syndrome are multi system disorders that result from improper interactions between various cell types. Even though the underlying mechanism remains to be fully understood, it is most likely that both the long and the short distance range cell interactions, which normally ensure the physiologic functioning of the pan- creas, and its relationships with the insulin-targeted organs, are altered. This review focuses on the short-range type of in- teractions that depend on the contact between adjacent cells and, specifically, on the interactions that are dependent on connexins. The widespread distribution of these membrane proteins, their multiple modes of action, and their interactions with conditions/molecules associated to both the pathogenesis and the treatment of the 2 main forms of diabetes and the metabolic syndrome, make connexins an essential part of the chain of events that leads to metabolic diseases. Here, we review the present state of knowledge about the molecular and cell biology of the connexin genes and proteins, their gen- eral mechanisms of action, the roles specific connexin species play in the endocrine pancreas and the major insulin- targeted organs, under physiological and patho-physiological conditions. Keywords: Gap junctions, cell coupling, Cx36, Cx26, Cx32, Cx40, Cx43, Cx45, pancreas, arteries, liver, metabolic syndrome. INTRODUCTION The emergence of multi cellularity some 800,000 million ago, was dependent on and associated with the development of new modalities for signalling, whereby close and distant cells, whether of a same or a different tissue, could coordi- nate their function. With evolution, such a coordination sys- tem has developed in a complex network in which signals diffusing in the intercellular spaces of the islets interplay with signalling cascades dependent on membrane proteins that concentrate at cell contacts [1]. These mechanisms en- sure both indirect cell-to-cell interactions, which are medi- ated by neurotransmitters, hormones, ions, nucleotides and other second messengers diffusing in the intercellular spaces, and direct cell-to-cell communication, which are mediated by cell adhesion molecules, integrins, receptors, junctional molecules and other proteins establishing cell contact [1]. In turn, these mechanisms of intercellular communication com- bine in the long and the short distance range to ensure the proper function of many organs, with both the redundance which is required for the maintenance of vital functions, and the moment-to-moment modulation which is needed to adapt to the changing needs of the organism. In vertebrates, an almost consistent feature of this net- work is the signalling dependent on connexins [2-5]. These proteins, which are encoded by a family of 20 genes in hu- mans, form permselective cell-to-cell channels, that cluster at gap junction domains of the membrane of most cell types, and that mediate the diffusion-driven exchange of cytosolic ions and molecules between adjacent cells. Connexins may also fulfil functions that do not require cell-to-cell communi *Address correspondence to this author at the Department of Cell Physiol- ogy and Metabolism, University of Geneva, C.M.U., 1 rue Michel Servet, 1211 Geneva 4, Switzerland. Phone: (4122) 7025210; Fax: (4122) 7025260; E-mail: Paolo.Meda@medecine.unige.ch cation, and are ascribed to either the formation of hemichan- nels in non junctional domains of the cell membrane, to a specific regulation of gene expression and/or to interactions with other cytosolic and membrane partners [2-5]. Recent work on rodents shows that specific connexins fulfill essential functions in all the cell types that play a prominent role in the onset and/or maintenance of diabetes and of the metabolic syndrome, including the pancreatic beta cells that secrete insulin, the endothelial and smooth muscle cells of the vessels that transport the hormone, the liver he- patocytes that initially sense it, and the renin-producing cells of the kidney that control blood pressure [6-9]. These find- ings, the expression of connexins in the corresponding hu- man tissues and the recent identification of pathogenic po- lymorphisms of the cognate genes, raise the novel, intriguing possibility that a dysregulation of the connexin-dependent signaling may be implicated in the patho-physiology and/or maintenance of both diabetes and hypertension [2-5]. The goal of this chapter is to briefly review what is known about the connexins that may participate in type 1 and type 2 diabetes, as well as in the related metabolic syn- drome. Specifically, we will focus on the connexin species that are expressed by the insulin-producing beta cells of pan- creas (Cx36), and the endothelial and smooth muscle cells of arterial vessels (Cx37, Cx40, Cx43 and Cx45). CONNEXINS : THE BARE ESSENTIALS Connexins are Coded by a Multi-Gene Family The 21 connexins that are expressed in mammals (Fig. 1), including humans, are coded by a similar number of dif- ferent genes ( http://www.genenames.org/genefamily/gj. php for humans; http://www. informatics.jax.org/ for ro- dents. Unless otherwise indicated, we use throughout the text