Diabetes mellitus is a widespread disease which an estimated 285 million people in the world suffer from, and these numbers are on the rise making it one of the largest threats to human health in the coming decades. Early research has shown that restoration of the β cell mass by either stimulating β cell replication or β cell neogenesis may be a viable strategy in diabetes therapy. Some proteins such as the INGAP (hamster Reg3delta) have been shown to be involved in β cell regeneration and therefore may be potential sources of new drugs for diabetes treatment. The INGAP protein and peptide as well as other members of the Reg3 family of proteins such as HIP (human Reg3alpha/β) have been shown to have an effect on β cell regeneration, however this effect as well as their mechanism of action in the pancreas is unclear. This review described current knowledge about the mechanism of action and activity of INGAP and other members of the Reg3 family of proteins in β cell regeneration.
Keywords: Diabetes mellitus; Reg proteins; Pancreas; Islet regeneration
The Family of Reg ProteinsThe family of Reg proteins have over the past several years received much attention because the Reg proteins are highly upregulated during pancreatic regeneration and in diabetic patients [1][2][3]. Their roles are very intriguing but poorly understood. The Reg family constitutes a conserved protein family in human and rodents. The Reg proteins are divided into four classes based on their primary protein structure: Reg1, Reg2, Reg3 and Reg4. In the class of Reg1 and Reg3 have different subtypes have been identified. Reg2 is only found in hamster and mouse. All classes except Reg4 have shown to be involved in pancreatic regeneration, for this reason Reg4 will not be described further in this thesis. The different Reg proteins found in mouse, human, rat and hamster, are listed in Table 1 A list of Reg proteins found in four different species. The proteins are grouped into one of four classes, based on their primary structure. For Reg1 and Reg3 different subtypes have been found. The nomenclature of the Reg proteins can be a bit confusing because the proteins have been discovered separately in different fields and therefore given different names. For example, in the literature the Reg3α protein is also referred to as PAP (pancreatitis-associated protein) and HIP (hepatocarcinamo-intestine-pancreas), Reg1 as PTP (pancreatic stone protein), human REG3β as human REG3α and mouse REG3δ as INGAP, which is actually a hamster protein, believed to belong to the Reg3 proteins [2].The Reg proteins are secreted proteins consisting of 155-180 amino acids, supported by presence of human REG3a/β in serum and Reg1 and Reg2 in the lumen of mouse pancreatic ducts [4,5]. They all contain a calcium-dependent carbohydrate binding recognition domain (c-type lectin), but are not known to bind to carbohydrates.Most Reg proteins have six cysteine residues forming disulphide bonds, suggesting relative similar 3D configurations. The genes encoding the different ...