Regulation of blood glucose concentrations requires an adequate number of pancreatic
-cells that respond appropriately to blood glucose concentrations. The collective -cell
numbers are often referred to as the -cell mass (Matveyenko and Butler, 2008).
Autoimmune destruction of -cells in type 1 diabetes causes the complete disappearance of -cells and causes an absolute insulin deficiency (Rahier et al., 2008).
Whereas,type 2 diabetes is characterized by a progressive decline in -cellfunction and chronic insulin resistance, where obesity is a major risk factor in the development of the disease. However, most people who are obese and relatively insulin resistant do not develop diabetes as -cells compensate for the insulin resistance for long periods of time with an increase in secretory capacity and an increase in β-cell mass, or both (Kahn, 1994, DeFronzo, 1997, Polonsky, 2000).
An increase in -cell mass also happens during pregnancy when maternal metabolism undergoes profound changes and maximum nutrient supply is required for the developing foetus. Detailed rodent studies of β-cell mass and insulin secretion during pregnancy has shown that, there is marked insulin resistance accompanied by a dramatic increase in the insulin response to glucose and an almost doubling of the -cells mass in rodents, although the latter may not happen to the same extent in human pregnancy. Rat
-cell mass and insulin secretion decreases rapidly after birth reaching pre-pregnancy values at around 10 days postpartum (Edström et al., 1974, Parsons et al., 1992).
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Regulation of the -cell mass involves a balance between -cell replication and apoptosis, and can include islet neogenesis from exocrine pancreatic ducts. Disruption of any of these pathways of -cell formation or increased rates of -cell death could cause a decrease in -cellmass (Butler et al., 2003).
Rodent models of diabetes, such as the ob/ob and db/db mice (Gapp et al., 1983) and the Zucker fatty rat (Tokuyama et al., 1995), and hyperinsulienaic humans with obesity and/or type 2 diabetes exhibit mild to marked islet hyperplasia at varying times of their disorders (Pinar et al., 2000). However, the factors contributing to -cell hyperplasia in insulin-resistant states are not well understood.
Deficits of -cell mass have been found in various autopsy studies from different European, Asian, and North American populations, where the patients of type 2 diabetes have been reported to have significant reductions in -cell pancreatic area compared with nondiabetic individuals (Klöppel et al., 1985, Butler et al., 2003). The decrease in
-cell mass in type 2 diabetes individuals has been estimated to be about 40% (Maclean and Ogilvie, 1955).
The number of islet -cells present at birth is mainly generated by the proliferation and differentiation of pancreatic progenitor cells, a process called neogenesis. Shortly after birth, -cell neogenesis stops and a small proportion of cycling -cells can still expand the cell number to compensate for increased insulin demands, although at a slow rate. It appears that in the absence of major external stimuli, the -cell population has only a very limited potential for regeneration, unlike liver. This is probably due to the limited replication capacity of -cells and to the fact that neogenesis from precursor cells is not readily reactivated. Yet, under certain conditions where major external stimuli are applied, there can be a quite vigorous regenerative expansion of the -cell mass (Bouwens and Rooman, 2005).
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In NOD mice, -cells are destroyed by a spontaneous autoimmune reaction leading to a type 1-like diabetes condition. Immune suppression in combination with GLP-1 analog- treatment could restore normoglycaemia and improve islet histology (Ogawa et al., 2004). This involves regeneration as well as increased survival of -cells. In animal models of type 2 diabetes induced by 90–95% pancreatectomy, daily administration of the GLP-1 analog exendin-4 during 10 days post pancreatectomy decreases the development of diabetes. Where, exendin-4 stimulates the regeneration of the pancreas and expansion of the -cell mass by the processes of neogenesis and replication of - cells (Xu et al., 1999).
1.3.3.4. The insulin receptor and insulin function
The insulin receptor belongs to the receptor/tyrosine kinase family, which plays critical roles in development, cell division and metabolism (Fantl et al., 1993). The activation of the receptor/tyrosine kinase family by their cognate ligands causes autophosphorylation and selective protein substrates exclusively on tyrosine residues.
The insulin receptor is composed of two alpha subunits and two subunits linked by disulphide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked -chains penetrate through the plasma membrane. Both receptor-subunits are glycosylated during the process of translation and contain complex N-linked carbohydrate side chains with terminal sialic acid residues, which are necessary for normal folding and function of the receptor (Elleman et al., 2000).
The insulin receptor substrate (IRS) proteins are a family of cytoplasmic adaptor proteins that were first identified for their role in insulin signalling. There are at least four members of the IRS protein family, including IRS-1, -2, -3, and -4. IRS-1 and IRS- 2 are expressed in nearly all cells and tissues. Humans express one additional family member, IRS-4, which is more restricted in its expression pattern and is found primarily
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in brain, kidney, thymus and liver and IRS-3, is expressed in rodents, but not in humans (Lavan et al., 1997, Björnholm et al., 2002). Most insulin responses are produced or modulated through tyrosine phoshorylation of IRS-1 or IRS-2.
The function of insulin is to control glucose homeostasis by stimulating the clearance of glucose into skeletal muscle and, to a lesser degree, liver and adipose tissue. In muscle and adipocytes, insulin-stimulated glucose uptake is achieved by the translocation of the insulin-sensitive glucose transporter (GLUT-4) from intracellular storage vesicles to the cell surface (James et al., 1988). Insulin also suppresses endogenous glucose production from glycogenolysis and gluconeogenesis in the liver and it inhibits lipolysis in adipose tissue.