The Importance Of Insulin

Insulin is a pivotal hormone which keeps the organism in metabolically balanced state by performing variety of cellular functions (Kahn, 1985). Insulin has an anabolic action on protein, fat and glycogen and also stimulates the expression of genes and DNA synthesis (Weiland et al., 1991). Insulin also promotes uptake of glucose in muscles, liver and adipose tissue thus maintains the glucose homeostasis in vivo (Roy et al., 1998). Insulin signaling at target tissues involves several biological functions such as cellular growth and development as well as homeostasis of glucose, fat, and protein metabolism (Kahn, 1985). Insulin is also known to promote energy storage by increasing glucose and free fatty acid uptake (Wu et al., 2006) and stimulates

Insulin acts majorly through two pathways :– MAP kinase signaling pathways, which is important for cellular growth and development, and PI3K pathway, which is important for metabolic functions (Siddle, 2011). Insulin receptor belongs to a highly-conserved family of growth factor receptors with intrinsic tyrosine kinase activity. The insulin receptor is a tetramer with an extracellular domain containing α subunits and a transmembrane domain containing β subunits (α2β2 configuration). Insulin binds to α domain of its receptor, which is followed by a rapid conformational change in the receptor that leads to phosphorylation of specific tyrosine residues of the β subunits. This inturn enables insulin receptor to phosphorylate IRS on tyrosine residues. These phosphorylated tyrosine residues then serve as docking sites for downstream effector molecules. This phosphorylation of IRS by insulin receptor is considered to be a crucial step in insulin signaling (Becker et al., 1990) (Siddle, 2011). IRS has many subtypes (IRS1-6) expressed in insulin-responsive

Particularly, phosphorylation of the IRS molecules on specific serine/threonine residues such as serine 307 leads to decreased ability of insulin receptor to phosphorylate tyrosine residues of IRS. This eventually leads to degradation of the IRS and thereby impairs insulin signaling (Paz et al., 1997). Various hormones and metabolites such as TNFα and FFA have been implicated in this process. The level of these hormones and metabolites is increased in obesity and contributes to the development of insulin resistance through Tyr 307 phosphorylation of IRS (Zick, 2001). Also, increased activity of protein tyrosine phosphatase (PTP1B), which is known to decrease tyrosine phosphorylation of insulin receptor and IRS, is crucial for negative-feedback down regulation of insulin signaling and has been also implicated in insulin resistance (Goldstein et al., 2000). It has been reported that mice lacking the PTP1B gene show increased insulin sensitivity and are also protected against insulin resistance caused by a high fat diet (Delibegovic et al., 2009). Another phosphatase which has been shown to negatively regulate insulin signalling is protein phosphatase 2A (PP2A) (Ugi et al., 2004). The PP2A is a heterodimeric serine/threonine phosphatase with broad substrate specificity and diverse cellular functions. Among