**5.3 Hyperinsulinemia: Altered insulin/IGF signaling**

Hyperinsulinemia generally develops as a compensatory response to the decreased insulin mediated actions under the insulin-resistant conditions (McKeehan et al., 1984). Experimental (Cai et al., 2001; Escobar et al., 2009; Rahman et al., 2007; Vikram et al., 2010a; b; 2011a; Vikram et al., 2010c) and clinical/epidemiological (Hammarsten et al., 2009; Hammarsten and Hogstedt, 2001; Nandeesha et al., 2006) studies indicate that the hyperinsulinemia is an independent contributor to the prostatic cell proliferation and pathogenesis of the BPH. Further, hyperinsulinemic condition can contribute to the augmented prostatic growth by several ways such as (i) increasing the serum level of IGF-I (Chokkalingam et al., 2002; Nam et al., 1997), (ii) possibility of the binding of insulin with the IGF-I receptor (IGF-IR) under the hyperinsulinemic conditions and (iii) binding of IGF-I to the insulin receptor (IR) (Belfiore and Frasca, 2008; Li et al., 2005). Further, IR has two isoforms, A and B, the former is having metabolic as well as mitogenic effects while B is mainly concerned with the metabolic effects. IR isoforms exhibit difference in the binding affinities to the ligand(s) and downstream signaling cascade (Giudice et al., 2011; Kosaki et al., 1995; Leibiger et al., 2001; Sciacca et al., 2003; Uhles et al., 2003; Vogt et al., 1991). IGF-II binds to the IR-A and mediates its growth promoting effects but not with IR-B (Frasca et al., 1999; Morrione et al., 1997). This means that insulin, IGF-I and IGF-II competes to bind with the IR-A, while only insulin binds with the IR-B. The hybrid receptors, IR-A/IR-B and IR/IGF-I further complicates the molecular diversification of the insulin signaling system. IR-A/IR-B hybrid receptors were found to bind to both insulin and IGF-II and therefore, resemble IR-A homodimers rather IR-B homodimers (Blanquart et al., 2008). The IR/IGF-IR hybrid receptors (Pandini et al., 2002; Soos et al., 1990) are activated by both insulin as well as IGF-I, but the IGF-I effect is predominant, and it resembles IGF-1R homodimers rather IR homodimers (Langlois et al., 1995). The IGF and insulin signaling system has been summarized in figure 1. Prostate is known to have both isoforms of the IR (Cox et al., 2009). Experimental studies investigating the effect of dietary habits (particularly dietary fat) on the expression of IR isoforms and signaling kinetics might provide valuable insight in the understanding of the pathogenesis of the BPH under the insulin-resistant, obese and diabetic conditions.
