Despite evidence for the impact of insulin on intestinal epithelial physiology and pathophysiology, the expression patterns, roles, and regulation of insulin receptor (IR) and IR isoforms in the intestinal epithelium are not well characterized. (IECs) and that IR-B impacts cell proliferation. Our findings provide evidence that IR-B expression is significantly lower in highly proliferative IESCs and progenitor cells versus post-mitotic, differentiated IECs and in subconfluent and undifferentiated versus differentiated Caco-2 cells. IR-B is also reduced in ApcMin/+ tumors and highly tumorigenic CRC cells. These differences in IR-B were accompanied by altered levels of mRNAs encoding muscleblind-like 2 (MBNL2), a known regulator of IR alternative splicing. Forced IR-B expression in subconfluent and undifferentiated Caco-2 cells reduced proliferation and increased biomarkers of differentiation. Our findings indicate that the impact of insulin on different cell types in the intestinal epithelium might differ depending on relative IR-B IR-A expression levels and Pyraclonil provide new evidence for the roles of IR-B to limit proliferation of CRC cells. and upregulation of is associated with reduced IR-B levels and insulin resistance of skeletal muscle in patients with myotonic dystrophy (Cruz Guzmn et al., 2012; Dansithong et al., 2005; Paul et al., 2006), demonstrating a crucial role for these RNA-binding proteins in both IR-B expression and insulin sensitivity. IR-B has high affinity for insulin and much lower affinity for the structurally related ligands, insulin-like growth factors 1 and 2 (IGF1 and IGF2). IR-A binds insulin and IGF2 with high affinity, whereas it binds IGF1 with an tenfold lower affinity (Belfiore et al., 2009; Frasca et al., 1999). Previous studies demonstrated that IR-B is highly expressed and predominates over IR-A in specialized adult tissues, such as liver, skeletal muscle, adipose tissue, pancreas and kidney, where it mediates metabolic effects of insulin on nutrient uptake, handling Pyraclonil or storage (Lin et al., 2013; Moller et al., 1989; Mosthaf et al., 1990). IR-A is thought to play a role in fetal growth because it is highly expressed during embryogenesis and can mediate the growth-promoting effects of IGF2 (Belfiore et al., 2009). Upregulation of IR-A has been reported in breast, ovarian, colon and thyroid cancer cell lines and/or human tumors (Belfiore et al., 2009; Frasca et al., 1999; Jones et al., 2006; Kalla Singh et al., 2011; Kalli et al., 2002; Sciacca et al., 1999; Vella et al., 2002). Because IR-A can bind both insulin and the IGFs, which are typically linked to cell proliferation and survival, these findings support current views Pyraclonil that IR-A may mediate cancer cell proliferation or survival in response to insulin or the IGFs (Belfiore et al., 2009; Belfiore and Malaguarnera, 2011; Cohen and LeRoith, 2012; Frasca et al., 1999; Jones et al., 2006; Kalla Singh et al., 2011; Kalli et al., 2002; Sciacca et al., 1999; Vella et Rabbit Polyclonal to CNGA2 al., 2002). Increasing attention is being focused on IR-A as a potential mediator of anti-IGF1R therapy evasion in cancer cells (Buck et al., 2010; Ulanet et al., 2010). Less is known about expression profiles and physiological roles of IR-B versus IR-A in normal, highly proliferative adult tissues, such as the intestinal epithelium. The intestinal epithelium is not traditionally considered to be a major target of the metabolic actions Pyraclonil of insulin, although it is the first organ exposed to digested nutrients. A need for a better understanding of the role of insulin and IRs in the intestinal epithelium is highlighted by recent studies linking obesity, hyperinsulinemia and insulin resistance, or insulin therapies used in diabetes mellitus, to risk of gastrointestinal cancers (Gough et al., 2011; Kant and Hull, 2011; Keku et al., 2005; Wong et al., 2012; Yuhara et al., 2011). Epidemiological studies have linked elevated plasma insulin and reduced spontaneous apoptosis in normal colonic epithelium to risk Pyraclonil of precancerous colorectal adenomas (Keku et al., 2005). A small but mounting body of evidence suggests that obesity and type-2 diabetes are associated with insulin resistance at the level of the enterocyte, which might promote aberrant lipid handling and exacerbate dyslipidemia, (Federico et al., 2006; Haidari et al., 2002; Hayashi et al., 2011). Despite this evidence for potential roles of insulin in aberrant cell growth, survival or dysfunction of differentiated enterocytes, little is known about the expression or specific functions of the IR, and particularly IR-A and IR-B isoforms in the intestinal epithelium. The small intestinal epithelium is the most proliferative tissue in the body, with constant renewal of the epithelium.
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