Purpose of review To summarize recent evidence that IGF1 mediates growth effects of multiple trophic factors and discuss clinical relevance. Recent findings Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogues in short bowel syndrome and Crohn’s disease. This review highlights evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn’s disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that SOCS protein induction by GH or GLP2 in normal or inflamed intestine, may limit IGF1-induced growth, but protect against risk of dysplasia or fibrosis is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed. Summary IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed.

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Insulin receptor (IR) has been little studied in intestinal epithelium, despite evidence that obesity and hyperinsulinemia promote intestinal dysfunction and cancer. In other organs, two IR splice variants mediate metabolism (IR‐B) or growth (IR‐A). This study examined IR‐A and IR‐B in intestinal stem cells (ISC), progenitors, and differentiated lineages isolated from Sox9‐EGFP reporter mice, normal tissue (N) and tumors (T) of ApcMin/+ mice, and colorectal cancer cells (CRC). Effects of IR‐B overexpression were tested in Caco2 CRC. We hypothesized that IR‐B predominates in differentiated normal lineages or differentiated CRC, limits CRC proliferation, and promotes differentiation.ResultsIR‐A predominates in ISC and progenitors; IR‐B predominates in differentiated lineages. IR‐B is downregulated in T vs N of ApcMin/+ mice and aggressively growing CRC. In Caco2 CRC, IR‐A and IR‐B are both expressed during exponential growth, but IR‐B and an IR‐B splicing enhancer are dramatically upregulated during spontaneous differentiation. Overexpression of IR‐B in Caco2 CRC dramatically reduced proliferation, but accelerated and enhanced expression of the differentiation marker sucrase. We conclude that maintained or upregulated IR‐B expression may be critical to differentiation of intestinal epithelial cells or CRC and protective against colon cancer growth. Grants: F31AG040943, NIH DK040247–19.

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Little is known about expression and roles of insulin receptor (IR) in the intestinal epithelium despite emerging links between obesity, hyperinsulinemia, and intestinal dysfunction or cancer risk. IR exists as an IR‐B isoform that mediates insulin's metabolic actions and an IR‐A isoform implicated in fetal growth and recently, cancer. This study used Sox9‐EGFP reporter mice, ApcMin/+ mice, and human colorectal cancer cell lines (CRC) to test the hypothesis that IR‐A and IR‐B have distinct expression profiles in highly proliferative vs differentiated normal intestinal epithelial cells (IEC) or CRC.ResultsIR‐A predominates in highly proliferative intestinal epithelial stem cells and progenitors, while IR‐B predominates in differentiated lineages. In ApcMin/+ mice, the IR‐B:IR‐A ratio is dramatically decreased in tumor vs non‐tumor tissue in small intestine (0.65 ± 0.02 vs 1.3 ± 0.03) and colon (0.63 ± 0.1 vs 1.27 ± 0.9). The IR‐B:IR‐A ratio is higher in CRC with the ability to differentiate vs undifferentiated, aggressively growing CRC. The ratio of IR‐B:IR‐A is significantly increased in differentiated vs undifferentiated Caco2 cells (2.2 ± 0.2 vs 1.5 ± 0.1). We conclude that relative expression levels of IR‐B:IR‐A may be critical determinants of normal IEC or CRC differentiation. Grants: F31AG040943 (SFB) and NIH DK040247‐19 (PKL).