Loss of Glucagon-Like Peptide-2–Induced Proliferation Following Intestinal Epithelial Insulin-Like Growth Factor-1–Receptor Deletion

Rowland, Katherine; Trivedi, Shivangi; Lee, Daiyoon; Wan, K.K.; Kulkarni, Rohit; Holzenberger, Martin; Brubaker, Patricia L.

doi:10.1053/j.gastro.2011.09.014

Cited by 73 publications

(69 citation statements)

References 40 publications

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“…In contrast to what would have been anticipated from some previous studies (24,39,40), but in line with data on the intestinal IR by Andres et al (23), the loss of neither the IR nor the IGF-IR impairs gut development or growth. However, as we did not study IR/IGF-IR double-knockout mice, we cannot exclude potential compensation during development or in very specific cellular functions.…”

Section: Discussionsupporting

confidence: 87%

“…Several studies in rodents have suggested an additional role of the insulin receptor (IR) and the closely related IGF-I receptor (IGF-IR) in promoting gut maturation and development (18–22). However, previous studies in mice with an IR knockout in the intestinal epithelium did not identify any major role of the IR in glucose or lipid metabolism (23), nor were any changes in proliferation or intestinal length detected upon tamoxifen-induced deletion of the IGF-IR (24). In these studies, however, glucose uptake and the effects of aging were not directly assessed, and the IGF-IR deletion was performed in young adult mice after intestinal development was complete.…”

Section: Introductionmentioning

confidence: 89%

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Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor

et al. 2017

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Insulin receptors (IRs) and IGF-I receptors (IGF-IR) are major regulators of metabolism and cell growth throughout the body; however, their roles in the intestine remain controversial. Here we show that genetic ablation of the IR or IGF-IR in intestinal epithelial cells of mice does not impair intestinal growth or development or the composition of the gut microbiome. However, the loss of IRs alters intestinal epithelial gene expression, especially in pathways related to glucose uptake and metabolism. More importantly, the loss of IRs reduces intestinal glucose uptake. As a result, mice lacking the IR in intestinal epithelium retain normal glucose tolerance during aging compared with controls, which show an age-dependent decline in glucose tolerance. Loss of the IR also results in a reduction of glucose-dependent insulinotropic polypeptide (GIP) expression from enteroendocrine K-cells and decreased GIP release in vivo after glucose ingestion but has no effect on glucagon-like peptide 1 expression or secretion. Thus, the IR in the intestinal epithelium plays important roles in intestinal gene expression, glucose uptake, and GIP production, which may contribute to pathophysiological changes in individuals with diabetes, metabolic syndrome, and other insulin-resistant states.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 89%

Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor

et al. 2017

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“…Administration of the GLP-2R antagonist GLP-2(3–33) or genetic GLP-2R deficiency reverses refeeding-induced intestinal adaptation [30–32]. Furthermore, IGF-1R KO reverses the intestinotrophic effect of exogenous GLP-2 and refeeding-induced intestinal adaptation [13], suggesting that endogenous GLP-2 released in response to luminal nutrients or other stimuli increases crypt cell proliferation via GLP-2R activation, IGF-1 release and IGF-1R activation.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, GLP-2 reduced indomethacin (IND)-induced mortality, accompanied by decreased intestinal injury [12], suggesting that GLP-2 is a candidate therapy for NSAID-induced enteropathy. The intestinotrophic effect of GLP-2 is mediated by insulin-like growth factor-1 (IGF-1) derived from lamina propria myofibroblasts in the intestinal submucosa [13], which accelerates the proliferation of crypt enterocytes, increasing villus height. Stable GLP-2 analogs are usually used in these studies, since GLP-2 is rapidly degraded by dipeptidyl peptide IV (DPPIV), similar to the related hormone, insulinotropic GLP-1 [14].…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

et al. 2013

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Backgrounds & Aims We studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury. Methods Intestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was intragastrically (ig) or intraperitoneally (ip) given before or after indomethacin treatment. L-alanine (L-Ala) and 5′-inosine monophosphate (IMP) were co-administered ig after the treatment. Results Indomethacin treatment induced intestinal ulcers which gradually healed after treatment. Pretreatment with ig or ip K579 given either at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or L-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and L-Ala + IMP further accelerated intestinal ulcer healing. Conclusion DPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.

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“…Absent IGF2 mRNA expression was confirmed by RT-PCR [12]. The intestine-specific IGF1R knockout mice (IGF1R-IKO) have been characterized previously [15] and neither baseline crypt depth nor villus height were affected. We also verified that there was no phenotypic difference in crypt depth or villus height in unoperated IGF2-KO.…”

Section: Resultsmentioning

confidence: 99%

Insulin-like growth factor 2 and its enterocyte receptor are not required for adaptation in response to massive small bowel resection

Sun

Choi

Guo

et al. 2014

Journal of Pediatric Surgery

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Purpose Enhanced structural features of resection-induced intestinal adaptation have been demonstrated following the administration of multiple different growth factors and peptides. Among these, the insulin-like growth factor (IGF) system has been considered to be significant. In this study, we employ mutant mouse strains to directly test the contribution of IGF2 and its enterocyte receptor (IGF1R) toward the adaptation response to massive small bowel resection (SBR). Methods IGF2-knockout (IGF2-KO) (n=8) and intestine specific IGF1R-knockout mice (IGF1R-IKO) (n=9) and their wild type (WT) littermates (n=5, n=7, respectively) underwent 50% proximal SBR. At post-operative day 7, structural adaptation was measured as crypt depth and villus height. Rates of enterocyte proliferation and apoptosis were also recorded. Results The successful deletion of IGF2 and IGF1R expression in the enterocytes was confirmed by RT-PCR and Western blot, respectively. Normal adaptation occurred in both IGF2-KO and IGF1R-IKO mice after 50% SBR. Post-operative rates of proliferation and apoptosis in both IGF2-KO and IGF1R-IKO mice were no different than their respective controls. Conclusion IGF2 and functional IGF1R signaling in enterocytes are both dispensable for resection-induced adaptation responses. The mechanism for IGF-stimulation of intestinal adaptation may involve other ligands or cellular compartments within the intestine.

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Loss of Glucagon-Like Peptide-2–Induced Proliferation Following Intestinal Epithelial Insulin-Like Growth Factor-1–Receptor Deletion

Cited by 73 publications

References 40 publications

Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor

Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

Insulin-like growth factor 2 and its enterocyte receptor are not required for adaptation in response to massive small bowel resection

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