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

Abstract

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.

Chronic Exposure to Palmitate Impairs Insulin Signaling in an Intestinal L-cell Line: A Possible Shift from GLP-1 to Glucagon Production

“…Although the role of insulin on GLP-1 release has not yet been fully clarified, insulin receptors have been described in intestinal L-cells [8,64,65] and their loss has been shown to be associated with impaired GLP-1 secretion and altered expression of intestinal epithelial genes related to glucose uptake and metabolism [8,53,65]. The activated form of the IR is able to phosphorylate both IRS-1-PI3K-AKT and MAPK pathways in L-cells.…”

Comment on Ussar et al. Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor. Diabetes 2017;66:886–896

“…It was with great disappointment that I read the recently published article by Ussar et al (1). Although the authors did a commendable job in characterizing the intestinal phenotypes of male intestinal epithelial insulin receptor and IGF-I insulin receptor knockout mice (VILIRKO and VILIGFRKO, respectively) as compared with floxed control animals, they failed to include female animals as well as an essential control group, namely, the villin-cre mice.…”

Response to Comment on Ussar et al. Regulation of Glucose Uptake and Enteroendocrine Function by the Intestinal Epithelial Insulin Receptor. Diabetes 2017;66:886–896

“…We thank Dr. Brubaker for her letter ( 1 ) regarding our recent publication ( 2 ). She raised two questions that we agree are very important: choice of proper controls and use of both sexes in animal studies.…”

“…In the current study ( 2 ), we were able to take advantage of inherent controls in our experimental design. Specifically, we did not need a “villin-cre only” control because we used the same villin-cre transgenic mice to induce loss of the IGF-I receptor in the intestinal epithelium, and the resultant mice had no phenotype for any of the parameters assessed ( 2 ).…”

“…In the current study ( 2 ), we were able to take advantage of inherent controls in our experimental design. Specifically, we did not need a “villin-cre only” control because we used the same villin-cre transgenic mice to induce loss of the IGF-I receptor in the intestinal epithelium, and the resultant mice had no phenotype for any of the parameters assessed ( 2 ). This indicates not only that the intestinal IGF-I receptor is dispensable for the parameters assessed but also that the villin-cre transgene used in this study itself did not mimic the phenotypes observed in the intestinal epithelial insulin receptor knockout (VILIRKO) mice.…”