A DYRK inhibitor ameliorates glucose homeostasis and increases incretin-producing cells in diabetic mice.

Abstract

Incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have been shown to improve hyperglycemia in patients with type 2 diabetes, suggesting that an enhanced capacity of GIP and GLP-1 production could be beneficial in type 2 diabetes. We have recently found that dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitors reduce glucose levels and increase the number of intestinal gip-expressing K-cells and glp-1-expressing L-cells in zebrafish. However, their effects on mammals require exploration in greater detail. In this study, we examined whether oral administration of a DYRK inhibitor, ID-8, to diabetic db/db mice affects glucose homeostasis, plasma levels of insulin, incretins, number of intestinal K-cells and L-cells and pancreatic cell volume in vivo. ID-8-treated mice showed a significant reduction in HbA1c levels and decreased blood glucose levels after oral glucose tolerance test along with enhanced plasma levels of insulin, total-GIP and total-GLP-1. The number of K-cells and L-cells in the intestines of ID-8-treated mice was increased, and a subset of these cells were co-stained with a DYRK-regulated transcriptional factor, nuclear factor of activated T cells 4 (NFATc4), but not co-localized with the proliferation marker EdU. There were no significant differences of pancreatic β- and α-cell mass between the ID-8- and vehicle-treated mice. Moreover, mRNA levels of incretins were significantly increased in ID-8-treated human intestinal organoids. Our present study demonstrated that ID-8 improved hyperglycemia in association with enhanced plasma levels of insulin and incretins as well as an increased number of K-cells and L-cells in diabetic mice; therefore, it may be a novel therapeutic agent for diabetes.