RF04 | PSUN297 Genetic Knockout of Intestinal Hexokinase Domain Containing Protein-1 Affects Enterocyte Glucose Transport in Mice Fed High Fat Diet

Abstract

Abstract Hexokinase domain containing protein-1, or HKDC1, is a widely expressed novel hexokinase that is genetically associated with elevated 2-hour gestational blood glucose levels during an oral glucose tolerance test, suggesting a role for HKDC1 in postprandial glucose regulation during pregnancy. Our earlier studies utilizing transgenic mice containing whole-body HKDC1 knockdown, or mice in which hepatic HKDC1 was overexpressed or knocked out, indicated that HKDC1 is important for whole-body glucose homeostasis in aging and pregnancy, through modulation of glucose tolerance, peripheral tissue glucose utilization, and hepatic energy storage. However, our knowledge of the precise mechanisms by which HKDC1 regulates postprandial glucose homeostasis under normal and diabetic conditions is lacking. As the intestine is the main entry portal for dietary glucose, and since HKDC1 is highly expressed within the intestine, in this study we assessed and characterized the in vivo significance of intestine-specific HKDC1 in regulating glucose homeostasis under normal and obesogenic conditions. We developed an intestine-specific HKDC1 knockout mouse model, HKDC1Int-/-, utilizing Cre-mediated recombination of HKDC1 in which Cre was expressed under the control of the villin gene promoter, leading to genetic knockout of HKDC1 solely within the intestinal epithelium. Mice were maintained until 28 weeks of age on either a normal chow diet or a high fat diet to develop obesity, hyperglycemia, and insulin resistance. While no overt glycemic phenotype was observed, 28-week-old HKDC1Int-/- mice fed a high fat diet exhibited an increased glucose excursion following an oral glucose load compared to mice expressing intestinal HKDC1. This finding was not due to differences in insulin levels, whole-body insulin tolerance, or gluconeogenesis, nor was it a result of alterations in enterocyte glucose utilization or a reduction in peripheral skeletal muscle glucose uptake. Furthermore, the enhanced glucose excursion was related to transport of glucose through the intestinal epithelium, as mice administered an intraperitoneal glucose load did not exhibit alterations in post-load glycemic excursion. Assessment of intestinal glucose transporters in high fat diet-fed HKDC1Int-/- mice indicated an increased expression of GLUT2 in the enterocyte apical membrane in the fasting state. Taken together, our results indicate that intestine-specific HKDC1 contributes to postprandial glycemic regulation by modulating dietary glucose transport across the intestinal epithelium under conditions of enhanced metabolic stress, such as obesity, hyperglycemia, and diabetes. Presentation: Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.