RF04 | PSUN298 Loss of β-Cell Glut2 Does Not Affect Systemic Glucose Homeostasis in Mice

Abstract

Abstract Contribution of β-cell GLUT2 to systemic glucose homeostasis remains controversial in humans. For example, recent publications indicate that GLUT2 is not a major glucose transporter in β-cells in humans and therefore may not be involved in regulating systemic glucose homeostasis, which is in strong contrast to its previously assumed contribution to influencing systemic glucose balance. Although global Glut2 knockout mice develop diabetes, the contribution of β-cell Glut2 toward this phenotype is unknown. To determine the role of β-cell Glut2 in systemic glucose homeostasis, we crossed Glut2LoxP/LoxP mice with INSCreERT2 mouse strain to obtain mice that will potentially lack Glut2 specifically in β-cells (β-Glut2 KO) after administration of tamoxifen (100 mg/kg, i.p., once daily for five days) to induce the Cre-Lox recombination. We measured 6 h fasting blood glucose levels, glucose tolerance, and glucose-induced insulin secretion in the β-Glut2 KO mice. We observed that the KO mice had normal fasting blood glucose levels (male: 194.2 ±9.3 vs 192.0 ±3.5; female: 177.3 ±8.5 vs 157.3 ±9.8 mg/dL, Control vs. β-Glut2 KO). Similarly, the β-Glut2 KO mice exhibited normal glucose tolerance following oral administration of 60 mg glucose (Area under the curve for glucose tolerance, male: 39,911 ±1,632 vs. 39,633 ±1,275; female: 47,321 ±3,294 vs. 43,673 ±2,677 mg/dL*min, Control vs. β-Glut2 KO). Moreover, the KO mice had normal glucose-stimulated insulin secretion (baseline fasting plasma insulin levels: male - 0.84 ±0.14 vs. 0.5 ±0.01; female - 0.45 ±0.09 vs 0.48 ±0.1; plasma insulin levels 20 min. after oral glucose administration: male - 2.39 ±0.13 vs 2.48 ±0.51; female - 1.63 ±0.3 vs 1.11 ±0.12 ng/ml, Control vs. β-Glut2 KO). We had validated the loss of β-cell Glut2 using mRNA in situ hybridization. Altogether, our findings indicate that β-cell Glut2 is not essential for regulating systemic glucose homeostasis in mice, which was also observed recently with human β-cells. Therefore, the currently assumed major role of β-cell GLUT2 in directly influencing blood glucose levels needs to be reexamined to better understand the pathophysiology of impaired glucose homeostasis in diabetes. Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.