Linda Gallo

Background and aims: The contribution of the kidneys to blood glucose control has become increasingly recognized. This includes both endogenous glucose production in fasting states and the reabsorption of filtered glucose; the latter being the target of novel type 2 diabetes drug class, sodium-dependent glucose transporter (SGLT)-2 inhibitors. Our laboratory has identified the presence of the insulin-sensitive glucose transporter, GLUT4, in kidney proximal tubule cells. We aimed to ascertain the role of this transporter in blood glucose control and kidney function.
Materials and methods: Proximal tubule cell-specific GLUT4 knockout mice (GLUT4 KO) were generated by breeding GLUT4 floxed mice with iL1-sglt2-cre mice and compared to wildtype littermates (WT). Twentyweek old male and female mice were studied (n=11-16/group). An oral glucose tolerance was performed and kidney function determined using 24 h urine collections.
Results: Male mice lacking the GLUT4 transporter in renal proximal tubule cells had elevated blood glucose levels in both fed (12.4 ± 0.8 vs 10.5 ± 0.3 mmol.l-1) and fasted (10.7 ± 0.7 vs 9.1 ± 0.3 mmol.l-1) states, and impaired glucose tolerance during the OGTT (AUGC: 2,145 ± 201 vs 1,691 ± 72 mmol.l-1 x 120 min) compared to WT littermates (p<0.05). There was a trend (p=0.06) for reduced urine flow rate (1.3 ± 0.2 vs 1.9 ± 0.2 ml.24h-1) and smaller kidneys (368 ± 10 vs 411 ± 18 mg) in these male GLUT4 KO mice compared to WT. There were no differences in food or water consumption between groups. Conversely, in female mice, deletion of the GLUT4 transporter from kidney proximal tubule cells did not affect blood glucose levels, kidney weight, or urine production. Conclusion: These findings highlight sex-specific differences in the role of proximal tubule GLUT4 in whole-body glucose homeostasis and urine formation. This may have implications for therapeutic targeting of renal glucose reabsorption in the treatment of type 2 diabetes. Further assessment of peripheral insulin sensitivity, kidney handling of glucose, and overall kidney function is ongoing.