Altered proximal tubule glucose metabolism in X-linked hypophosphatemic mice

In the present study we examined renal proximal tubule glucose metabolism in the X-linked hypophosphatemic (Hyp/Y) mouse. Compared to those in its normal (+/Y) littermate, Hyp/Y mouse proximal tubules showed a higher rate of glucose production when using glutamine or alpha-ketoglutarate as a substrate. The glucose production rate was not, however, different when using malate or fructose as the substrate. PTH stimulated glucose production in +/Y, but not Hyp/Y, mouse proximal tubules. The PTH resistance in Hyp/Y mouse involves steps at and post-cAMP formation, because in Hyp/Y mouse proximal tubules PTH effects a lesser stimulation of cAMP generation, and addition of 8-bromo-cAMP failed to increase the glucose production rate. The rate of glucose utilization as a whole was not different in the two groups, but the rate of glucose metabolized through the pentose cycle (PC) pathway was markedly lower in Hyp/Y mouse proximal tubules. The lower PC activity in Hyp/Y mouse proximal tubules did not result from a defect of PC enzymes, because both glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase enzyme activities were intact, and phenazine methosulfate was able to stimulate PC activity. The higher rate of glucose production and the lower rate of PC activities persisted in the in vitro cultured Hyp/Y mouse proximal tubular cells. These results suggest that the altered glucose metabolism in the Hyp/Y mouse proximal tubule is not maintained by external influences and may be an abnormality intrinsic to these cells.