Correlation Between Urate Transporters And Hyperuricemia In Diabetes Mellitus And Its Mechanisms

Objective To study the correlation of hyperuricemia with DM and IGR through epidemiological investigation of DM in Lanzhou, Gansu province. And to clarify the mechanism of hyperuricemia in patients with DM result from the altering of URAT1 expression by stimulating human proximal tubular cell(HK-2) with high glucose to mimic hyperglycemia in DM. Methods By stratified random cluster sampling method, we made epidemiological investigation among 2364 residents in Lanzhou and compared the prevalence of hyperuricemia in DM and IGR. The simple of 2364 residents were devided into several groups according to gender and the level of SUA. We analyzed the epidemiological characteristics of SUA, and compared the effect of hyperuricemia on IGR and DM. HK-2cells were stimulated with high glucose to mimic hyperglycemia in DM, and the URAT1 protein levels were detected with RT-PCR,Western Blot analysis in different time(6h,24 h,48h). Meanwhile Akt/GSK- 3 beta pathway inhibitor LY294002 and Licl were added to observe whether the URAT1 expression under high glucose were effected via Akt/GSK- 3beta signaling pathway in HK- 2 cells. Results 1.The overall morbidity of hyperuricemia was16.6% in Lanzhou, and the prevalence of hyperuricemia increased with age. The level of HUA was significantly larger in male than that in female[(325.13±95.43)vs(258.31±83.28)umol/L,P<0.01]. The prevalence of DM and IGR were11.5% and 24.8%. 2. The prevalence of hyperuricemia was larger in DM and IGR than that in normal people(28.6%/22.5%vs12.1%, P < 0.01). The prevalences of DM and IGR in hyperuricemia people were significantly larger than that in normal HUA people(DM19.9%vs9.9%, P<0.01;IGR33.7%vs23.0%,P<0.01) and were rising along with SUA increasing. 3. In addition, HUA was independently related to DM and IGR according to logistic regression analysis. 4. The expression of URAT1 in high glucose group were significantly higher than that in control group in HK-2cells(P < 0.05) and high glucose increased URAT1 expression in a time-dependent manner while benzene bromide Malonesuppressed the expression of URAT1 significantly(P<0.05). 5. Similarly, the activation of Akt/GSK and upregulation of URAT1 induced by high glucose were prevented by pretreatment with Akt inhibitor LY294002 and GSK-3βinhibitor Licl. Conclusion The morbidity of hyperuricemia、DM and IGR in Lanzhou is 11.5%、24.8% and 16.6% separately.The prevalence of hyperuricemia was correlated to the increasing prevalence of DM and IGR,and elevated SUA level is an independent factor of prevalence of DM and IGR. Monitoring and controling of HUA can reduce the possibility of occurrence and the development of DM.Our research demonstrated that the upregulation of renal URAT1 is responsible for hyperuricemia in Vitro. High glucose may be a key stimulator on upregulation of URAT1,and this process might be mediated via the PI3K/Akt/GSK-3β signaling pathway. These results suggest that intervening the URAT1 expression via PI3K/Akt/GSK-3βpathway in HK-2 cells may be a new target to prevent and treat hyperuricemia in patients with DM.