In this study, we explored the changes in SUA and 24-hour UUA and FEUA levels before and after taking dapagliflozin 10 mg once daily for one week, as well as comparing the changes of parameters of insulin resistance and islet β-cell function before and after treatment. We found decreased SUA levels and increased FEUA levels after taking dapagliflozin, both with statistically significant differences. Additionally, there were improvements in glycemic control, insulin resistance and islet β-cell function but without statistically significant differences. We also found a positive correlation between the improvement of glycemic control and Stumvoll 1st phase index and Stumvoll 2nd phase index, which suggested the alleviation of glucotoxicity solely benefits islet β-cell function.
UA is the final metabolic product of purine compounds. Disorders of UA metabolism may cause hyperuricemia and gout. In recent years, a large body of studies have proved the clinical significance of UA in the development of various metabolic disorders, including T2DM18-20. One one hand, the prevalence of hyperuricemia in patients with T2DM is higher than that in subjects with NGT; on the other hand, hyperuricemia has been linked to both micro- and macrovascular complications in patients with DM 21. Hyperuricemia can result from elevated UA production or reduced renal excretion. It was thought that hyperuricemia in patients with DM was dominated by reduced UA excretion because of decreased UA clearance and increased reabsorption caused by hyperinsulinemia22, 23 and decreased GFR resulting from diabetic nephropathy.
Traditionally, parameters to evaluate the ability of the kidneys to excrete UA include 24-hour UUA, clearance rate of UA, FEUA, excretion of UA per volume of glomerular filtration and UUA to urinary creatinine ratio, among which FEUA and 24-hour UUA are subject to less of an impact from the eGFR. However, the level of 24-hour UUA is affected by many factors, including dietary purine intake, amount of drinking water, urine output, renal function, and SUA. Some scholars recommend a more accurate and reliable index, FEUA, instead of 24-hour UUA to quantify the level of UA excretion24. In our study, we found levels of both 24-hour UUA and FEUA increased in subjects with T2DM at baseline. While the SUA levels were still higher than that of subjects with NGT, we speculate that the increased renal excretion of UA in urine might reflect an already compensatory mechanism of high SUA levels, or increased UA production might be the major cause of hyperuricemia in those patients with T2DM because increased oxidative stress resulting from T2DM and lipid peroxidation could lead to increased SUA levels, which act as endogenous antioxidants to protect the body25. Similar to our results, it was also reported in previous research that the mechanism of hyperuricemia is most likely due to overproduction of UA in certain patients with DM26.
A variety of studies have reported reduced SUA levels after taking SGLT2 inhibitors. A post hoc analysis of prospectively collected data within the CANVAS program reported canagliflozin reduced serum urate concentrations and reduced events related to gout among patients with T2DM3. A meta-analysis of 62 randomized controlled trials involving 34 941 patients quantified the effect of any of the SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, tofogliflozin, licogliflozin, or ipragliflozin) on reducing SUA levels in patients with T2DM27. However, in most previous studies, the reduced SUA levels were observed 12–26 weeks after treatment28, and a few studies reported the excretion of UA could result in reduction of SUA in the first couple weeks29. Our study found the SUA-lowering effect of dapagliflozin can act within one week, and the level of SUA decreased significantly to nearly the same level of healthy subjects accompanied by a significant increase in FEUA, and there was a linear correlation between changes in the SUA and FEUA levels. The exact mechanism of the SUA-lowering effect of SGLT2 inhibitors is still unclear; the most widely accepted hypothesis is the possible involvement of the renal GLUT9 (SLC2A9) transporter, which is likely to play a predominant role in exchange of extracellular glucose for intracellular urate and act to enhance urinary urate excretion30. There are two GLUT9 transporter isoforms, which only differ in their N-termini: isoform 1 (GLUT9a) localized at the basolateral membrane and isoform 2 (GLUT9b) localized at the apical membrane of tubular cells. GLUT9b could also be found in the proximal tubule and in the collecting duct. Glycosuria resulting from SGLT2 inhibition causes an increased concentration of glucose in the proximal tubule, which could eventually lead to increased exchange of UA for reabsorbing glucose via GLUT9, while in collecting ducts, lesser glycosuria inhibits UA reabsorption via GLUT930-33.
Reductions in insulin sensitivity and insulin secretion are the hallmarks of T2DM, and a large number of studies have revealed that hyperglycemia and hyperlipidemia are critical risk factors for islet β-cell dysfunction, which are known as β-cell glucotoxicity and lipotoxicity6. Currently, the beneficial effects of SGLT2 inhibitors on islet β-cell function have been reported. For example, canagliflozin34 and dapagliflozin35 were proven to improve hepatic and muscle insulin resistance, respectively. Empagliflozin-induced glycosuria improved islet β-cell function and insulin sensitivity36. However, a recent study using [18F]-fluorodeoxyglucose and positron emission tomography (PET) to measure tissue insulin sensitivity during the process of the hyperinsulinemic euglycemic clamp technique found no changes in tissue-level insulin sensitivity after treatment with dapagliflozin37. However, considering most of those studies used a relatively long period of treatment, and the improvement of islet β-cell function accompanied by the improvement in lipotoxicity achieved by loss of weight and amelioration in lipid metabolism, it was difficult to evaluate the individual effect of the alleviation of glucotoxicity on islet β-cell function. Thus, Shimo et al.38 analysed C57BL/KsJ db/db mice treated for one week with 10 mg/kg/day empagliflozin, and they found expression levels of β-cell-related factors improved, such as MafA, insulin 1 and PDX1, from gene levels to protein levels, and the enhancement of β-cell proliferation was observed. However, the glucose-stimulated insulin secretion of isolated islets was not observed in the group treated with empagliflozin. They concluded that the alleviation of glucotoxicity for one week could alleviate expression levels of genes associated with islet β-cell function but was insufficient to achieve substantial improvement in islet β-cell function. In our study, a short period of treatment with dapagliflozin reduced glucose levels represented by the AUCGlu according to 3-hour OGTT, but without statistically significant difference, which indicated the emergence of obvious hypoglycemic effects requires more than one week of treatment. A certain degree of improvement in insulin sensitivity and β-cell function could be observed, but without statistically significant differences. On the one hand, we thought it was because the glucotoxicity had not been completely relieved, and there was no obvious difference in the improvement of islet β-cell function; on the other hand, it might be because the improvement in glucotoxicity in one week was not enough in humans to achieve obvious improvement in islet β-cell function, which was in accord with findings in animal experiments38. Furthermore, the linear correlation found between changes of AUCGlu and parameters representing islet β-cell function, but not between glucose levels and insulin sensitivity parameters, showed improvement in islet β-cell function and was more related to improvement in glucose control after a short period of treatment. However, whether SGLT2 inhibitors can improve islet β-cell function by alleviation of glucotoxicity alone requires further research in larger sample populations and longer treatment periods.
In this prospective, pilot and exploratory study, in addition to hypoglycemic treatment, we found the effect of dapagliflozin on reducing SUA levels within one week. However, the sample size is small, and in-depth studies containing larger participants and different treatment period groups (including one-week, two-week, and four-week period groups) can be conducted to further explore the effects of treatment with SGLT2 inhibitors on the indicators of UA levels and islet β-cell function.