In this study, we explored the changes of SUA, 24-hour UUA and FEUA levels before and after taking dagligliflozin 10 mg once daily for one week, also comparing the changes of parameters of insulin resistance and islet β-cell secretion function before and after treatment. We found decreased SUA levels and increased FEUA levels after taking dagligliflozin, both showing significant differences. Also, there were improvement in glycemic control, insulin resistance and islet β-cell secretion function but without significant differences. We also found the 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 the islet β-cell secretion function.
UA is the final metabolic product of purine compounds. Disorders in UA metabolism may cause hyperuricemia and gout. In recent years, a large body of studies have proved the clinical significance of UA in development of various metabolic disorders including T2DM15–17. One the one hand, the prevalence of hyperuricemia in T2DM subjects is higher than in NGT subjects, on the other hand, hyperuricemia has been linked to both micro- and macrovascular complications in DM patients18. Hyperuricemia can result from elevated UA production and reduced renal excretion. As for the main cause of hyperuricemia in DM patients, it was thought dominated by reduced UA excretion because of decreased UA clearance and increased reabsorption caused by hyperinsulinemia19, 20 and decreased GFR resulted from diabetic nephropathy.
Traditionally, parameters to evaluate the renal ability 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 impact of eGFR. Whereas, the level of 24-hour UUA is affected by many factors including dietary purine intake, the 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 quantification method to evaluate the level of uric acid excretion21. In our study, we found the levels of 24-hour UUA and FEUA were both increased in T2DM subjects at baseline, while the SUA levels were still higher than that of NGT subjects, we speculate that 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 T2DM patients because increased oxidative stress resulted from T2DM and lipid peroxidation could lead to increased SUA levels which acted as an endogenous antioxidants to protect the body22. Similar to our results, it was also reported in a previous research that the mechanism of hyperuricemia is most probably due to overproduction of UA in certain DM patients23.
There have been a variety of researches confirmed the reduced SUA levels after taking SGLT2 inhibitors. A posthoc analysis of prospectively collected data within the CANVAS Program reported canagliflozin reduced serum urate concentration and also 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 (Enpagliflozin, Canagliflozin, Dapagliflozin, Tofogliflozin, Lucigliflozin, or Ipragliflozin) on reducing SUA levels in T2DM patients24. However, in most previous studies, the reduced SUA levels were observed in 12–26 weeks after treatment25, a few reported the excretion of UA could result in reduction of SUA in the first couple weeks26. Our study found the UA-lowering effect of dapagliflozin can act within one-week, and the level of SUA decreased significantly to nearly the same level of healthy subjects, accompanying with the significant increase in FEUA, and the changes of SUA and FEUA levels were linear correlation. The exact mechanism of the UA-lowering effect of SGLT2 inhibitors is still unclear, the most widely accepted hypothesis is that the possible involvement of the renal SLC2A9 (GLUT9) transporter. The increase in glucose excretion in the urine could eventually result in an increased exchange of UA in the apical membrane of tubular cells causing an increased transporting of UA from blood to the urine, thus increasing urine UA levels and decreasing SUA levels 27.
Reductions in insulin sensitivity and insulin secretion are the hallmark characteristics of T2DM, and a large number of studies have revealed that hyperglycemia and hyperlipidemia are critical risks 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, canagliflozin28 and dapagliflozin29 were proved to improve hepatic and muscle insulin resistance, respectively. Enpagliflozin-induced glycosuria improved islet β-cell function and insulin sensitivity were also observed30. Whereas, a recent study using [18F]-fluorodeoxyglucose and positron emission tomography (PET) to measure tissue insulin sensitivity during hyperinsulinemic euglycemic clamp technique, reported no effect on tissue-level insulin sensitivity was observed31. However, considering most those studies used a relatively long period treatment, and the improvement of islet β-cell function accompanied with the improvement of lipotoxicity that 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.32 analyzed C57BL/KsJ db/db mice treated for one week with 10 mg/kg/day enpagliflozin, 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, glucose-stimulated insulin secretion of isolated islets was not observed in enpagliflozin treated group. They concluded that, although alleviation of glucotoxicity for one week could alleviate the 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 treatment of dapagliflozin reduced glucose levels represented by AUCGlu according to 3-hour OGTT, but without significant difference, which indicated the emergence of obvious hypoglycemic effects requires more than one-week treatment. A certain degree of improvement in insulin sensitivity and β-cell function could be observed, but without statistical differences. As for the reasons, on the one hand, we thought it was because the glucose toxicity had not been completely relieved, there was no obvious difference in the improvement of islet β-cell function; on the other hand, it might be due to the improvement of glucose toxicity in one-week was not enough in humans to achieve obvious improvement in islet β-cell function, which accorded with the findings in the animal experiment32. Furthermore, the linear correlation found between changes of AUCGlu and parameters representing islet β-cell secretion function, but not between glucose levels and insulin sensitivity parameters, showed improvement in islet β-cell secretion function was more related to improvement in glucose control after a short period treatment. However, whether SGLT2 inhibitors can improve the islet β-cell function by alleviation of glucotoxicity alone, requiring further researches in larger sample populations, and longer treatment period.
This is a prospective, pilot and exploratory study, we found the effect of dapagliflozin on reducing SUA levels in addition to hypoglycemic treatment within one week. However, the sample size is small, and further studies containing different treatment period groups (including one-week, two-week, and four-week) can be conducted to observe the indicators of UA levels and islet β-cell function.