The aim was to investigate the peculiarities of uric acid metabolism in patients with type 2 diabetes depending on the phenotypes of obesity under the conditions of therapy with dapagliflozin. 165 patients with type 2 diabetes were examined (71 women and 94 men, aged from 32 to 82 years, duration of diabetes from 1 to 32 years), without significant impairment of renal function and severe CVD, who had poor Т2D compensation during previous treatment. Groups of patients were formed: 1 – non-obese (BMI < 30 kg/m2; n = 72, w/m = 33/39); 2 – diagnosed obesity (BMI ≥ 30 kg/m2; n = 93, w/m = 38/55). Within each group, subgroups were distinguished with a normal level of visceral fat (VF < 12 units), n = 44/26 in groups 1 and 2, and subgroup with increased (VF ≥ 12 units), n = 28/67, respectively. The peculiarities of anthropometric and body composition indices (by bioimpedance method), as well as the characteristics of carbohydrate metabolism, serum lipid spectrum, uric acid metabolism and hormonal parameters, namely the levels of insulin and glucocorticoids: cortisol and dehydroepiandrosterone (DHEA-S) in the groups of patients, were analyzed. It was found that the non-obese phenotype was accompanied by lower levels of uricemia compared to obese individuals, due to lower urate reabsorption, under conditions of lower mean insulin concentrations, lower VF and total fat % levels, which characterizes predominantly catabolic type of metabolism. In group 1, an increased level of UA clearance and urate fractional excretion were found, which possibly related to a compensatory increase in the elimination of UA in the renal tubules. The highest values of HGFRT in this group indicates a relative deficiency of the anabolic pathway of reutilization. In the obese phenotype, higher levels of uricemia, reduced rates of UA elimination (high reabsorption), and higher rates of urate reutilization (reduced HGFRT value) were recorded, which was associated with such external signs as increased waist, skinfold thickness, and VF levels. The listed signs indicate predominantly anabolic type of metabolism in obesity, which is characterized by increased lipogenesis with lipids accumulation in adipose tissue and increased de novo purines synthesis under the influence of relatively high concentrations of insulin. A high level of insulin also exerts a hypouricosuric effect by influencing the expression of urate transporters .In non-obese patients, higher purine degradation and lipolysis may be due to the elevated cortisol and decreased DHEA-S levels, i.e., an increase in the cortisol/DHEA-S ratio compared to obese patients. Relatively high levels of cortisol in the non-obese group can be attributed to the higher activity of the enzyme 11β-GSD. In contrast to the group of non-obese individuals, the predominance of anabolic processes in obese individuals may be associated with relatively high levels of anabolic hormones (insulin and DHEA-S) and lower levels of cortisol. It has been shown that in non-obese and obese subjects after long-term treatment with dapagliflozin (12 months), there was a decrease in body fat percentage and a parallel increase in hydration, an increase in muscle mass, and an improvement of body composition and skeletal / visceral index along with improvements in glycemic control and a decrease in BMI. A significant decrease in TG was found in the non-obese subgroup with high VF, and a trend was observed in both subgroups with obesity. After treatment, a decrease in uricemia levels in subgroups with obesity. At the same time, an increase in UA clearance and fractional UA excretion was observed, without significant changes in the rate of glomerular filtration of endogenous creatinine. These changes indicate a decrease in renal SC reabsorption in the proximal tubules. A decrease in UA levels in obese patients can also be explained by a decrease in the amount of general and especially visceral fat, where UA production occurs. It was shown that SGLT2i therapy contributed to the normalization of the GC balance. A significant difference in the clinical effect of 12-months SGLT2i therapy on the cortisol and DHEA-S ratio between groups of patients with a non-obese and obese phenotype was revealed. In non-obese patients, dapagliflozin therapy increased the level of DHEA-S and the cortisol/DHEA-S ratio. Positive metabolic effects in patients with an obese phenotype are obviously associated with improving carbohydrate and lipid /metabolism and body composition.
The obtained results confirm the feasibility of using SGLTi therapy and confirm effectiveness in optimizing of morpho-metabolic characteristics in T2DM patients with different phenotypes.
Key words: diabetes, obesity, metabolic syndrome, body composition, uric acid metabolism, lipid spectrum, insulin, cortisol, dehydroepiandrosterone, SGLT2i, dapagliflozin, diagnosis, individual approach, cardiovascular diseases, glycated hemoglobin, phenotype, pharmacotherapy
