**7. Functional activity of β-cells and HOMA-IR**

Data from the analysis of pancreatic β-cell function condition have certain scientific and practical interest. For instance, in the Sitagliptin and metformin combined therapy group, a significant increase in HOMA-β index by 23.4 ± 22.6 relative units (33.06%), р <0.0001 was observed compared to the group that receiving metformin monotherapy, where increase in this index has not reached a statistical significance and equaled 4.86 ± 1.63 relative units (11.08%), р > 0.05.

Furthermore, the work has obtained statistically significant insulin level lowering in both groups. For instance, on a background of Sitagliptin therapy in combination with metformin therapy, insulin level decreased by 15.68%, (р <0.001), and on metformin monotherapy, insulin level decreased by 7.57%, (р <0.001).

Before treatment, both groups showed increase in proinsulin level, after 6 months of therapy, we achieved significant decrease in the proinsulin level in group I (Sitagliptin + metformin) by 29.17%, (р <0.001), and in group II (metformin) by 13.79%, (p < 0.001). Proinsulin/insulin ratio is increased when the functional activity of β-cells is decreased and is an indication of more marked apoptosis in pancreatic β-cells. We established that on Sitagliptin therapy in combination with metformin, a significant decrease by 10.38%, (р <0.05) was observed in proinsulin/insulin ratio, while in metformin monotherapy group, a decrease in this ratio was insignificant, by 2.84%, (p > 0.05) (**Figure 7**). This should be considered as a long-term positive effect of Sitagliptin on the function of pancreatic β-cells.

It is important to note that on combined therapy С-peptide level increased by 55.83%, (р < 0.0001); and by 6.3%, (р < 0.05) in metformin monotherapy group. HOMA-IR significantly lowered in both groups. However, we have not detected statistically significant difference between the groups' dynamics. It decreased by 32% (р < 0.0001) in group I, and by 11.05% (р < 0.0001) in group II. The decrease in homeostasis model assessment of insulin resistance is the evidence of improvement in peripheral glucose disposal. Positive effect on β-cell function is associated with lowering of glucotoxicity, weight loss, insulin resistance, and improvement

**Figure 7.** Function of β-cells of the pancreas and HOMA IR in dynamics. \*P between groups <0.05.

in metabolic health, which promoted lowering of the "stress" on the insular apparatus of the pancreas. β-cell function improvement is promising in stabilization of T2D progression.

The results of the correlation analysis are displayed in **Table 2** and in **Figure 8**.

Thus, as can be seen from the correlation analysis, an additional therapeutic effect on glycemic control in patients with T2D and obesity is associated with a decrease in the amount of visceral fat and a change in the secretion of adipose tissue hormones. **Table 3** presents a comparative analysis of the main parameters, depending on the type of therapy.


**8. Discussion**

**Parameters Group 1,**

Adiponectin, mkg/ml

**Figure 8.** Correlation between the dynamics of the VF and HbA1c.

**Sitagliptin + metformin**

The study investigates the effect of Sitagliptin in combination with metformin as well as of metformin monotherapy on carbohydrate and fat metabolism in patients who required their therapy to be intensified. According to the data received, after 24 weeks, the positive dynamics of HbA1c was followed by a significant decrease in mean fasting glycemia and postprandial glycemia in group I, while in group II (on metformin monotherapy), the

**Table 3.** Comparative characteristics of the main parameters depending on the type of therapy.

**Group 2, Metformin**

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7.63 ± 2.56 9.59 ± 3.03 7.41 ± 2.43 7.9 ± 2.44 <0.001

**Before treatment After treatment Before treatment After treatment** HbA1c 8.3 ± 1.66 6.66 ± 1.24 8.35 ± 1.75 7.62 ± 1.39 <0.001 BMI, kg/m2 34.78 ± 4.87 32.96 ± 5.04 35.45 ± 4.3 34.76 ± 4.33 <0.001

Leptin, ng/ml 23.87 ± 13.43 16.49 ± 9.63 23.87 ± 9.61 22.66 ± 9.61 <0.001 VF, sm2 300.73 ± 80.88 280.11 ± 84.16 334.62 ± 70.55 328.85 ± 70.4 <0.001 SF, sm2 375.88 ± 91.55 371.37 ± 98.04 431.25 ± 54.13 429.3 ± 54.52 >0.05 LDL, mmol/l 4.31 ± 0.73 3.53 ± 0.58 3.89 ± 0.61 3.51 ± 0.61 <0.001 ТG, mmol/l 4.28 ± 2.4 2.95 ± 1.73 4.31 ± 2.04 3.68 ± 1.86 <0.05 HOMA-IR 5.85 ± 4.15 3.49 ± 2.44 6.32 ± 5.0 4.32 ± 2.77 >0.05 HOMA-β 40.63 ± 25.99 64.04 ± 29.01 57.05 ± 35.43 61.91 ± 30.82 <0.005

**P between groups**

\*\*р < 0.05 significance of correlation coefficient at p < 0.05.

**Table 2.** Correlation analysis.

**Figure 8.** Correlation between the dynamics of the VF and HbA1c.


**Table 3.** Comparative characteristics of the main parameters depending on the type of therapy.

#### **8. Discussion**

in metabolic health, which promoted lowering of the "stress" on the insular apparatus of the pancreas. β-cell function improvement is promising in stabilization of T2D progression.

Thus, as can be seen from the correlation analysis, an additional therapeutic effect on glycemic control in patients with T2D and obesity is associated with a decrease in the amount of visceral fat and a change in the secretion of adipose tissue hormones. **Table 3** presents a com-

The results of the correlation analysis are displayed in **Table 2** and in **Figure 8**.

**Figure 7.** Function of β-cells of the pancreas and HOMA IR in dynamics. \*P between groups <0.05.

parative analysis of the main parameters, depending on the type of therapy.

**Показатели, динамика Адипонектин Лептин** HbA1c r = −0.39\* r = 0.32\* VF r = −0.54\* r = 0.33\* body mass r = −0.75\*\* r = 0.45\*\* BMI r = −0.74\*\* r = 0.45\*\* WC r = −0.62\*\* r = 0.43\*\* LDL r = −0.29\*\* r = 0.3\*\* TG r = −0.33\*\* r = 0.16 HOMA IR r = −0.53\*\* r = 0.37\*\* HOMA β r = 0.29\*\* r = −0.33\*\* Leptin r = −0.63\* —

\*

p < 0.01 significance of correlation coefficient at р < 0.01. \*\*р < 0.05 significance of correlation coefficient at p < 0.05.

**Table 2.** Correlation analysis.

64 Diabetes and Its Complications

The study investigates the effect of Sitagliptin in combination with metformin as well as of metformin monotherapy on carbohydrate and fat metabolism in patients who required their therapy to be intensified. According to the data received, after 24 weeks, the positive dynamics of HbA1c was followed by a significant decrease in mean fasting glycemia and postprandial glycemia in group I, while in group II (on metformin monotherapy), the decrease in glycemia did not reach statistical significance. An important advantage in our study was that, despite the common belief about neutral effect that DPP-4 inhibitors have on weight, we demonstrated that with the addition of Sitagliptin to metformin, there was a more marked weight loss and decrease of BMI and visceral fat depot, compared to the group of patients on metformin monotherapy. What was a "pure" contribution of DPP-4 inhibitor + metformin combination, and what was due to lifestyle changes in both groups could not be determined in this work, therefore, further prospective studies including quantitative calculation of energy inputs are required. The study of adipokine status, specifically leptin and adiponectin, was of particular interest. The main function of leptin is forming a communication pathway link between adipocytes and the brain [19]. Leptin secretion positively correlates with the amount of adipose tissue, which we also demonstrated in our work. In addition to the anorectic effect in the adjustment of eating behavior, leptin also stimulates energy intake. During increased energy intake exceeding the body's requirements, the leptin level increases, which prevents further food consumption and increases energy expenditure, and that leads to negative energy balance and rebalancing of energy. Most obese patients have high leptin levels, but this does not lead to weight loss, which confirms the fact that obese patients may develop resistance to leptin. Leptin's effect disorder in obesity can be a leading factor in the development of insulin resistance and fat and glucose metabolism disorder. In our work, on a background of combined Sitagliptin and metformin therapy, the leptin level was reduced by 30.47% and in the metformin monotherapy group by 5.41%. We associate decrease in leptin level with weight loss and a decrease in the amount of fat.

**9. Conclusion**

**List of abbreviations**

DM diabetes mellitus IR insulin resistance

DPP-4 dipeptidyl peptidase type 4

GLP glucagon-like peptide

BM body mass

BMI body mass index

GF glucose fasting

VFA visceral fat area

VF visceral fat

MRI-МРТ

HbA1c glycated hemoglobin

PPG postprandial glycemia

SFA subcutaneous fat area

Our study demonstrated the important role of correction of fat metabolism disorders in improving glycemic control in patients with diabetes and obesity. Regression of visceral fat according to the MRI results was accompanied by the recovery of levels of adipokine hormones, which led to an improvement in the parameters of carbohydrate and fat metabolism. Contrary to common belief, we consider Sitagliptin as a drug that promotes weight loss. The chapter demonstrates that ultimately it is the reduction of the visceral depot that plays a key role in the correction of carbohydrate metabolism disorders. The parameters of the lipid profile and glycemic control are significantly improved as the pathogenetic effect on patient's body weight as well as on the structure of its adipose tissue. Recovery of such indicators as HOMA-IR and HOMA-β proves the possibility of disease management by correcting disor-

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The study has been performed at the personal expense of the authors. The authors claim that

ders of fat metabolism in patients with T2D and obesity in the early stages.

**Information regarding funding and conflict of interest**

there is no conflict of interest regarding data disclosed in the article.

In both study groups, the initial adiponectin levels were lower than reference values. After 24 weeks of therapy, adiponectin content in blood increased by 27.06% in the group receiving Sitagliptin and metformin combination, and by 7.16% in the group receiving metformin monotherapy. Adiponectin with its effect on the reduction of insulin resistance, which is characteristic of patients with T2D and obesity, and also its anti-inflammatory, antidiabetic and antisclerotic effects make it an additional therapeutic target. In our study, an increase of adiponectin is most likely associated with a decrease of body weight and VFA, according to the data of the correlation analysis. However, there are publications which make it known that GLP-1 promotes an increase in adiponectin level [20, 21], the Sitagliptin therapy was followed by increase in adiponectin level [22, 23].

Correlational analysis demonstrated correlation of glycemic control in T2D obese patients with reducing visceral fat amount and with recovery of secretion of adipose tissue hormones.

In addition, the study showed a significant improvement in the functional activity of pancreatic β-cells against combined Sitagliptin and metformin therapy, which was confirmed by an increase in the HOMA-β index, a decrease in the ratio of proinsulin/insulin, in contrast to metformin monotherapy, where the change in these indices did not reach statistical significance. A possible mechanism for improving the function of β-cells can be a decrease in lipotoxicity, against a background of a decrease in the level of TG inhibiting β-cell function.
