Trelagliptin inhibits the enzyme dipeptidyl-4 (DPP-4) to treat type 2 diabetes and it may possess the potential to improve insulin resistance. However, the molecular mechanism is not known. In a research by Zhenhua Liu et.al., the effect of trelagliptin succinate in improving insulin resistance was investigated. 

Insulin Resistance

Metabolic diseases have become one of the leading public health issues due to high-calorie diets and lack of physical activity. Insulin resistance is the pathophysiological basis of metabolic diseases. It increases the risk of various diseases, including type 2 diabetes, coronary heart disease, fatty liver, obesity and hypertension. Adipose tissue has vital effect on insulin-stimulated glucose intake, and thus, a prime role in energy balance. The insulin sensitive glucose transporter, GLUT4 mediates the glucose transport in adipose tissue by continuous cycling between the intracellular storage vesicles and plasma membrane. Any derangement in the translocation of GLUT4 will result in impairment of glucose uptake, eventually leading to insulin resistance.

Trelagliptin is the first long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, which reduces the activity of DPP-4. The degradation of GLP-1 was inhibited by trelagliptin to effectively decrease the glycated hemoglobin in patients with type 2 diabetes. In addition to hypoglycemic effect of trelagliptin, a reduction of cholesterol and low-density lipoprotein as well as an improvement the function of islet β cells in type 2 diabetes (T2D) patients had been observed. The combined use of DPP-4 inhibitor and insulin effectively improved the insulin resistance of elderly T2D patients. Another DPP-4 inhibitor (sitagliptin) improved insulin resistance in α and β islet cells in overweight patients. Studies using a combination of DPP-4 inhibitor with antidiabetic drugs showed positive effects against T2D. Saxagliptin combined with metformin improved insulin resistance and promoted an increase in insulin secretion. These studies show that DPP-4 inhibitors have a positive effect of improving insulin resistance. In clinical trials, it was found that trelagliptin not only effectively control the concentrations of blood glucose in patients with T2D but also improve insulin resistance. However, the mechanism of improving insulin resistance is unclear. 

Possible Mechanism

Trelagliptin succinate promoted the glucose intake in primary rat adipocytes. Furthermore, trelagliptin succinate increased the amount of GLUT4 protein in the outer membrane, indicating that trelagliptin succinate promoted glucose intake via stimulation of GLUT4 translocation in adipocytes. Trelagliptin succinate also decreased the secretion of free fatty acids and resistin in rat adipocytes. Thus, the mechanism of trelagliptin succinate in improving insulin resistance may also be related to a reduced secretion of free fatty acids and resistin. By the use of insulin-resistant 3T3-L1 adipocytes, we also showed that trelagliptin succinate promoted glucose intake equivalent to the effects of sodium orthovanadate. Trelagliptin succinate promoted the expression and phosphorylation of AKT and IRS-1 suggesting them as targets of trelagliptin succinate in the PI-3K/AKT leading to improvement of insulin resistance.

Reference

[1] Trelagliptin succinate: DPP-4 inhibitor to improve insulin resistance in adipocytes. doi:10.1016/j.biopha.2020.109952