The possible renoprotective effect of denatonium benzoate in a rat model of type 2 diabetes: role of Krüppel-like factor 6 (KLF6)

Bitter taste-sensing type 2 receptors (TAS2Rs) were first discovered in the oral cavity, but their detection in extra-oral tissues like gastrointestinal tract and kidney leads to modulation of multiple (patho) physiological processes. Krüppel-like factor (KLF6) is a novel regulator of β-cell adaptation to metabolic stress and involved in multiple processes in vascular system. This research aimed to assess the possible metabolic and renal protective effect of TAS2R agonist denatonium benzoate and the antidiabetic drug sitagliptin in diabetic rats. Forty male Sprague Dawley rats were included and divided into two main groups: normal control group and fructose-fed streptozotocin-induced diabetic group. Diabetic group was subdivided into four subgroups untreated: sitagliptin, denatonium, and sitagliptin + denatonium-treated groups. All treated groups showed improvement of glycemic and lipid profiles and UACR with enhancement of renal KLF6 expression and improved histological architecture of diabetic kidney. The combination group showed the best results with most renal corpuscles returning to normal and biochemical values close to normal control. Compared to the diabetic control group, the combination group showed significantly lower fasting blood glucose, HbA1C, UACR, TGs, and LDL-C values (≈3.44, 2.1, 3.5, 1.6, and 1.5-fold reduction, respectively), and significant elevation of serum GLP, HDL-C, and renal KLF6 expression (≈2.1, 2.0, and 3.7-fold increase, respectively). Significant correlations were detected between KLF6 expression and various parameters in all rats of the experiment. This study concluded the promising role of denatonium benzoate and its combination with sitagliptin in the management of diabetes and its renal complications.