Efficacy of Metformin Course Application Combined with Intranasal Insulin in Treating Rats with Cafeteria Diet-Induced Obesity

Abstract

The so-called cafeteria diet (CD), rich in saturated fats and light fast-digesting carbohydrates, leads to obesity and is a risk factor for type 2 diabetes. Metformin (MF) is often used to correct diet-induced obesity, but in some patients, it elicits serious side effects, which requires dose reduction, including through its co-application with drugs potentiating MF effects. Intranasally administered insulin (INI), which per se has a restorative potential in the treatment of metabolic disorders, is a candidate for the role of such a drug. This work was aimed to study the efficacy of a 3-week combined course of MF (100 mg/kg/day, perorally) and INI (1.5 or 6.0 IU/kg/day) to correct metabolic and hormonal disorders in male rats with CD-induced obesity (CDIO). It was shown that in CDIO rats, the MF + INI combination normalized body weight and abdominal fat, as well as restored glucose homeostasis, lipid metabolism, basal and glucose-stimulated insulin and leptin levels. Compared to MF monotherapy, a combined course of MF + INI application more effectively restored insulin sensitivity, as assessed by a decrease in the insulin resistance index, and normalized glucose tolerance, as assessed by a decrease in AUC_0–120, the integrated area under glucose concentration curves in the glucose tolerance test. The combination of MF with INI at a dose of 1.5 IU/kg/day normalized thyroidal status, disturbed in CDIO, while the combination of MF with INI at a dose of 6 IU/kg/day exacerbated the hypothyroid state, mainly due to hyperactivation of thyroid-stimulating hormone secretion and the development of thyroid resistance to this hormone. Thus, a combined course of MF with relatively low-dose INI, which has no negative effects on the thyroid axis, appears promising for correcting metabolic and hormonal indices in CDIO, including functional restoration of the thyroid system.