Potentiation of the restorative effect of semaglutide on metabolic and hormonal parameters in rats with diet-induced type 2 diabetes mellitus with intranasally administered insulin

Semaglutide, a glucagon-like peptide-1 receptor agonist, is widely used for the treatment of type 2 diabetes mellitus (DM2), but it is not effective in some patients, which requires the development of approaches to enhance its therapeutic effect. The combined use of semaglutide with other drugs is promising, including intranasally administered insulin (IAI), which improves certain metabolic and hormonal parameters in DM2 through central mechanisms. Aim of the study was to investigate the effects of combined and separate administration of semaglutide and IAI to male rats with DM2 on the body weight and fat mass, metabolic and hormonal parameters, including thyroid hormone levels.

Material and methods. DM2 was induced by a high-fat diet (15 weeks) and streptozotocin injection (15 mg/kg). Semaglutide (50 μg/kg/day, subcutaneously) and IAI (0.5 and 2.0 IU daily per rat) were administered separately and together for 4 weeks. Hormonal levels were measured using ELISA, glucose tolerance and glucose-stimulated insulin and leptin content were assessed by a glucose tolerance test.

Results. The combined use of semaglutide and IAI normalized the body weight and adipose tissue and restored the glucose homeostasis, insulin sensitivity, and lipid metabolism. The combination of semaglutide and IAI was superior to semaglutide monotherapy in terms of fat loss, normalization of glucose and glycated hemoglobin levels in the blood, and weakening of insulin resistance. Semaglutide restored the thyroid hormones concentration decreased at DM2. In the group treated with semaglutide and 2.0 IU IAI, the increase in free triiodothyronine level and the free triiodothyronine/free thyroxine ratio was more pronounced than with semaglutide monotherapy, indicating potentiation of the latter’s effect on the thyroid axis in the presence of IAI.

Conclusions. A model of DM2 in rats has shown that combination therapy with semaglutide and IAI is superior to semaglutide monotherapy in terms of its ability to restore a number of metabolic and hormonal parameters, and this effect depends on the dose of IAI.

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