Background: Metformin, a first-line drug for type 2 diabetes mellitus (T2DM), restores metabolic and hormonal parameters by acting on both peripheral tissues and the central nervous system. Intranasally administered insulin (INI), which enters the brain directly, normalizes insulin signaling in the hypothalamus and other brain regions, impaired in T2DM, and thereby improves the central regulation of metabolism, eating behavior and the endocrine system. We have suggested that co-administration of metformin and INI will enhance their restorative effects in T2DM. Objective: To carry out a comparative study of the restorative effects of separate and combined treatment of male T2DM rats with metformin and INI on glucose sensitivity and the plasma levels of insulin, leptin, glucagon-like peptide-1 (GLP-1), thyroid hormones and testosterone. Methods: T2DM2 was induced by high-calorie diet (3 months) and streptozotocin (15 mg/kg/day). Diabetic rats were treated with metformin (100 mg/kg/day) and INI (0.5 IU/rat/day) during four weeks. Results: Metformin improved glucose homeostasis and normalized basal and glucose-stimulated levels of insulin, leptin and GLP-1. Co-administration with INI enhanced the metformin improving effects on insulin sensitivity and the insulin and leptin levels. Metformin and INI normalized the levels of thyroid hormones and testosterone, and their combined use caused the activation of the thyroid system, as indicated by a significant increase in thyroid hormones levels. Conclusion: In male diabetic rats, co-administration of metformin and INI improves restorative effects of metformin on insulin and leptin sensitivity and enhances INI-induced stimulation of the thyroid system, the activity of which is reduced in T2DM.
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