AbstractBariatric surgery (BS), including sleeve gastrectomy (SG), gastric bypass (GB), and ileal transposition (IT), is one of the approaches currently used for the correction of metabolic disturbances in type 2 diabetes mellitus (DM2) with obesity. However, the efficiency of these approaches and their impact on hypothalamic signaling and hormonal status in severe forms of DM2 without obesity remain poorly characterized. The aim of this work is to study the effect of IT, SG, and GB on insulin, leptin, ghrelin, and glucagon-like peptide-1 (GLP-1) levels in the blood and on the expression of the genes encoding the main components of the hypothalamic signaling systems in rats with a decompensated form of DM2 induced by a high-fat diet (three months) and a single low dose of streptozotocin (25 mg/kg, two months after the start of the diet). Pronounced hyperglycemia, impaired glucose tolerance, a decrease in the glucose-stimulated GLP-1 level, a slight decrease in the insulin and leptin levels, and a slight increase in the ghrelin level are detected in diabetic rats. Expression of genes encoding the GLP-1 receptor, the orexigenic agouti-related peptide (AgRP), and phosphotyrosine phosphatase 1B and SOCS3, the negative regulators of the leptin and insulin pathways, is increased in the hypothalamus. IT in diabetic rats leads to a reduction of glucose levels 120 min after glucose loading, an increase of basal and glucose-stimulated GLP-1 levels, and normalization of the expression levels of the phosphotyrosine phosphatase 1B, SOCS3, AgRP, and GLP-1 receptor genes, which is indicative of restoration of the hypothalamic signaling responsible for the control of energy metabolism and insulin sensitivity. Glucose tolerance is improved in the case of SG and GB, and an increase in the basal and glucose-stimulated GLP-1 levels is demonstrated in the case of SG, but no significant effects on the expression of the hypothalamic genes are observed in SG and GB. Thus, IT is the most efficient bariatric surgical intervention among those studied for the treatment of severe DM2 forms without obesity.