Type 2 diabetes mellitus (T2DM) is one of the prevalent pathologies in modern civilization and has obesity as the main risk factor. However, the prevalence of T2DM has been increasing despite the low prevalence of obesity in some populations, including the Japanese subjects. With or without obesity, non-alcoholic fatty liver disease (NAFLD) is constantly associated with T2DM. NAFLD is characterized by an increase in: hepatic lipids, glycogen content and pro-inflammatory parameters exacerbated by mediators secreted by myeloid cells from bone marrow stem cells in the circulation and in other tissues, such as adipose tissue. The persistent chronic hyperglycemia in the evolutionary course of T2DM can induce persistent changes in the chromatin of pro-inflammatory genes of bone marrow hematopoietic stem cells that define their differentiation into pro-inflammatory M1 macrophages, exacerbating the existing NAFLD. Thus, we hypothesized that the renewal of bone marrow stem cells by transplantation can alter the course of T2DM and hepatic metabolism. This proposal is part of the Regular FAPESP Project (2018 / 25892-8). To prove our hypothesis, we will perform bone marrow stem cell transplantation from normoglycemic Wistar (WT) animals to spontaneously diabetic Goto-Kakizaki (GK) rats without obesity, which in itself could promote liver inflammation. The recipient animals at 28 days of age will be submitted to immunosuppression by busulfan and cyclophosphamide for 3 days before transplantation. On the fourth day, the animals will receive stem cells from WT donors and will be followed for 50 days for complete restoration of the immune system. The following parameters will be evaluated in recipient animals: 1) pre-transplant glycemic profile by fasting glycemia and 45 days post-transplant by glucose and insulin tolerance tests; 2) the liver tissue as to its metabolic profile assessed by the content of glycogen (colorimetric method), triglycerides and cholesterol (biochemical tests); and 3) activity of liver enzymes AST, ALT and Gamma GT (enzymatic assays) in blood serum. Bone marrow transplantation containing stem cells from normoglycemic WT animals to GK rats can reverse or attenuate the diabetic condition of recipient animals leading to significant changes in liver tissue. These results would prove that the diabetic state is associated with an inflammatory condition established in the leukocyte progenitor cells in the bone marrow with direct influence on liver parameters.
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