Anti-tumor Effects Of Glipizide In Patients With Diabetes And Breast Cancer

Objects: Diabetes and breast cancer are two major diseases that seriously threaten human health.As the incidence of diabetes and breast cancer rises year by year,the number of diabetic patients with breast cancer increases.In recent years,the relationship between diabetes and breast cancer has gradually been taken seriously.According to research,diabetes may be one of the high-risk factors for breast cancer.Glipizide is a second-generation sulphonylurea hypoglycemic agent and has been widely used clinically since the 1960 s and 1970 s.Epidemiological studies have shown that long-term use of glipizide in diabetic patients can reduce the risk of breast cancer.Some scholars have found that glipizide can inhibit tumor angiogenesis,thereby inhibiting the growth of breast cancer.However,there are many clinical studies on patients of diabetes with breast cancer,and there are few reports on animal models for diabetes with breast cancer.In addition,chemotherapy for the treatment of diabetes combined with breast cancer is mostly used in clinical practice combined with insulin,because chemotherapy drugs can cause abnormal glucose metabolism,and will increase the burden of treatment.For this reason,if there is a drug that can play a therapeutic role in both diabetes and breast cancer,it will be a boon to diabetic patients with breast cancer.The purpose of our experiment was to examine the efficacy of glipizide in the treatment of diabetes with breast cancer and to discuss glipizide in the treatment of diabetes.Methods : Diabetes mellitus with breast cancer MMTV-PyMT mouse model was established by using streptozotocin(STZ)to induce spontaneous breast cancer in MMTV-PyMT mice.Secondly,STZ was used to induce diabetes in BALB/c mice.4T1 cells were inoculated subcutaneously in mice to establish a BALB/c mouse model of diabetes with breast cancer.The effect of diabetes on breast cancer in a mouse model was observed;And after treatment with glipizide,observation of changes in body weight,blood glucose,and tumor volume of mice during treatment was observed,and pathological techniques was used to for mouse tissue to evaluatethe efficacy of glipizide in the treatment of diabetes with breast cancer;To investigate the metabolic mechanism of glipizide in the treatment of diabetes with breast cancer,we first conducted a metabolomic study on the MMTV-PyMT mouse model of diabetes with breast cancer.The mouse serum and tumor tissue extracts were collected for 1H NMR spectra analyzation.Differential metabolites between control mice and model mice were screened by metabolomics techniques and multiparametric analysis.Diabetes' s impact on breast cancer was analyzed by analyzing metabolite changes.Based on the metabolic changes in the mouse model of diabetes with breast cancer,the blood lipids of the treated mice were detected.The genes involved in lipid metabolism in the treated tumor tissues were screened by qPCR.Results:1.Successfully constructed the mouse model of diabetes with breast cancer,and changed the histological structure of mouse pancreas,resulting in islet ? cell atrophy,necrosis,and promote islet cell proliferation in mice.2.In the mouse model of diabetes combined with breast cancer,the tumor volume of diabetic mice with breast cancer was found to be significantly larger than that of mice without diabetes-associated breast cancer,and the tumor weight was also significantly increased.3.The number of tumors in the diabetes-associated breast cancer mice that invade the surrounding tissues was significantly higher than that in mice without diabetes.Moreover,the number of micrometastasis nodes in lung tissues of diabetic mice with breast cancer was significantly higher than that in control mice.4.Glipizide-treated mice have improved pancreatic lesions compared to DMSO-treated diabetics with breast cancer,inhibited islet alpha cell proliferation in mice,and protected residual islet beta cells from further destruction.5.Compared with DMSO treated diabetes mellitus,the blood glucose,tumor volume and tumor weight of glipizide treatment group were significantly reduced,and glipizide was able to significantly reduce the proliferation of tumor cells and the formation of tumor microvessels.6.In the MMTV-PyMT mouse model of diabetes combined with breast cancer,compared with the non-diabetic MMTV-PyMT mouse model,the serum lipid and unsaturated fatty acid content of diabetic mice with MMTV-PyMT showed a decreasing trend.The content of alanine,methionine,glutamic acid,choline,carnitine,betaine,taurine,lysine,?-glucose,and ?-glucose were increased;in tumor tissues,in tissues of pyruvate and gallbladder the contents of alkali,betaine,taurine,?-glucose,?-glucose,tyrosine,and histidine showed a decreasing trend,and the contents of low-density lipoprotein/low-density lipoprotein,lactic acid,and glycogen increased.7.Glipizide can increase the levels of HDL-c and LDL-c in diabetes mellitus with breast cancer MMTV-PyMT mice,but have no significant effect on blood lipids in diabetes with breast cancer BALB/c mice;Glipizide can up-regulate the expression of PPAR-? in mouse tumor tissues.Among the genes involved in the regulation of fatty acid metabolism,glipizide can upregulate the expression of acsl3 and acsl4.Conclusion: Our experimental results establish two mouse models of diabetes combined with breast cancer;we verified that glipizide can inhibit the growth of diabetes-associated breast cancer tumors;screen out metabolically significant differences in metabolic pathways and metabolic pathways in diabetes-associated breast cancers.It verified that glipizide can up-regulate the expression of PPAR-? in diabetic breast cancer tissues and also up-regulate the expression of acsl3 and acsl4 involved in fatty acid metabolism.