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Aim To investigate the role of metabolites of eicosapentaenoic acid (EPA) in promoting the transdifferentiation of pancreatic α cells to β cells. Methods Male C57BL/6J mice were injected intraperitoneally with 60 mg/kg streptozocin (STZ) for five consecutive days to establish a type 1 diabetes (T1DM) mouse model. After two weeks, they were randomly divided into model groups and 97% EPA diet intervention group, 75% fish oil (50% EPA +25% DHA) diet intervention group, and random blood glucose was detected every week; after the model expired, the regeneration of pancreatic β cells in mouse pancreas was observed by immunofluorescence staining. The islets of mice (obtained by crossing GCG
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Objective:To explore any effect of 8 weeks of high-intensity interval training (HIIT) on glycemia and pancreatic β-cell function among persons with type 2 diabetes to provide data for optimizing their exercise protocol.Methods:Sixty patients with type 2 diabetes and without a habit of regular exercise were randomly divided into an exercise group ( n=30) and a control group ( n=30). Both groups maintained their daily living habits, except that the exercise group practiced HIIT on a power vehicle ergometer 3 times a week for 8 weeks. Before and after the intervention, the 2-hour oral glucose tolerance test (OGTT) was conducted to evaluate glycemia and pancreatic β-cell function. Body composition was also detected using dual-energy X-ray absorptiometry. Results:After the intervention a significant decrease was observed in the fasting blood glucose, mean blood glucose, glycosylated hemoglobin, blood glucose levels at the end of a 2h OGTT, blood glucose area under the curve and homeostatic model assessment of insulin resistance, as well as waist circumference and abdominal fat content of the exercise group. And there was a significant increase in the homeostatic model assessment of pancreatic β-cell function and disposition index among the exercise group. In the control group no significant differences were observed.Conclusion:Eight weeks of HIIT can improve glycemia and pancreatic β-cell function and reduce abdominal fat among persons with type 2 diabetes. It can be used as an effective rehabilitation protocol.
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Objective:To evaluate the effects of ketogenic diet(KD) on pancreatic β-cell dedifferentiation in db/db mice.Methods:In animal study, 8-week-old db/db male mice with type 2 diabetes mellitus(T2DM) were randomly divided into 3 groups: T2DM model group(ND), KD group, 75% caloric restriction(CR) group, and male C57BL/6 mice of the same age as normal control group(C) fed with standard diet. Both C and ND groups were on ad lititum feeding of chow, the KD group was free to eat the ketogenic diet, and the CR group was the positive control group, consuming 75% of the calories of the ND group every day. Four weeks after different diet intervention, body weight, fasting blood glucose, fasting insulin, glucose tolerance and blood β-hydroxybutyric acid(BHB) were measured. Morphology and structure of pancreatic islet was observed by hematoxylin-eosin staining(HE). Immunofluorescence co-staining was used to observe the expression of mouse pancreatic β-cell specific transcription factors.Results:After 4 weeks diet intervention, the fasting blood glucose, insulin and the area under the curve of blood glucose in KD group was significantly decreased( P<0.05); When compared with ND group, the morphology and structure of the islets in the KD group were more regular, and the number of islet cells increased as revealed with HE staining. Pancreatic immunofluorescence co-assay showed that KD not only restored the number and arrangement of β-cells and the ratio of β/α-cell in the pancreatic islets, but also reversed the expression of specific β-cell transcription factors such as pancreatic duodenal homeobox factor-1(PDX1). Conclusion:KD can reduce fasting blood glucose, fasting insulin and improve glucose tolerance in db/db mice, which may be related to its ability to restore the expression of specific β-cell transcription factors and reverse the dedifferentiation of pancreatic β-cells.
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Aim To investigate the protective effect of hesperidin (HSD) on the injury of mouse pancreatic beta cells induced by high glucose and fatty acid and the underlying mechanism. Methods MIN6 cells were treated with high glucose and fatty acid after pretreatment of HSD. Cell counting kit-8 (CCK-8) and Hoechst 33258 fluorescence staining were used to determine the proliferation and apoptosis of MIN6 cells. Western blot was used to detect the expressions of apoptosis-related proteins Bcl-2 and Bax. RT-PCR was used to detect the expressions of inflammatory factors tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). ELISA was used to test the insulin secretion of pancreatic islets. Results High glucose and fatty acid decreased the ratio of Bcl-2/Bax, increased the expression of inflammatory factors TNF-α and IL-1β and inhibited the insulin secretion of mouse pancreatic islets. After pretreatment of HSD, the cell viability and Bcl-2/Bax ratio of MIN6 increased, the expressions of inflammatory factors TNF-α and IL-1β decreased, and the insulin secretion of mouse pancreatic islets increased. Conclusions HSD could resist the apoptosis of mouse pancreatic islet B cell line MIN6 induced by high fat and high glucose, reduce the secretion of inflammatory factors and improve the insulin secretion of pancreatic islets.
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Prolactin is a polypeptide hormone that regulates cell growth and development. Recent studies have shown that prolactin is involved in the regulation of glucose metabolism and is closely related to blood glucose homeostasis. This paper is to review the research progress of prolactin in islet β cells, including the understanding of prolactin and its receptor, the associations of prolactin with glucose metabolism, and the proliferation, apoptosis and secretion of pancreatic beta cells.
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Proinsulin is the precursor of mature insulin.Proinsulin to insulin ratio reflects the degree of pancreatic β-cell dysfunction and the progression of type 2 diabetes, and may predict the risk of diabetes development.Some variants in susceptibility genes of diabetes are associated with the elevation of proinsulin to insulin ratio.Moreover, several antidiabetic drugs are able to decrease the proinsulin to insulin ratio in patients with type 2 diabetes.Therefore, the proinsulin to insulin ratio may act as a simple and useful indicator in the etiological study, risk prediction, disease progression and therapeutical evaluation in type 2 diabetes.
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Histone deacetylase 1 ( sirtuin 1, SIRT1) is an important member of deacetylase family, and plays an important role in the process of malignant tumor and embryonic development. In this article it was found that overexpression of SIRT1 could accelerate the DNA synthesis in human pancreatic beta cell CRL-1837 and inhibit cell senescence. SIRT1 also could bind to p53 as detected by co-immunoprecipitation and could change the phosphorylation level of p53.
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mTOR pathway plays a critical role in cell proliferation, growth and metabolism. This pathway is composed of two different large protein complexes, mTORC1 and mTORC2, which have their distinct downstream effects. Its inhibitor, rapamycin, has been proved to cause β-cell damage and glucose intolerance. Furthermore, various transgenic mouse models and ex vivo studies have revealed that mTORC1 and mTORC2 are both essential for maintaining normal β cell mass and function, whereas the underlying molecular mechanism and the relevance of the whole mTOR signaling to pathogenesis of type 2 diabetes remain to be explored and further clarified.
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Objective To investigate the Toll like receptor-4 (TLR4) expression on pancreatic islet beta-cell of septic rat and its effects on glucose regulation.Methods SD male septic rats were made with LPS intra-abdominal injection in a dose of 5 mg/kg body weight and it repeated once 3 h later.Rats were randomly (random number) divided into four groups randomly (n =5 in each):normal control group,LPS group,LPS antibody group and PLS with LPS antibody group.The expression and protein level of TLR4 were measured by RT-PCR,Western-blot and immunochemistry analysis respectively.IVGTT (intra-venous glucose tolerant test) was used to measure the glucose and insulin levels 6 hours after LPS administration and as well as in control group,and then their AUC were calculated.Results The TLR4 protein and mRNA expressed on pancreatic islet beta-cell of normal rat were significantly up-regulated 6 hours after LPS administration,while its up-regulation could be inhibited when LPS antibody was used in advance (P ＜ 0.01).Rat blood glucose levels were higher at 10,30,60 and 120 min in LPS group and insulin levels were lower at 30,60,120 min compared with normal control (P ＜ 0.01).LPS antibody improved the insulin secretion and then blood glucose level distinctly decreased during 30-120 min period after LPS challenge proved by IVGTT test.Conclusions TLR4 expression up-regulated on pancreatic islet beta-cell of septic rat and LPS-TLR4 system might be a mechanism of stress hyperglycemia genesis.
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Objective: To investigate the hypoglycemic effect of geniposide and to explore the mechanism. Methods: The diabetic mice were induced by a single dose of 90 mg/kg streptozotocin (STZ) injection followed by four-week high-fat diets and randomly divided into three groups: normal control (con), diabetic model (diab), and geniposide (gen, 100 mg/kg) groups. Body weight and fasting blood glucose were measured during the treatment. Thirty days later, the oral glucose tolerance test (OGTT) was performed, blood samples were collected to measure insulin concentration in plasma. The morphological changes of pancreas pathology and β-cell proliferation were examined by immuno-fluorescent staining of insulin and Ki67. The phosphorylations of AKT and GSK-3β (p-AKT and p-GSK-3β) in liver tissues were detected by Western blotting assay. Results: Compared with the diab group, geniposide showed significantly hypoglycemic effect, together with lowering body weight, increasing the insulin content in plasma, and improving OGTT. The immuno-fluorescent staining showed the islets destruction caused by hyperglycemia was recovered by geniposide. The β-cell proliferation presented by Ki67 staining increased as compared with that in the diab group. Moreover, both p-Akt and p-GSK-3β levels in the liver tissue were upregulated by geniposide remarkably. Conclusion: The present study demonstrates that geniposide could ameliorate the hyperglycemia in diabetic mice by enhancing the pancreatic β-cell proliferation and activation of AKT signaling pathway in liver.
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Objective To investigate the effect of trichostatin A (TSA) and 5-azacitidine (5-AzaC) on pancreatic β-cells impaired by cytokine,via measuring the proliferation,apoptosis,and function of pancreatic β-cells.Methods RIN-m5f was impaired by interleukin-1β and interferon-γin vitro,and treated with TSA and 5-AzaC.Experiment groups included blank control group,cytokine induction group,0.05/0.10 μmoL/L TSA group,0.63/1.25 μmoL/L 5-AzaC group,and0.10 μmol/L TSA plus 1.25 μmol/L 5-AzaC group.The viability of RIN-m5f cells was detected by MTT assay.Apoptotic rate was determined by Annexin V-fluorescein isothiocyanate (FITC) /propidium iodide flow cytometry.Insulin secretion was measured by enzyme-linked immunosorbent assay.Results The viability of RIN-m5f cells in 0.05/0.10 μmoL/L TSA group,0.63/1.25 μmol/L 5-AzaC group,and 5-AzaC plus TSA group was 70.1％/79.2 ％,67.3 ％/82.9 ％,and 89.1％ respectively,being higher than that in the cytokine group (33.9％,P＜0.05) ; the apoptosis rate was 10.3％/10.5％,7.9％/9.6％,and 8.2％,being lower than that in the cytokine group (16.6％,P＜0.05) ; the capacity of glucose-stimulated insulin secretion of all the treated groups was higher than that in the cytokine group (P＜0.05).Conclusion TSA and 5-AzaC might promote the proliferation of pancreatic β-cells impaired by cytokines,inhibit its apoptosis and recover its insulin secretion.
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Objective To clarify the protective effect of nrsodeoxycholic acid ( UDCA ) on endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cell of streptozotocin ( STZ )-induced diabetic rats.Methods Rats( n =40) received a single injection STZ( 50 mg/kg) intra-peritoneally and formed a β-cell injury model.Weight-matched normal rats( the control group,n =10 ) were injected with the buffer alone.STZ-treated rats with persistent random blood glucose higher than 16.7 mmol/L for 1 week were considered as diabetic status( n=14 ),then divided randomly into STZ-induced diabetes mellitus ( DM ) group ( n =7 ) and UDCA-treated DM group ( n =7 ).UDCA (40 mg· kg- 1,d-1 ) was administered daily by intragastric intubations throughout the experimental period (30 d).During the entire experiment,blood glucose in all rats was assessed.By the end of the experiment,all rats were sacrificed with the pancreas removed and the blood sample collected immediately.Fasting insulin levels were assayed by radioimmunoassay.The morphological changes of pancreatic β-cells apoptosis were determined by TUNEL assay.RNA in pancreas was abstracted and microarray containing 89 pieces of apoptosis related genes was applied.The related gene expressions were detected by RT-PCR and Western blot.Results The concentration of blood glucose in diabetic rats was gradually decreased after UDCA treatment,but at the end of the experiment it was still higher than that in the normal control group.The treatment with UDCA raised the fasting insulin level in diabetic rats,but this concentration was significantly lower as compared to the control group.Based on TUNEL stained tissue sections,the percentage of β-cell apoptosis of UDCA-treated DM group was significantly lower than that of STZ-induced diabetic group(P＜0.05 ).Among 89 genes,42 genes up-regulated and 46 genes down-regulated in diabetic rats,some of which were ameliorated by UDCA treatment.The expressions of Caspase-3,Bax,Bip,and CHOP mRNA in pancreas of DM group were significantly up-regulated as compared with those in the control group ( P ＜ 0.05 ) ; while the expression of Bcl-2 mRNA was markedly down-regulated (P＜0.05 ).However,these parameters in the U DCA-treated animals showed a marked improvement.Conclusion Ursodeoxycholic acid seems to protect pancreatic β-cell from apoptosis in STZ-induced diabetes by attenuating the severity of endoplasmic reticulum stress.
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AIM: The main purpose of this study is to investigate the regulatory role of C/EBPα in mouse vesicular glutamate transporter 2(mVGLUT2) gene expression. METHODS: The promoter region of mVGLUT2 was cloned to PGL3-basic vector. Site-direction mutation was used to identify the CCAAT-enhancer-binding protein α(C/EBPα) binding site. The promoter activity was observed by luciferase system. The binding between C/EBPα protein and mVGLTU2 promoter region was determined by EMSA. The C/EBPα gene expression was inhibited by its specific siRNA. RESULTS: mVGLUT2 promoter activity decreased about 50% after mutation of C/EBPα binding site. EMSA showed that C/EBPα protein bound onto mVGLUT2 promoter region. Meanwhile, when C/EBPα gene expression was inhibited by its specific siRNA, mVGLUT2 promoter activity, mRNA level and protein level were decreased about 60%, 40% and 45%, respectively. CONCLUSION: C/EBPα is involved in the regulation of mVGLUT2 gene expression.