Application of single cell RNA sequencing in the treatment of diabetes / 中华内分泌代谢杂志

Single-cell RNA sequencing (scRNA-seq) is used for transcriptome profiling at the individual cell level, which is capable of screening in differentially gene expression that results from genetic mutation. Islet-based developmental atlas and heterogeneity characterization are currently the main applications of scRNA-seq in diabetes. scRNA-seq also can be used to mark and purify the functional β cells from resident adult stem cells in the pancreatic islets, which is expected to improve the outcome of islet β cells transplantation in type 1 diabetic patients. In addition, the technique can aid in learning diabetic β cell dedifferentiation and immunomodulatory functions. Although the study of scRNA-seq in diabetic retinopathy, nephropathy, atherosclerosis, and peripheral neuropathy is still at a nascent stage, scRNA-seq has great potential in a wide range of biomedical and clinical applications.

Medicated effect of CDKN1B on promoting proliferation of islet β cells in diabetes mellitus / 中国综合临床

The serious decrease in the number of functional β cells is one of the main features in the pathogenesis of diabetes mellitus. CDKN1B is a new kind of regulatory protein, which can bind and inactivate cyclin and cyclin-dependent kinase complex to control the process of cell cycle. It was suggested that down-regulation or deletion of CDKN1B in islet β cells could accelerate the proliferation of islet β cells, thus increasing the number of islet β cells, which is of great significance for treatments of diabetes.

Oral nano-formulation improves pancreatic islets dysfunction via lymphatic transport for antidiabetic treatment

Type 2 diabetes mellitus (T2DM) therapy is facing the challenges of long-term medication and gradual destruction of pancreatic islet β-cells. Therefore, it is timely to develop oral prolonged action formulations to improve compliance, while restoring β-cells survival and function. Herein, we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property, which combined apical sodium-dependent bile acid transporter-mediated intestinal uptake and lymphatic transportation. In this system, taurocholic acid (TCA) modified poly(lactic-co-glycolic acid) (PLGA) was employed to achieve pancreas location, hydroxychloroquine (HCQ) was loaded to execute therapeutic efficacy, and 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) was introduced as stabilizer together with synergist (PLGA-TCA/DLPC/HCQ). In vitro and in vivo results have proven that PLGA-TCA/DLPC/HCQ reversed the pancreatic islets damage and dysfunction, thus impeding hyperglycemia progression and restoring systemic glucose homeostasis via only once administration every day. In terms of mechanism PLGA-TCA/DLPC/HCQ ameliorated oxidative stress, remodeled the inflammatory pancreas microenvironment, and activated PI3K/AKT signaling pathway without obvious toxicity. This strategy not only provides an oral delivery platform for increasing absorption and pancreas targetability but also opens a new avenue for thorough T2DM treatment.

TGF-β-related Signaling Pathways in Pathogenesis of Diabetes and Prospect of Chinese Medicine Intervention： A Review / 中国实验方剂学杂志

The incidence of diabetes has been on the rise as the result of lifestyle changes， especially the high-fat diet and reduced exercise. Thus， it has become a global public health problem and it is an urgent task to explore effective therapy. There has been an explosion of research on the relationship of transforming growth factor-β （TGF-β） signaling pathways with diabetes complications and tumors， but the role of the pathways in the occurrence and progression of diabetes remains unclear. TGF-β signaling pathways can be activated by many factors， directly or indirectly leading to the apoptosis of islet β cells and insulin resistance （IR）， and thus they are expected to become new targets for the treatment of diabetes. TGF-β-related signaling pathways involve AMP-activated proteinkinase （AMPK）， protooncogene （c-Myc）， Ski-relatednovel protein N （SnoN）， Smad ubiquitination regulatory factor 1 （Smurf1）， miR-335-5p， and other signaling molecules. They participate in the occurrence and development of IR， apoptosis of islet β cells， insulin secretion disorder， fibrosis of adipocytes， and metabolic disorder of adipocytes， and inhibit the browning of white adipose tissue， playing an important part in the pathological process of human diabetes. According to traditional Chinese medicine （TCM）， the pathogenesis of diabetes is the deficiency of Qi and Yin， and the late stage is characterized by the syndrome of Qi deficiency， and Yang deficiency and blood stasis， which should be treated according to the principle of replenishing Qi and nourishing Yin， warming Yang and activating blood. It has been found that the efficacy of some Chinese medicinals and compound prescriptions on diabetes is closely related to the TGF-β signaling pathways. This paper reviews TGF-β-associated signaling pathways， elucidating the roles of them in pathogenesis of diabetes， and analyzes the relationship of TGF-β-associated signaling pathways with the effect of compound Chinese medicine prescriptions against diabetes. This study is expected to lay a theoretical basis for the research on the treatment diabetes.

Effects of recombinant human syntaxin-4(STX4) on lipopolysaccharide-induced islet β-cell INS-1 injury and underlying mechanism / 中华内分泌代谢杂志

Objective:To explore the effect of recombinant human syntaxin-4(STX4) on lipopolysaccharide(LPS)-induced injury in islet β-cells(INS-1).Methods:Pancreatic islet β-cells(INS-1) were divided into Control (blank control), LPS (LPS treatment), LPS+ NC (transfection of negative control vector, LPS treatment), and LPS+ STX4 (transfection of pcDNA-STX4, LPS treatment) groups. RT-qPCR and Western blot were used to detect STX4 mRNA and protein expression, flow cytometry to detect apoptosis, DCFHDA method to detect reactive oxygen species(ROS) level, xanthine oxidation method to detect superoxide orgotein dismutase(SOD) level, colorimetric method to detect glutathione peroxidase(GSH-Px) level, ammonium molybdate colorimetric method to detect catalase(CAT) level, thiobarbituric acid method to detect malonaldehyde(MDA) level, ELISA method to detect the level of interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), and insulin secretion levels under glucose conditions secreted by cells, Western blot method to detect Cleared Caspase-3, Bcl-2 Associated X Protein(Bax), p65 protein expression. After treatment with NF-κB signaling pathway activator, STX4 up-regulated islet β-cell INS-1 was given LPS stimulation, and the same method was used to measure apoptosis, ROS, SOD, GSH-Px, CAT, MDA levels and secreted IL-1β, TNF-α, insulin levels and Cleaved Caspase-3, Bax, p65 protein levels.Results:Compared with the Control group, the expression of STX4 mRNA and protein in islet β cells of the LPS group decreased, the apoptosis rate, ROS level, and MDA levels increased, and the levels of SOD, GSH-Px, and CAT decreased, the levels of IL-1β, TNF-α increased, the level of insulin secreted by the cells decreased, and the expression levels of Cleaved Caspase-3, Bax, and p65 also increased. NF-κB pathway activator treatment reversed the effect of up-regulated STX4 on islet β-cell apoptosis, ROS, SOD, GSH-Px, CAT, MDA levels and secreted IL-1β, TNF-α levels, and Cleaved Caspase-3 , Bax and p65 protein levels.Conclusion:Up-regulation of STX4 alleviated LPS-induced islet β cell oxidative damage, apoptosis and inflammatory factor release. The underlying mechanism might be related to the inhibition of activated NF-κB signaling pathway.

Clinical Efficacy of Modified Huanglian Wendantang in Treatment of Newly Diagnosed Type 2 Diabetes Mellitus with Phlegm (Dampness)-Heat Syndrome / 中国实验方剂学杂志

Objective:To observe the efficacy of modified Huanglian Wendantang in treating newly diagnosed type 2 diabetes mellitus （T2DM） with phlegm （dampness）-heat syndrome， in order to study the effect on islet β cell function and adipocytokines. Method:A total of 130 patients were randomly divided into two groups by random number table （65 cases in each group）. The 60 patients in control group completed the treatment （4 patients fell off or lost visit， 2 were eliminated because of breach of plan）， and the 61 patients in observation group completed the treatment （3 patients fell off， 1 were eliminated）. And 20 healthy volunteers were taken as normal control group. Both groups′ patients got lifestyle interventions and metformin hydrochloride tablets （1 tablet/time， 1 time/day during the meal）. In addition， patients in control group got Huazhuo Qingshen Keli in the morning and at night， 5 g/time， 2 times/day， and patients in observation group got modified Huanglian Wendantang， 1 dose/day. And the treatment was lasted for 3 months. Before and after treatment， levels of fasting blood glucose （FBG）， postprandial 2 blood glucose （PBG）， HbA1c and fasting insulin （FINS）， insulin resistance index （HOMA-IR）， insulin sensitivity index （InISI）， islet β cell function index （HOMA-β）， early insulin secretion index （I30/△G30） and late insulin secretion index （AUCI30~I120/G30~G120）， total cholesterol （TC） and triglycerides （TG）， high-density lipoprotein （HDL-C）， low-density lipoprotein （LDL-C）， adiponectin， TNF -α （TNF-α）， resistin and leptin were detected. And syndrome of phlegm （dampness） combined with heat were scored， and the safety was discussed. Result:The total effective rate in observation group was 91.80% （56/61）， which was higher than 78.33% （47/60） in control group （χ2=4.333， P<0.05）. And the score of phlegm （dampness）-heat syndrome was lower than that in control group （P<0.01）， levels of FBG， PBG， HbA1c， HOMA-IR， AUCI30~I120/G30~G120， TC， TG， LDL-C， TNF-α， leptin and resistin were lower than those in control group （P<0.01）， while levels of I30/△G30， HOMA-β， InISI， HDL-C and adiponectin were higher than those in control group （P<0.01）. There was no adverse reaction related to modified Huanglian Wendantang. Conclusion:In addition to treatment with metformin， modified Huanglian Wendantang can effectively control blood glucose and lipid， regulate adipocyte factor， improve early and late phase insulin secretion， improve the function of β cell and insulin sensitivity of islet， improve IR， with a better comprehensive efficacy and a safety in clinical use.

Relationships between islet β-cell function and infection,inflammation and major organ function in multiple organ dysfunction syndrome patients with severe traumatic hemorrhage / 重庆医学

Objective To analyse the relationships between islet β-cell function and infection,inflammation and major organ function in multiple organ dysfunction syndrome (MODS) patients with severe traumatic hemorrhage.Methods A total of 187 cases of MODS patients hospitalized in the 94th Hospital of PLA from January 2013 to January 2016 were selected,and were divided into the MODS survival group (MODS-S group,104 cases) and MODS dead group (MODS-D group).Other 100 healthy subjects were selected as the control group.The fasting blood glucose (GLU0) and insulin (INS0) levels,blood glucose (GLU30) and insulin (INS30) levels after 30 min of glucose loading,and levels of soluble triggering receptor expressedon myeloid cells-1 (sTREM-1),tumor necrosis factor-α (TNF-a),interleukin-6 (IL-6),alanine aminotransferase (ALT),creatinine (Cre) and creatine kinase isoenzyme (CK-MB) in different groups were determined.The insulin-β-cell function was evaluated by homeostasis model assessment of β-cell function (HOMA-β) index and ratio of insulin increment and blood glucose increment after 30 min of glucose loading (ΔINS30/ΔGLU30),and their relationships to other indexes,including sTREM-1,TNF-α,IL-6,GLU0,ALT,Cre and CK-MB,in MODS patients with severe traumatic hemorrhage were analysed.Results The HOMA-β and AINS30/AGLU30 ratio in the MODS-D group were lower than those in the MODS-S group,and levels of sTREM-1,TNF-α,IL-6,ALT,Cre and CK-MB in the MODS-D group were higher than those in the MODS-S group,there were statistically significant differences (P＜0.01).In MODS patients with severe traumatic hemorrhage,HOMA-β and ΔINS30/AGLU30 was both negatively correlated with sTREM-1,TNF-α,IL-6,GLU0,ALT,CreandCK-MB (r=-0.356 4,-0.532 1,-0.345 8,-0.772 1,-0.762 5,-0.684 8,-0.606 4;r=-0.428 5,-0.567 8,-0.487 0,-0.743 6,-0.781 7,-0.717 6,-0.640 1,P＜0.01).Conclusion MODS patients with severe traumatic hemorrhage have islet β-cell dysfunction which may be used as a prognostic and diagnostic indicator.

Relationships between islet β-cell function and infection,inflammation and major organ function in multiple organ dysfunction syndrome patients with severe traumatic hemorrhage / 重庆医学

Objective To analyse the relationships between islet β-cell function and infection,inflammation and major organ function in multiple organ dysfunction syndrome (MODS) patients with severe traumatic hemorrhage.Methods A total of 187 cases of MODS patients hospitalized in the 94th Hospital of PLA from January 2013 to January 2016 were selected,and were divided into the MODS survival group (MODS-S group,104 cases) and MODS dead group (MODS-D group).Other 100 healthy subjects were selected as the control group.The fasting blood glucose (GLU0) and insulin (INS0) levels,blood glucose (GLU30) and insulin (INS30) levels after 30 min of glucose loading,and levels of soluble triggering receptor expressedon myeloid cells-1 (sTREM-1),tumor necrosis factor-α (TNF-a),interleukin-6 (IL-6),alanine aminotransferase (ALT),creatinine (Cre) and creatine kinase isoenzyme (CK-MB) in different groups were determined.The insulin-β-cell function was evaluated by homeostasis model assessment of β-cell function (HOMA-β) index and ratio of insulin increment and blood glucose increment after 30 min of glucose loading (ΔINS30/ΔGLU30),and their relationships to other indexes,including sTREM-1,TNF-α,IL-6,GLU0,ALT,Cre and CK-MB,in MODS patients with severe traumatic hemorrhage were analysed.Results The HOMA-β and AINS30/AGLU30 ratio in the MODS-D group were lower than those in the MODS-S group,and levels of sTREM-1,TNF-α,IL-6,ALT,Cre and CK-MB in the MODS-D group were higher than those in the MODS-S group,there were statistically significant differences (P＜0.01).In MODS patients with severe traumatic hemorrhage,HOMA-β and ΔINS30/AGLU30 was both negatively correlated with sTREM-1,TNF-α,IL-6,GLU0,ALT,CreandCK-MB (r=-0.356 4,-0.532 1,-0.345 8,-0.772 1,-0.762 5,-0.684 8,-0.606 4;r=-0.428 5,-0.567 8,-0.487 0,-0.743 6,-0.781 7,-0.717 6,-0.640 1,P＜0.01).Conclusion MODS patients with severe traumatic hemorrhage have islet β-cell dysfunction which may be used as a prognostic and diagnostic indicator.

Influence of rat pancreatic islet α cells and its secretions in function of β cells / 吉林大学学报(医学版)

Objective:To investigate the influence of α cells and glucagon-like peptide l (GLP-1) in the function of β cells (INS-1 cells) in the rats,and to elucidate the possible mechanism of α cells and INS-1 cells transplantation in influencing hypoglycemia.Methods:The proliferation abilities of INS-1 cells after treated with 10％,20％ and 30％ islet α-cell conditioned medium and 0.03,0.30,3.00,30.0 mg · L-1 of GLP-1 were analyzed by MTT assay.The levels of insulin secretion of INS-1 cells after treated with 10％,20％,30％ α cells,α-cell conditioned medium and different concentrations of GLP-1 were analyzed by enzyme linked immunosorbent assay (ELISA).The concentrations of Ca2+ in INS-1 cells after treated with high glucose and GLP-1 were analyzed by laser confocal microscope.The expression levels of insulin protein after treated with different concentrations of islet α-cell conditioned medium and different concentrations of GLP-1 were detected by Western blotting methed.After the INS-1 cells,the mixture of INS-1 cells and α cells were transplanted into the left renal capsule of the nude mice,the blood glucose levels and the kidney morphology were observed.The levels of insulin/glucagon in the transplanted cells were detected by immunohistochemistry.Results:Compared with control group,both of α-cell conditioned media and GLP-1 promoted the INS-1 cell proliferation and insulin secretion (P ＜ 0.05).The laser confocal microscope results revealed that GLP-1 stimulated the increased intracellular Ca2+ concentration in INS-1 cells (P＜ 0.05).Compared with control group,there was no significant difference in the expression levels of insulin protein in the insulin-1 cells after treated with islet α cell conditioned medium and GLP-1 (P＞0.05).Compared with pre transplantation,the blood glucose level in the transplanted INS-1 cells was significantly decreased at 35 d after renal capsul trasplantation (P＜0.05),and even hypoglycemia presented renal capsular in the diabetic nude mice;the transplantation site was obviously swollen.However,the levels of blood glucose had no change of the diabetic rats after transplated with the mixture of INS-1 and α cells (P＜0.05).The expression of insulin and glucagon in the INS-1 transplanted cells were found by immunohistochemistry staining.Conclusion:Pancreatic islet α cells and their secretions can promote the INS-1 cell proliferation and insulin secretion,and the mixture of INS-1 cells and α cells transplanted under the renal capsule of the diabetic nude mice can reduce the hypoglycemic effect of INS-1 cell transplantation which might be related to the INS-1 cells that can express both of insulin and glucagon genes.

Influence of rat pancreatic islet α cells and its secretions in function of β cells / 吉林大学学报(医学版)

Objective:To investigate the influence of α cells and glucagon-like peptide l (GLP-1) in the function of β cells (INS-1 cells) in the rats,and to elucidate the possible mechanism of α cells and INS-1 cells transplantation in influencing hypoglycemia.Methods:The proliferation abilities of INS-1 cells after treated with 10％,20％ and 30％ islet α-cell conditioned medium and 0.03,0.30,3.00,30.0 mg · L-1 of GLP-1 were analyzed by MTT assay.The levels of insulin secretion of INS-1 cells after treated with 10％,20％,30％ α cells,α-cell conditioned medium and different concentrations of GLP-1 were analyzed by enzyme linked immunosorbent assay (ELISA).The concentrations of Ca2+ in INS-1 cells after treated with high glucose and GLP-1 were analyzed by laser confocal microscope.The expression levels of insulin protein after treated with different concentrations of islet α-cell conditioned medium and different concentrations of GLP-1 were detected by Western blotting methed.After the INS-1 cells,the mixture of INS-1 cells and α cells were transplanted into the left renal capsule of the nude mice,the blood glucose levels and the kidney morphology were observed.The levels of insulin/glucagon in the transplanted cells were detected by immunohistochemistry.Results:Compared with control group,both of α-cell conditioned media and GLP-1 promoted the INS-1 cell proliferation and insulin secretion (P ＜ 0.05).The laser confocal microscope results revealed that GLP-1 stimulated the increased intracellular Ca2+ concentration in INS-1 cells (P＜ 0.05).Compared with control group,there was no significant difference in the expression levels of insulin protein in the insulin-1 cells after treated with islet α cell conditioned medium and GLP-1 (P＞0.05).Compared with pre transplantation,the blood glucose level in the transplanted INS-1 cells was significantly decreased at 35 d after renal capsul trasplantation (P＜0.05),and even hypoglycemia presented renal capsular in the diabetic nude mice;the transplantation site was obviously swollen.However,the levels of blood glucose had no change of the diabetic rats after transplated with the mixture of INS-1 and α cells (P＜0.05).The expression of insulin and glucagon in the INS-1 transplanted cells were found by immunohistochemistry staining.Conclusion:Pancreatic islet α cells and their secretions can promote the INS-1 cell proliferation and insulin secretion,and the mixture of INS-1 cells and α cells transplanted under the renal capsule of the diabetic nude mice can reduce the hypoglycemic effect of INS-1 cell transplantation which might be related to the INS-1 cells that can express both of insulin and glucagon genes.

The Mechanism Behind the Anti-Apoptotic Effects of TNK on Islet β Cell in Type 2 Diabetic ZDF Rats / 世界科学技术-中医药现代化

This study aimed to investigate the anti-apoptotic effects of Tangnaikang (TNK) on islet β cells in Zucker diabetic fatty (ZDF) rats.Six male fa/+ ZDF rats were took as the control group,while other thirty male fa/fa ZDF rats were divided into five groups at random:the model group,the metformin group,the high-,mediumand low-dose TNK groups,depending on their body weight and random blood glucose.Prior to the administration,fasting blood glucose and fasting insulin were measured by drawing blood with inner canthusl.Materials were prepared when administered for six weeks.Fasting blood glucose and fasting insulin were detected again.When the sections of the rat pancreatic tissue were embedded,the morphological changes of the islet were observed via HE staining,and the apoptosis of islet β cell were observed using TUNEL.Positive expression of Caspase-3,the transduction enzyme of cell death signal,was tested by immunohistochemical method.It was found that the fasting blood glucose of the (fa/fa) ZDF rats in the high-,medium-and low-dose TNK group was significantly improved after administration (P ＜ 0.01).The serum insulin of rats in the high-,medium-and low-dose TNK group arised compared with the model group,while the high-and low-dose TNK group showed differences in a statistical sense.Compared with the model group,the HOMA-IR of all the treatment group decreased,while significant difference was presented between the high-dose TNK group and the metformin group.HE staining showed that the morphology of the islet β cell of the rats in all the treatment group was improved.The results of TUNEL showed significantly apoptotic changes on islet β cell of the fa/fa ZDF rats.Compared with the model group,the positive expression of TUNEL in the metformin group and the high-dose TNK group were significantly reduced (P ＜ 0.05).The result of immunohistochemistry method showed that the protein levels of Caspase-3 in the metformin group and the high-dose TNK group decreased (P ＜ 0.05).In conclusion,it was demonstrated that TNK effectively reduced the apoptosis of islet β cells in fa/fa ZDF rats,which presented a protective effect.

MicroRNAs with the Regeneration and Differentiation of Islet β cells and the Targeted Therapy of Traditional Chinese Medicine / 世界科学技术-中医药现代化

MicroRNAs (miRNAs) are a class of non-coding RNAs about 18-25 nucleotides in length,involved in post-transcriptional genes regulation process.Previous studies showed that miRNAs played an important regulatory role in pancreatic development,gene expression,and synthesis and secretion of insulin.A variety of miRNAs which expressed in islet β cells may affect the proliferation and differentiation of islet β cells.Since miRNAs showed tissue specificity,their expression changes were closely related to some diseases.Thus,integrative studies with miRNAs over the essence of syndromes of traditional Chinese medicine could provide new ideas for the treatment of diabetes.

Betatrophin and glucose-lipid metabolism / 中华内分泌代谢杂志

Betatrophin,discovered in 2013,is a protein secreted by liver,white adipose tissues,and brown adipose tissues.Betatrophin can improve glucose tolerance in mice by promoting islet β cell proliferation and increasing the number of β cells significantly and specifically.At the same time,Betatrophin is involved in lipid metabolism.Betatrophin may work as the new target for treatment of diabetes and disorders of lipid metabolism.

Protective effect of Jinlida granules on islet β cells in diabetes mellitus rats / 第二军医大学学报

Objective to investigate the protective effect of Jinlida granules on islet β cells in diabetes mellitus rats. Methods Diabetic models were induced by high-fat diet and intraperitoneal injection of streptozotocin (STZ) in SD rats. The study was divided into model group, Jinlida granule group (0.75, 1.5, 3.0g/kg) α-lipoic acid group, insulin group, and metformin group. Each group was given corresponding drugs, with insulin given by subcutaneous injection and other drugs given by intragastric administration. The body weight, fasting blood glucose (FBG), fasting insulin (FINS), glycosylated hemoglobin (HbAlc), the activities of super oxide dismutase (SOD) and glutathione (GSH), and the contents of malondialdehyde(MDA), IL-10 and TNF-« were examined 2 months later. The pancreatic tissues were immunostained for insulin. Results Compared with the model group, the levels of FBG and HbAlc were decreased in other groups (P<0. 05, P< 0. 01). The activities of SOD and GSH were significantly increased (P<0. 01) and the levels of MDA, IL-1β and TNF-α were significantly decreased (P<0. 01) In high-dose (3. 0 g/kg) Jinlida granule group, with increased islet area as shown by pathological staining. Conclusion Jinlida granule has protective effect against STZ-induced islet β cell injury in diabetic rats.

Effect of intermittent high glucose on INS-1 cell proliferation and the expression of skp2-p27 / 中华内分泌代谢杂志

Objective To investigate the effect of intermittent high glucose on proliferation, apoptosis, and cell cycle progression of INS-1 cells, and the possible intracellular pathways activated by intermittent high glucose. Methods Cell viability was evaluated by cell counting kit, the cell cycle was determined by flow cytometry,Annexin-V/PI double-labeled cell apoptosis detection kit was used to monitor cell apoptosis. Cell cycle related protein Skp2 and p27 expressions were detected by Western blot. Results ( 1 ) Both intermittent and constant high glucose significantly inhibited the growth of INS-1 cells, and the former effect was more significant. ( 2 ) Intermittent and constant high glucose levels significantly increased apoptosis in INS-1 cells, and the former effect was more significant. (3) Intermittent and constant high glucose levels significantly inhibited the cell process, the G0/G1 cell cycle arrest also was induced by intermittent high glucose, resulting in lowered proportion of the G2/M phase and S phase of INS-1 cells. (4) Intermittent and constant high glucose significantly decreased the level of protein Skp2 and increased the level of cell cycle related protein p27. Conclusion Intermittent high glucose levels affect INS-1 cell growth and proliferation, as well as induce cell apoptosis, probably by decreasing the level of protein Skp2 and increasing the level of p27 in the cells, resulting in arrest of progression through the G1 phase to the S phase of INS1 cells, and thus impairment of cell proliferation.

Progress of genome-wide association studies in type 2 diabetes mellitus / 中华内分泌代谢杂志

Genome-wide association studies ( CWAS) use high-throughout genotyping technologies to investigate the relation of hundreds of thousands of gene markers(genotype) with clinical conditions and measurable traits (phenotype). Type 2 diabetes mellitus results from the interaction of environmental factors with genetic variants. Many progresses have been acquired from GWAS. New gene regions have been discovered to be involved in the development and function of islet (3-cells, which provides new strategies for the etiology investigation, prevention, and treatment of type 2 diabetes mellitus.

Liraglutide: A novel therapy for type 2 diabetes——Report of "Diabetes Dialogue" International Forum / 中华内分泌代谢杂志

"Diabetes Dialogue" is an international forum of latest cutting-edge research on diabetes. The major topics in the 5th event in 2008 were the novel targets in the treatment of type 2 diabetes. In particular, the latest developments in incretin-based therapies, especially glucagon-like peptide-1 (GLP-1) -based therapies, and their effects on the β-cells have been provided. Studies suggested that type 2 diabetes is characterized by progressively deteriorated β-cell function with the presence of insulin resistance. Owing to its glucose-dependant glucose lowering effect and the effect on improvement of β-cell function, GLP-1 has become the novel target of therapies. Liraglutide, a GLP-1 analogue developed by Novo Nordisk, is one of the novel therapies in the treatment of type 2 diabetes. Many studies have demonstrated that liraglutide showed both an efficacious and sustained effect on glycemic control and a significant improvement of 13-cell function. As a result, recently the role of GLP-1 or GLP-1 analogue in the management of type 2 diabetes has gained more popularity and liraglutide is considered as a promising drug in the treatment of type 2 diabetes.

Effects of "glucotoxicity", "lipotoxicity" and "glucolipotoxicity" on islet β-cells / 中华内分泌代谢杂志

Glucotoxicity, lipotoxicity and glucolipotoxieity are secondary phenomena following the primary pathogenesis, including the effects of genetic and environmental factors of type 2 diabetes. However, there exist two theories: (1) Lipotoxicity, presents before blood glucose rising, may trigger off a chain reaction which results in hyperglycemia. Hence the term " diabetes mellipidus" was proposed. (2) Hyperglycemia is a prerequisite for lipotoxicity. It seems more appropriate to state that (1) the glucotoxieity and iipotoxicity may present separately or concurrently in type 2 diabetes; (2) The combined glucolipotoxicity should describe the deleterious actions by higher levels of both glucose and free fatty acids on β-cell function, which finally causes progressive deterioration of insulin secretion.

Preservation of β-cell function in type 2 diabetes by GLP-1 based therapy / 中华内分泌代谢杂志

Type 2 diabetes is characterized by deteriorated β-cell function and progressive loss of β-cell mass. Pancreatic islets are a target of high concentrations of glucose, pro-inflammatory cytokines and free fatty acid levels, which are associated with obesity, insulin resistance and β-cell apeptosis. Therapy targeting β-cell dysfunction is crucial in the treatment of type 2 diabetes. GLP-1, one of the incretin hormones, has been demonstrated to improve glycaemic control and β-cell function through its multiple physiological effects. In this review, the mechanisms involved in β-cell dysfunction and β-cell loss are addressed, and the updates in GLP-1 based therapy for the preservation of β-cell mass and β-cell function in type 2 diabetes are also reviewed.

Recent progress in the research of the impact of glucagon-like peptide-1 on islet β-cells / 中华内分泌代谢杂志

Glucagon-like poptide-1 (GLP-1) is an incretin secreted by the enteroendocrine L cells of the gut. Upon the activation of GLP-1 receptor, adenylyl cyclase is activated and cAMP is generated, leading to the activation of protein kinase A and Epac signal pathway. GLP-1 could also activate calcium/calmodulin pathway as well as mitogen-activated protein kinases and phosphatidyl inositol-3 kinase pathway. GLP-1 not only stimulates the phase 1 and phase 2 insulin secretion, but also increases insulin synthesis. GLP-1 also stimulates proliferation and differentiation of islet β-cells, and protects β-cell from apoptosis and modulates endoplasmic reticulum stress response leading to promotion of β-cell adaptation and survival.