Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan...Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.展开更多
AIM： To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism. METHODS： Pdmary rat islets were isolated from male Sprague-Dawley rats by collag...AIM： To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism. METHODS： Pdmary rat islets were isolated from male Sprague-Dawley rats by collagenase digestion and treated with different concentrations （1, 3, 10 and 30 μmol/L） of berberine or 1 μmol/L Glibenclamide （GB） for 24 h. Glucose-stimulated insulin secretion （GSIS） assay was conducted and insulin was determined by radioimmunoassay. 3-（4,5-Dimethylthiazol-2-yl）- 2,5-diphenyltetrazolium bromide （MTT） assay was performed to evaluate cytotoxicity. The mRNA level of hepatic nuclear factor 4 alpha （HAIF4α） was determined by reverse transcription polymerase chain reaction （RT-PCR）. Indirect immunofluorescence staining and Western blot analysis were employed to detect protein expression of HNF4α in the islets. Glucokinase （GK） activity was measured by spectrophotometric method. RESULTS： Berberine enhanced GSIS rather than basal insulin secretion dose-dependently in rat islets and showed no significant cytotoxicity on islet cells at the concentration of 10 μmol/L. Both mRNA and protein expressions of HNF4α were up-regulated by berberine in a dose-dependent manner, and GK activity was also increased accordingly. However, GB demonstrated no regulatory effects on HNF4α expression or GK activity. CONCLUSION： Berberine can enhance GSIS in rat islets, and probably exerts the insulinotropic effect via a pathway involving HNF4α and GK, which is distinct from sulphonylureas （SUs）.展开更多
Type 2 diabetes mellitus(T2DM)therapy is facing the challenges of long-term medication and gradual destruction of pancreatic isletβ-cells.Therefore,it is timely to develop oral prolonged action formulations to improv...Type 2 diabetes mellitus(T2DM)therapy is facing the challenges of long-term medication and gradual destruction of pancreatic isletβ-cells.Therefore,it is timely to develop oral prolonged action formulations to improve compliance,while restoringβ-cells survival and function.Herein,we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property,which combined apical sodiumdependent 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.展开更多
Objective:To investigate the impact of combining liraglutide with metformin on the enhancement of pancreatic islet function in patients with type 2 diabetes and coronary heart disease.Methods:60 patients with type 2 d...Objective:To investigate the impact of combining liraglutide with metformin on the enhancement of pancreatic islet function in patients with type 2 diabetes and coronary heart disease.Methods:60 patients with type 2 diabetes and coronary heart disease admitted from February 2022 to August 2023 were selected as research subjects.They were randomly assigned to either control or treatment groups,with 30 patients in each.The control group received metformin alone,while the treatment group received liraglutide in combination with metformin.Various indicators,including blood sugar levels,pancreatic islet function,and cardiac function between the two groups were compared.Results:The results of FPG,2hPG,HbA1c,HOMA-IR,NT-proBNP,and LVEDD in the treatment group were lower than those in the control group,whereas the values of FINS,HOMA-β,E/A,and LVEF in the treatment group were higher than those in the control group(P<0.05).Conclusion:The use of liraglutide in combination with metformin significantly benefits patients with type 2 diabetes and coronary heart disease.It leads to improved pancreatic islet function,better blood sugar control,and enhanced cardiac function.This combination therapy is recommended for clinical adoption.展开更多
Clostridium histolyticum is used for production of several proteolytic enzymes such as elastase, neutral proteases, clostripain and in particular collagenase. Besides industrial applications, collagenase has been indi...Clostridium histolyticum is used for production of several proteolytic enzymes such as elastase, neutral proteases, clostripain and in particular collagenase. Besides industrial applications, collagenase has been indispensable for medical purposes including isolation of pancreatic islets for diabetes treatment. The aim of this study was to optimize the method for production and partial purification of a new collagenase blend and to test its suitability for successful pancreatic islets isolation in a rat model. Bacterial strain of C. histolyticum was sequenced for presence of the collagenase genes. Different fermentation conditions were tested and the process of collagenase extraction was modified and optimized. Samples of collagenases were taken for western blot detection, activity assessment, and ability for dissociation of pancreatic tissue. Findings indicate that concentrated trypton growth medium with pepton was the most suitable for Clostridium growth and collagenase production. Whole genome sequencing revealed two genes for collagenase and also gene for clostripain. Western blot specific detection helped to select useful production modifications. Following these modifications was also improved the yield, morphology and in vitro function of intact pancreatic islets which were finally comparable or better than those achieved using standard blends of collagenase. The results support the use of the new collagenase blend for islet isolation giving thus the opportunity to choose an alternative product. Our next steps would lead to further enzyme purification through scaling up of the production method for a wider use.展开更多
Objective This study aimed to assess the protective value of adiponectin(APN)in pancreatic islet injury induced by chronic intermittent hypoxia(CIH).Methods Sixty rats were randomly divided into three groups:normal co...Objective This study aimed to assess the protective value of adiponectin(APN)in pancreatic islet injury induced by chronic intermittent hypoxia(CIH).Methods Sixty rats were randomly divided into three groups:normal control(NC)group,CIH group,and CIH with APN supplement(CIH+APN)group.After 5 weeks of CIH exposure,we conducted oral glucose tolerance tests(OGTT)and insulin released test(IRT),examined and compared the adenosine triphosphate(ATP)levels,mitochondrial membrane potential(MMP)levels,reactive oxygen species(ROS)levels,enzymes gene expression levels of Ant1,Cs,Hmox1,and Cox4 i1 which represented mitochondrial tricarboxylic acid cycle function,the protein and gene expression levels of DRP1,FIS1,MFN1,and OPA1 which represented mitochondrial fusion and division,and the protein expression levels of BAX,BCL-2,cleaved Caspase-3,and cleaved PARP which represented mitochondrial associated apoptosis pathway of pancreatic islet.Results OGTT and IRT showed blood glucose and insulin levels had no differences among the NC,CIH and CIH+APN groups(both P>0.05)at 0 min,20 min,30 min,60 min,120 min.However,we found that compared to NC group,CIH increased the ROS level,reduced ATP level and MMP level.The islets of CIH exposed rats showed reduced gene expression levels of Ant1,Cs,Hmox1,and Cox4 i1,decreased protein and gene expression levels of MFN1 and OPA1,increased protein and gene expression levels of DRP1 and FIS1,increased protein expression levels of cleaved Caspase-3 and cleaved PARP,with lower ratio of BCL-2/BAX at protein expression level.All the differences among three groups were statistically significant.APN treated CIH rats showed mitigated changes in the above measurements associated with islet injuries.Conclusion APN may ameliorate the pancreatic islet injury induced by CIH via inhibiting the imbalance in mitochondrial fusion and division.展开更多
BACKGROUND: Islet stem cells are more or less retained in the procedure of islet isolation and purification, and are transplanted together with islet grafts. Keratoprotein (CK-19) and pancreatic duodenal hox gene 1 (P...BACKGROUND: Islet stem cells are more or less retained in the procedure of islet isolation and purification, and are transplanted together with islet grafts. Keratoprotein (CK-19) and pancreatic duodenal hox gene 1 (PDX-1) are markers of stem cells. This study was undertaken to examine the expression of these markers in pancreatic islet samples of different purity from rats. METHODS: A total of 30 male Sprague-Dawley rats were randomly assigned to 3 groups to undergo perfusion with V-type collagenase via the pancreatic duct, then the pancreas was excised, diced, shaken, digested and centrifuged to obtain islet sediments. The sediment from group A was not purified, while that from group B was purified with 25% Ficoll-400 and that from group C with 25% and 11% Ficoll-400. RNA was extracted from the different islet samples for reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of the pancreatic stem cell markers CK-19 and PDX-1 was assessed. RESULTS: The purity of islets in samples was (43.6 +/- 6.29)% in group A; (65.3 +/- 4.40)% in group B; and (77.6 +/- 6.36)% in group C (P<0.05). The expression of CK-19 and PDX-1 mRNA was significantly higher in group A than in groups B and C, but group C showed the lowest level of expression. CONCLUSION: The expression of CK-19 and PDX-1 mRNA in islet samples of different purity suggests the presence of stem cells in all islet samples.展开更多
Objective To evaluate the effects of acute glucose level changes on expression of prepro-orexin, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) mRNA in rat hypothalamus tissue and pancreatic islets cells. Metho...Objective To evaluate the effects of acute glucose level changes on expression of prepro-orexin, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) mRNA in rat hypothalamus tissue and pancreatic islets cells. Methods Thirty adult male Wistar rats were randomly divided into three equal groups (n = 10). The acute hypoglycemia rat model was induced by a single subcutaneous injection of insulin. Twenty acute hypoglycemia rats were divided into group B and group C. Group B was allowed to eat freely, while group C was food-deprived. Control rats were injected the same volume of saline. The effect of glucose levels (2.8 mmol/L and 8.3 mmol/L) on pancreatic islet cell orexin system was detected in pancreas islet cell cultured in vitro. The expression of prepro-orexin and OXR mRNA was examined in rat hypothalamus tissue and pancreatic islets cell cultured in vitro using reverse transcription-polymerase chain reaction (RT-PCR). Results Expression of orexin mRNA increased about 150% for the food-deprived hypoglycemia rats in comparison with control group (P < 0.01), whereas expression of OX1R mRNA decreased up to 30% (P < 0.01). However, expression of OX2R mRNA was unchanged in comparison with control group. In vitro, after incubation with 2.8 mmol/L glucose for 6 hours, the expression of prepro-orexin mRNA increased 2 times in rat pancreas islet cells in comparison with 8.3 mmol/L glucose group (P < 0.01). But the expression of OX1R mRNA was not sensitive to acute glucose fluctuation.Conclusions Orexin in rat hypothalamus is stimulated by decline in blood glucose and inhibited by signals related to feeding. Moreover, glucose plays a role in modulating the gene expression of prepro-orexin in rat pancreatic islet cells.展开更多
Objective To develop a method for maintaining viability and function of islets of Langerhans during the long term preservation.Methods We encapsulated Wistar Furth (WF) rat islets in hydrophilic macrobeads (diamet...Objective To develop a method for maintaining viability and function of islets of Langerhans during the long term preservation.Methods We encapsulated Wistar Furth (WF) rat islets in hydrophilic macrobeads (diameter 6-8 mm) made with agarose and collagen, then preserved them at 37℃ in a humidified atmosphere of air and 5% CO 2 for different time, and compared unencapsulated islets with encapsulated islets for their insulin secretion capability in vitro. At the same time, we have investigated their viability and insulin secreting function in vivo.Results Initially, there was no statistically significant difference in the insulin secretion values between the encapsulated and unencapsulated WF rat islets. While the unencapsulated islet insulin secretion decreased significantly within 2 weeks, the preserved and encapsulated islets maintained their viability and ability of insulin secretion for 40 weeks. In the in vivo study, the diabetic state was reversed in 92.8% of recipients transplanted with preserved macroencapsulated islets. The mice maintained normoglycemia for 157.6±49.3 days, at which point these macrobeads were retrieved. Glucose tolerance curves in the recipient mice were similar to those of normal mice. Conclusions These results indicate that it is a good method for long term preservation of islets by encapsulating islets in agarose and collagen, and then culturing them at 37℃ in a humidified atmosphere of air and 5% CO 2 before transplantation.展开更多
Objective To investigate in vitro heme oxygenase-1 gene (HO-1) delivery to human pancreatic islets by adenovirus vectors. Methods Recombinant adenovirus containing HO-1 or enhanced green fluorescent protein gene(EGFP)...Objective To investigate in vitro heme oxygenase-1 gene (HO-1) delivery to human pancreatic islets by adenovirus vectors. Methods Recombinant adenovirus containing HO-1 or enhanced green fluorescent protein gene(EGFP) was generated by using the AdEasy System. The purified human pancreatic islets were infected with recombinant adenovirus vectors at various multiplicity of infection (MOI). Transduction was confirmed by fluorescence photographs and Western blot. Glucose-stimulated insulin secretion was detected by using Human insulin radioimmunoassay kits and was used to assess the function of human islets infected by recombinant adenovirus.Results Viral titers of Ad-hHO-1 and Ad-EGFP were 1.96×109 and 1.99×109 pfu/mL, respectively. Human pancreatic islets were efficiently infected by recombinant adenovirus vectors in vitro. Transfection of human islets at an MOI of 20 did not inhibit islet function. Recombinant adenovirus mediated HO-1gene transfer significantly improved the islet function of insulin release when simulated by high level glucose. Conclusion Recombinant adenovirus is efficient to deliver exogenous gene into human pancreatic islets in vitro. HO-1 gene transfection can improve human islet function.展开更多
Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes...Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes mellitus. A successful whole pancreas or islet transplant offers the advantages of attaining normal or near normal blood glucose control and normal hemoglobin Alc levels without the risks of severe hypoglycemia associate with intensive insulin therapy. Both forms of transplants are also effective at eliminating the occurrence of significant hypoglycemic events （even with only partial islet function evident）. Whereas whole pancreas transplantation has also been shown to be very effective at maintaining a euglycemic state over a sustained period of time, thus providing an opportunity for a recipient to benefit from improvement of their blood glucose control, it is associated with a significant risk of surgical and post-operative complications. Islet transplantation is attractive as a less invasive alternative to whole pancreas transplant and offers the future promise of immunosuppression-free transplantation through pretransplant culture. Islet transplantation however, may not always achieve the sustained level of tight glucose control necessary for reducing the risk of secondary diabetic complications and exposes the patient to the adverse effects of immunosuppression. Although recent advances have led to an increased rate of obtaining insulin-independence following islet transplantation, further developments are needed to improve the longterm viability and function of the graft to maintain improved glucose control over time.展开更多
Objective： To investigate the effect of Heme oxygenase-1 （HO-1） gene transfection on the viability of cultured rat islets, and to explore the potential value of HO-1 gene in islet transplantation. Methods：Recombin...Objective： To investigate the effect of Heme oxygenase-1 （HO-1） gene transfection on the viability of cultured rat islets, and to explore the potential value of HO-1 gene in islet transplantation. Methods：Recombinant adenovirus vector containing human HO-1 gene（Ad-HO-1 ） or enhanced green fluorescent protein gene（Ad-EGFP） was generated by using AdEasy system respectively. The rat islets were transfected with Ad-HO-1, Ad-EGFP or blank vector and then cultured for 7 days. Transfection was confirmed by expression of EGFP and human HO-1 protein detected by fluorescence photographs and western blot, respectively. The insulin release upon different concentration of glucose stimulation was detected using insulin radioimmunoassay kit, and stimulation index（SI） was calculated. Glucose-stimulated insulin release was used ＇to assess islet viability. Results：Adenovirus vector successfully transferred HO-1 gene to rat islet cells in vitro, and the insulin release upon high level of glucose stimulation and stimulation index （SI） of Ad-HO-1-infected islets were significantly higher than those of Ad-EGFP-infected islets and control islets （P 〈 0.05）. Conclusion： Adenovirus-mediated HO-1 gene transfection is a feasible strategy to confer cytoprotection and therefore protect the viability of cultured rat islets.展开更多
Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017.The incidence and prevalence of diabetes is predicted to increase.To alleviate this potentially sev...Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017.The incidence and prevalence of diabetes is predicted to increase.To alleviate this potentially severe situation,safer and more effective therapeutics are urgently required.Mice have long been the mainstay as preclinical models for basic research on diabetes,although they are not ideally suited for translating basic knowledge into clinical applications.To validate and optimize novel therapeutics for safe application in humans,an appropriate large animal model is needed.Large animals,especially pigs, are well suited for biomedical research and share many similarities with humans,including body size,anatomical features,physiology,and pathophysiology.Moreover,pigs already play an important role in translational studies,including clinical trials for xenotransplantation.Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals,including porcine models of diabetes.This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.展开更多
The loss of or decreased functional pancreatic β-cell is a major cause of type 1 and type 2 diabetes. Previous studies have shown that adult β-cells can maintain their ability for a low level of turnover through rep...The loss of or decreased functional pancreatic β-cell is a major cause of type 1 and type 2 diabetes. Previous studies have shown that adult β-cells can maintain their ability for a low level of turnover through replication and neogenesis. Thus, a strategy to prevent and treat dia- betes would be to enhance the ability of β-cells to increase the mass of functionalβ-cells. Consequently, much effort has been devoted to identify factors that can effectively induce β-cell expansion. This review focuses on recent reports on small molecules and protein fac- tors that have been shown to promote β-cell expansion.展开更多
Using enzymatic assay and radioimmunoassay, we studied the functional status of pancreatic islet in 50 patients with acute leukemia. Oral glucose tolerance test and insulin and C peptide release were made in 40 patien...Using enzymatic assay and radioimmunoassay, we studied the functional status of pancreatic islet in 50 patients with acute leukemia. Oral glucose tolerance test and insulin and C peptide release were made in 40 patients before and after treatment .14 patients who revealed diabetic curve and delayed insulin and C peptide release before treatment showed normal values in 6 after therapy. Five patients with impaired glucose tolerance and decreased insulin and C peptide release before treatment showed normalization of these parameters following therapy. Five patients with normal pretreatment values disclosed abnormal post-treatment results. The remaining 16 patients displayed normal results both before and after therapy. Anti-insulin antibodies were negative, and glucagon level was normal in all the 50 patients. The red cell insulin receptor binding rate analysed in 47 patients was significantly higher than in controls (P< 0.001). We considered that the disturbed glucose metabolism in acute leukemia was not uncommon mainly due to the dysfunction of pancreatic islet β cells as a result of islet damage by leukemic cells, the effect of corticosteroid and chemotherapy and the preexisting diabetes. Impaired glucose metabolism had no influence on therapeutic effect.展开更多
Background Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD10...Background Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103＋ cells from wild type hosts. To circumvent this problem, in the present study, we invented an anti-CD103 immunotoxin （M290-SAP）. We investigated whether M290-SAP has capacity to eliminate CD103-expressing cells in vivo and protect transplanted islets from destroying by host immune cells.Methods Flow cytometry was used to analyze the efficacy of M290-SAP in depleting CD103-expressing cells in vivo.Then using allogenic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, the therapeutic efficacy of CD103-expressing cell depletion was addressed.Results M290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in peripheral lymphatic tissues of treated mice. Balb/c islets transplanted into streptozotocin-induced diabetic C57BL/6 mice under single M290-SAP treatment showed an indefinite survival time compared with untreated mice, M290-treated mice and IgG-SAP treated mice （mean survival time, ＞100 days vs. ＜20 days）. C57BL/6 islets transplanted into hyperglycemic NOD mice under single M290-SAP treatment showed a pronounced delay in allograft rejection compared with untreated mice （mean survival time 12-13 days vs. ＜7 days）. Immunological analysis of mice with long-term islet allograft survival revealed an obvious atrophy thymus and severe downregulation of alloimmunity of CD8 subpopulation response to allogenic stimulation.Conclusion Regardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in islet allograft rejection.展开更多
Stem cells are undifferentiated cells capable of self-renewal and differentiation,giving rise to specialized functional cells.Stem cells are of pivotal importance for organ and tissue development,homeostasis,and injur...Stem cells are undifferentiated cells capable of self-renewal and differentiation,giving rise to specialized functional cells.Stem cells are of pivotal importance for organ and tissue development,homeostasis,and injury and disease repair.Tissue-specific stem cells are a rare population residing in specific tissues and present powerful potential for regeneration when required.They are usually named based on the resident tissue,such as hematopoietic stem cells and germline stem cells.This review discusses the recent advances in stem cells of various tissues,including neural stem cells,muscle stem cells,liver progenitors,pancreatic islet stem/progenitor cells,intestinal stem cells,and prostate stem cells,and the future perspectives for tissue stem cell research.展开更多
Background The induced expression of heme oxygenase-1 （HO-1） in donor islets improves allograft survival. Cobalt protoporphyrin （CoPP） could significantly enhance the expression of HO-1 mRNA and protein in rat isl...Background The induced expression of heme oxygenase-1 （HO-1） in donor islets improves allograft survival. Cobalt protoporphyrin （CoPP） could significantly enhance the expression of HO-1 mRNA and protein in rat islet safely. Our work was to study how to protect pancreatic islet xenograft by CoPP-induction. Methods Islet xenografts treated with CoPP-induction and CoPP＋ Zinc protoporphyrin （ZnPP） in vitro and in vivo were randomly transplanted into murine subrenal capsule; then the graft survival time was compared by blood glucose level and pathological examination and meanwhile the interferon ~ （IFN-y）, tumor necrosis factor a （TNF-a）, interleukin 10 （IL-10） and IL-113 level in serum and their mRNA and HO-1 mRNA and protein expression were examined. Results Islets with CoPP-induction under low- and high-glucose stimulation exhibited much higher insulin secretion compared with other three groups. CoPP-induction could increase higher expression of HO-1 （mRNA： 3.33- and 76.09- fold in vitro and in vivo; protein： 2.85- and 58.72-fold）. The normoglycemia time in induction groups （（14.63±1.19） and （16.88±1.64） days） was significantly longer. The pathological examination showed less lymphocyte infiltration in induction groups. The IL-10 level and its mRNA in induction groups were significantly higher. Conclusions The HO-1 induced by CoPP would significantly improve function, prolong normoglycemia time and reduce lymphocyte infiltration. Meanwhile CoPP-induction in vivo had more beneficial effects than in vitro. Its mechanism could be related to immune-modulation of IL-10.展开更多
Glucagon is a potent glucose-elevating hormone that is secreted by pancreaticα-cells.While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypogly...Glucagon is a potent glucose-elevating hormone that is secreted by pancreaticα-cells.While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypoglycaemia,it is increasingly apparent that defects in the regulation of glucagon secretion contribute to impaired counter-regulation and hyperglycaemia in diabetes.It has therefore been proposed that pharmacological interventions targeting glucagon secretion/signalling can have great potential in improving glycaemic control of patients with diabetes.However,despite decades of research,a consensus on the precise mechanisms of glucose regulation of glucagon secretion is yet to be reached.Second messengers are a group of small intracellular molecules that relay extracellular signals to the intracellular signalling cascade,modulating cellular functions.There is a growing body of evidence that second messengers,such as cAMP and Ca^(2+),play critical roles inα-cell glucose-sensing and glucagon secretion.In this review,we discuss the impact of second messengers onα-cell electrical activity,intracellular Ca^(2+)dynamics and cell exocytosis.We highlight the possibility that the interaction between different second messengers may play a key role in the glucose-regulation of glucagon secretion.展开更多
基金funded by the National Natural Science Foundation of China (32371341,31872674)the Scientific and Technologic Foundation of Jilin Province (20230202050NC)the Fundamental Research Funds for the Central Universities (CGZH202206)。
文摘Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.
基金The National Natural Science Foundation of China,No.30500685
文摘AIM： To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism. METHODS： Pdmary rat islets were isolated from male Sprague-Dawley rats by collagenase digestion and treated with different concentrations （1, 3, 10 and 30 μmol/L） of berberine or 1 μmol/L Glibenclamide （GB） for 24 h. Glucose-stimulated insulin secretion （GSIS） assay was conducted and insulin was determined by radioimmunoassay. 3-（4,5-Dimethylthiazol-2-yl）- 2,5-diphenyltetrazolium bromide （MTT） assay was performed to evaluate cytotoxicity. The mRNA level of hepatic nuclear factor 4 alpha （HAIF4α） was determined by reverse transcription polymerase chain reaction （RT-PCR）. Indirect immunofluorescence staining and Western blot analysis were employed to detect protein expression of HNF4α in the islets. Glucokinase （GK） activity was measured by spectrophotometric method. RESULTS： Berberine enhanced GSIS rather than basal insulin secretion dose-dependently in rat islets and showed no significant cytotoxicity on islet cells at the concentration of 10 μmol/L. Both mRNA and protein expressions of HNF4α were up-regulated by berberine in a dose-dependent manner, and GK activity was also increased accordingly. However, GB demonstrated no regulatory effects on HNF4α expression or GK activity. CONCLUSION： Berberine can enhance GSIS in rat islets, and probably exerts the insulinotropic effect via a pathway involving HNF4α and GK, which is distinct from sulphonylureas （SUs）.
基金supported by National Natural Science Foundation of China(Nos.81972893,and 82172719)Excellent Youth Science Foundation of Henan province(212300410071,China)Training program for young key teachers in Henan Province(2020GGJS019,China)。
文摘Type 2 diabetes mellitus(T2DM)therapy is facing the challenges of long-term medication and gradual destruction of pancreatic isletβ-cells.Therefore,it is timely to develop oral prolonged action formulations to improve compliance,while restoringβ-cells survival and function.Herein,we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property,which combined apical sodiumdependent 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.
文摘Objective:To investigate the impact of combining liraglutide with metformin on the enhancement of pancreatic islet function in patients with type 2 diabetes and coronary heart disease.Methods:60 patients with type 2 diabetes and coronary heart disease admitted from February 2022 to August 2023 were selected as research subjects.They were randomly assigned to either control or treatment groups,with 30 patients in each.The control group received metformin alone,while the treatment group received liraglutide in combination with metformin.Various indicators,including blood sugar levels,pancreatic islet function,and cardiac function between the two groups were compared.Results:The results of FPG,2hPG,HbA1c,HOMA-IR,NT-proBNP,and LVEDD in the treatment group were lower than those in the control group,whereas the values of FINS,HOMA-β,E/A,and LVEF in the treatment group were higher than those in the control group(P<0.05).Conclusion:The use of liraglutide in combination with metformin significantly benefits patients with type 2 diabetes and coronary heart disease.It leads to improved pancreatic islet function,better blood sugar control,and enhanced cardiac function.This combination therapy is recommended for clinical adoption.
基金supported by MH CZ-DRO(“Institute for Clinical and Experimental Medicine—IKEM,IN 00023001”)by grant no.TA04010038 from Technology Agency of the Czech Republicby grant no.FV20139 from Ministry of Industry and Trade.
文摘Clostridium histolyticum is used for production of several proteolytic enzymes such as elastase, neutral proteases, clostripain and in particular collagenase. Besides industrial applications, collagenase has been indispensable for medical purposes including isolation of pancreatic islets for diabetes treatment. The aim of this study was to optimize the method for production and partial purification of a new collagenase blend and to test its suitability for successful pancreatic islets isolation in a rat model. Bacterial strain of C. histolyticum was sequenced for presence of the collagenase genes. Different fermentation conditions were tested and the process of collagenase extraction was modified and optimized. Samples of collagenases were taken for western blot detection, activity assessment, and ability for dissociation of pancreatic tissue. Findings indicate that concentrated trypton growth medium with pepton was the most suitable for Clostridium growth and collagenase production. Whole genome sequencing revealed two genes for collagenase and also gene for clostripain. Western blot specific detection helped to select useful production modifications. Following these modifications was also improved the yield, morphology and in vitro function of intact pancreatic islets which were finally comparable or better than those achieved using standard blends of collagenase. The results support the use of the new collagenase blend for islet isolation giving thus the opportunity to choose an alternative product. Our next steps would lead to further enzyme purification through scaling up of the production method for a wider use.
文摘Objective This study aimed to assess the protective value of adiponectin(APN)in pancreatic islet injury induced by chronic intermittent hypoxia(CIH).Methods Sixty rats were randomly divided into three groups:normal control(NC)group,CIH group,and CIH with APN supplement(CIH+APN)group.After 5 weeks of CIH exposure,we conducted oral glucose tolerance tests(OGTT)and insulin released test(IRT),examined and compared the adenosine triphosphate(ATP)levels,mitochondrial membrane potential(MMP)levels,reactive oxygen species(ROS)levels,enzymes gene expression levels of Ant1,Cs,Hmox1,and Cox4 i1 which represented mitochondrial tricarboxylic acid cycle function,the protein and gene expression levels of DRP1,FIS1,MFN1,and OPA1 which represented mitochondrial fusion and division,and the protein expression levels of BAX,BCL-2,cleaved Caspase-3,and cleaved PARP which represented mitochondrial associated apoptosis pathway of pancreatic islet.Results OGTT and IRT showed blood glucose and insulin levels had no differences among the NC,CIH and CIH+APN groups(both P>0.05)at 0 min,20 min,30 min,60 min,120 min.However,we found that compared to NC group,CIH increased the ROS level,reduced ATP level and MMP level.The islets of CIH exposed rats showed reduced gene expression levels of Ant1,Cs,Hmox1,and Cox4 i1,decreased protein and gene expression levels of MFN1 and OPA1,increased protein and gene expression levels of DRP1 and FIS1,increased protein expression levels of cleaved Caspase-3 and cleaved PARP,with lower ratio of BCL-2/BAX at protein expression level.All the differences among three groups were statistically significant.APN treated CIH rats showed mitigated changes in the above measurements associated with islet injuries.Conclusion APN may ameliorate the pancreatic islet injury induced by CIH via inhibiting the imbalance in mitochondrial fusion and division.
文摘BACKGROUND: Islet stem cells are more or less retained in the procedure of islet isolation and purification, and are transplanted together with islet grafts. Keratoprotein (CK-19) and pancreatic duodenal hox gene 1 (PDX-1) are markers of stem cells. This study was undertaken to examine the expression of these markers in pancreatic islet samples of different purity from rats. METHODS: A total of 30 male Sprague-Dawley rats were randomly assigned to 3 groups to undergo perfusion with V-type collagenase via the pancreatic duct, then the pancreas was excised, diced, shaken, digested and centrifuged to obtain islet sediments. The sediment from group A was not purified, while that from group B was purified with 25% Ficoll-400 and that from group C with 25% and 11% Ficoll-400. RNA was extracted from the different islet samples for reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of the pancreatic stem cell markers CK-19 and PDX-1 was assessed. RESULTS: The purity of islets in samples was (43.6 +/- 6.29)% in group A; (65.3 +/- 4.40)% in group B; and (77.6 +/- 6.36)% in group C (P<0.05). The expression of CK-19 and PDX-1 mRNA was significantly higher in group A than in groups B and C, but group C showed the lowest level of expression. CONCLUSION: The expression of CK-19 and PDX-1 mRNA in islet samples of different purity suggests the presence of stem cells in all islet samples.
基金Supported by Important FinancialIssueof Shi-Wu Programming Key Problem in Liaoning Provinceand Financial Issue for Scientific Research in the Department of Education.
文摘Objective To evaluate the effects of acute glucose level changes on expression of prepro-orexin, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) mRNA in rat hypothalamus tissue and pancreatic islets cells. Methods Thirty adult male Wistar rats were randomly divided into three equal groups (n = 10). The acute hypoglycemia rat model was induced by a single subcutaneous injection of insulin. Twenty acute hypoglycemia rats were divided into group B and group C. Group B was allowed to eat freely, while group C was food-deprived. Control rats were injected the same volume of saline. The effect of glucose levels (2.8 mmol/L and 8.3 mmol/L) on pancreatic islet cell orexin system was detected in pancreas islet cell cultured in vitro. The expression of prepro-orexin and OXR mRNA was examined in rat hypothalamus tissue and pancreatic islets cell cultured in vitro using reverse transcription-polymerase chain reaction (RT-PCR). Results Expression of orexin mRNA increased about 150% for the food-deprived hypoglycemia rats in comparison with control group (P < 0.01), whereas expression of OX1R mRNA decreased up to 30% (P < 0.01). However, expression of OX2R mRNA was unchanged in comparison with control group. In vitro, after incubation with 2.8 mmol/L glucose for 6 hours, the expression of prepro-orexin mRNA increased 2 times in rat pancreas islet cells in comparison with 8.3 mmol/L glucose group (P < 0.01). But the expression of OX1R mRNA was not sensitive to acute glucose fluctuation.Conclusions Orexin in rat hypothalamus is stimulated by decline in blood glucose and inhibited by signals related to feeding. Moreover, glucose plays a role in modulating the gene expression of prepro-orexin in rat pancreatic islet cells.
文摘Objective To develop a method for maintaining viability and function of islets of Langerhans during the long term preservation.Methods We encapsulated Wistar Furth (WF) rat islets in hydrophilic macrobeads (diameter 6-8 mm) made with agarose and collagen, then preserved them at 37℃ in a humidified atmosphere of air and 5% CO 2 for different time, and compared unencapsulated islets with encapsulated islets for their insulin secretion capability in vitro. At the same time, we have investigated their viability and insulin secreting function in vivo.Results Initially, there was no statistically significant difference in the insulin secretion values between the encapsulated and unencapsulated WF rat islets. While the unencapsulated islet insulin secretion decreased significantly within 2 weeks, the preserved and encapsulated islets maintained their viability and ability of insulin secretion for 40 weeks. In the in vivo study, the diabetic state was reversed in 92.8% of recipients transplanted with preserved macroencapsulated islets. The mice maintained normoglycemia for 157.6±49.3 days, at which point these macrobeads were retrieved. Glucose tolerance curves in the recipient mice were similar to those of normal mice. Conclusions These results indicate that it is a good method for long term preservation of islets by encapsulating islets in agarose and collagen, and then culturing them at 37℃ in a humidified atmosphere of air and 5% CO 2 before transplantation.
基金Supported by the National Natural Science Foundation of China (30571759).
文摘Objective To investigate in vitro heme oxygenase-1 gene (HO-1) delivery to human pancreatic islets by adenovirus vectors. Methods Recombinant adenovirus containing HO-1 or enhanced green fluorescent protein gene(EGFP) was generated by using the AdEasy System. The purified human pancreatic islets were infected with recombinant adenovirus vectors at various multiplicity of infection (MOI). Transduction was confirmed by fluorescence photographs and Western blot. Glucose-stimulated insulin secretion was detected by using Human insulin radioimmunoassay kits and was used to assess the function of human islets infected by recombinant adenovirus.Results Viral titers of Ad-hHO-1 and Ad-EGFP were 1.96×109 and 1.99×109 pfu/mL, respectively. Human pancreatic islets were efficiently infected by recombinant adenovirus vectors in vitro. Transfection of human islets at an MOI of 20 did not inhibit islet function. Recombinant adenovirus mediated HO-1gene transfer significantly improved the islet function of insulin release when simulated by high level glucose. Conclusion Recombinant adenovirus is efficient to deliver exogenous gene into human pancreatic islets in vitro. HO-1 gene transfection can improve human islet function.
文摘Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes mellitus. A successful whole pancreas or islet transplant offers the advantages of attaining normal or near normal blood glucose control and normal hemoglobin Alc levels without the risks of severe hypoglycemia associate with intensive insulin therapy. Both forms of transplants are also effective at eliminating the occurrence of significant hypoglycemic events （even with only partial islet function evident）. Whereas whole pancreas transplantation has also been shown to be very effective at maintaining a euglycemic state over a sustained period of time, thus providing an opportunity for a recipient to benefit from improvement of their blood glucose control, it is associated with a significant risk of surgical and post-operative complications. Islet transplantation is attractive as a less invasive alternative to whole pancreas transplant and offers the future promise of immunosuppression-free transplantation through pretransplant culture. Islet transplantation however, may not always achieve the sustained level of tight glucose control necessary for reducing the risk of secondary diabetic complications and exposes the patient to the adverse effects of immunosuppression. Although recent advances have led to an increased rate of obtaining insulin-independence following islet transplantation, further developments are needed to improve the longterm viability and function of the graft to maintain improved glucose control over time.
基金This work was supported by National Natural Science Foundation of China, No 30571759
文摘Objective： To investigate the effect of Heme oxygenase-1 （HO-1） gene transfection on the viability of cultured rat islets, and to explore the potential value of HO-1 gene in islet transplantation. Methods：Recombinant adenovirus vector containing human HO-1 gene（Ad-HO-1 ） or enhanced green fluorescent protein gene（Ad-EGFP） was generated by using AdEasy system respectively. The rat islets were transfected with Ad-HO-1, Ad-EGFP or blank vector and then cultured for 7 days. Transfection was confirmed by expression of EGFP and human HO-1 protein detected by fluorescence photographs and western blot, respectively. The insulin release upon different concentration of glucose stimulation was detected using insulin radioimmunoassay kit, and stimulation index（SI） was calculated. Glucose-stimulated insulin release was used ＇to assess islet viability. Results：Adenovirus vector successfully transferred HO-1 gene to rat islet cells in vitro, and the insulin release upon high level of glucose stimulation and stimulation index （SI） of Ad-HO-1-infected islets were significantly higher than those of Ad-EGFP-infected islets and control islets （P 〈 0.05）. Conclusion： Adenovirus-mediated HO-1 gene transfection is a feasible strategy to confer cytoprotection and therefore protect the viability of cultured rat islets.
文摘Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017.The incidence and prevalence of diabetes is predicted to increase.To alleviate this potentially severe situation,safer and more effective therapeutics are urgently required.Mice have long been the mainstay as preclinical models for basic research on diabetes,although they are not ideally suited for translating basic knowledge into clinical applications.To validate and optimize novel therapeutics for safe application in humans,an appropriate large animal model is needed.Large animals,especially pigs, are well suited for biomedical research and share many similarities with humans,including body size,anatomical features,physiology,and pathophysiology.Moreover,pigs already play an important role in translational studies,including clinical trials for xenotransplantation.Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals,including porcine models of diabetes.This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.
文摘The loss of or decreased functional pancreatic β-cell is a major cause of type 1 and type 2 diabetes. Previous studies have shown that adult β-cells can maintain their ability for a low level of turnover through replication and neogenesis. Thus, a strategy to prevent and treat dia- betes would be to enhance the ability of β-cells to increase the mass of functionalβ-cells. Consequently, much effort has been devoted to identify factors that can effectively induce β-cell expansion. This review focuses on recent reports on small molecules and protein fac- tors that have been shown to promote β-cell expansion.
文摘Using enzymatic assay and radioimmunoassay, we studied the functional status of pancreatic islet in 50 patients with acute leukemia. Oral glucose tolerance test and insulin and C peptide release were made in 40 patients before and after treatment .14 patients who revealed diabetic curve and delayed insulin and C peptide release before treatment showed normal values in 6 after therapy. Five patients with impaired glucose tolerance and decreased insulin and C peptide release before treatment showed normalization of these parameters following therapy. Five patients with normal pretreatment values disclosed abnormal post-treatment results. The remaining 16 patients displayed normal results both before and after therapy. Anti-insulin antibodies were negative, and glucagon level was normal in all the 50 patients. The red cell insulin receptor binding rate analysed in 47 patients was significantly higher than in controls (P< 0.001). We considered that the disturbed glucose metabolism in acute leukemia was not uncommon mainly due to the dysfunction of pancreatic islet β cells as a result of islet damage by leukemic cells, the effect of corticosteroid and chemotherapy and the preexisting diabetes. Impaired glucose metabolism had no influence on therapeutic effect.
文摘Background Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103＋ cells from wild type hosts. To circumvent this problem, in the present study, we invented an anti-CD103 immunotoxin （M290-SAP）. We investigated whether M290-SAP has capacity to eliminate CD103-expressing cells in vivo and protect transplanted islets from destroying by host immune cells.Methods Flow cytometry was used to analyze the efficacy of M290-SAP in depleting CD103-expressing cells in vivo.Then using allogenic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, the therapeutic efficacy of CD103-expressing cell depletion was addressed.Results M290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in peripheral lymphatic tissues of treated mice. Balb/c islets transplanted into streptozotocin-induced diabetic C57BL/6 mice under single M290-SAP treatment showed an indefinite survival time compared with untreated mice, M290-treated mice and IgG-SAP treated mice （mean survival time, ＞100 days vs. ＜20 days）. C57BL/6 islets transplanted into hyperglycemic NOD mice under single M290-SAP treatment showed a pronounced delay in allograft rejection compared with untreated mice （mean survival time 12-13 days vs. ＜7 days）. Immunological analysis of mice with long-term islet allograft survival revealed an obvious atrophy thymus and severe downregulation of alloimmunity of CD8 subpopulation response to allogenic stimulation.Conclusion Regardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in islet allograft rejection.
基金supported by grants from the National Natural Science Foundation of China(31988101 and 31730056 to YGC32125013 and 81772723 to DG+15 种基金32170804 to PH31930030 to LH91732301,31671072,31771140,81891001,91432111,81527901,31400977,31625013 to XW31625020,31830056,31861163006 to YAZ)the Ministry of Science and Technology of China(2017YFA0103601 to YGC2020YFA0509000,2017YFA0505500 to DG2017YFA0102700 to PH2019YFA0802001,2019YFA0801503 to LH2017YFA0102601,2019YFA0110100 to XW2020YFA0509002,2019YFA0802002 to YAZ)the Strategic Priority Research Program of the Chinese Academy of Science(XDA16020400 to PHXDA16020200 to YAZ)the Shanghai Science and Technology Commission(21XD1424200,21ZR1470100 to DG)the Basic Frontier Science Research Program of Chinese Academy of Sciences(ZDBS-LY-SM015 to DG)Space Medical Experiment Project of China Manned Space Program(HYZHXM01017 to PH)the Grants of Beijing Brain Initiative of Beijing Municipal Science&Technology Commission(Z181100001518004 to XW)。
文摘Stem cells are undifferentiated cells capable of self-renewal and differentiation,giving rise to specialized functional cells.Stem cells are of pivotal importance for organ and tissue development,homeostasis,and injury and disease repair.Tissue-specific stem cells are a rare population residing in specific tissues and present powerful potential for regeneration when required.They are usually named based on the resident tissue,such as hematopoietic stem cells and germline stem cells.This review discusses the recent advances in stem cells of various tissues,including neural stem cells,muscle stem cells,liver progenitors,pancreatic islet stem/progenitor cells,intestinal stem cells,and prostate stem cells,and the future perspectives for tissue stem cell research.
文摘Background The induced expression of heme oxygenase-1 （HO-1） in donor islets improves allograft survival. Cobalt protoporphyrin （CoPP） could significantly enhance the expression of HO-1 mRNA and protein in rat islet safely. Our work was to study how to protect pancreatic islet xenograft by CoPP-induction. Methods Islet xenografts treated with CoPP-induction and CoPP＋ Zinc protoporphyrin （ZnPP） in vitro and in vivo were randomly transplanted into murine subrenal capsule; then the graft survival time was compared by blood glucose level and pathological examination and meanwhile the interferon ~ （IFN-y）, tumor necrosis factor a （TNF-a）, interleukin 10 （IL-10） and IL-113 level in serum and their mRNA and HO-1 mRNA and protein expression were examined. Results Islets with CoPP-induction under low- and high-glucose stimulation exhibited much higher insulin secretion compared with other three groups. CoPP-induction could increase higher expression of HO-1 （mRNA： 3.33- and 76.09- fold in vitro and in vivo; protein： 2.85- and 58.72-fold）. The normoglycemia time in induction groups （（14.63±1.19） and （16.88±1.64） days） was significantly longer. The pathological examination showed less lymphocyte infiltration in induction groups. The IL-10 level and its mRNA in induction groups were significantly higher. Conclusions The HO-1 induced by CoPP would significantly improve function, prolong normoglycemia time and reduce lymphocyte infiltration. Meanwhile CoPP-induction in vivo had more beneficial effects than in vitro. Its mechanism could be related to immune-modulation of IL-10.
基金EFSD European Research Programme on New Targets for Type 2 Diabetes(Grant/Award Number:96406)Diabetes UK RD Lawrence Fellowship(Grant/Award Number:14/0005128)。
文摘Glucagon is a potent glucose-elevating hormone that is secreted by pancreaticα-cells.While well-controlled glucagon secretion plays an important role in maintaining systemic glucose homeostasis and preventing hypoglycaemia,it is increasingly apparent that defects in the regulation of glucagon secretion contribute to impaired counter-regulation and hyperglycaemia in diabetes.It has therefore been proposed that pharmacological interventions targeting glucagon secretion/signalling can have great potential in improving glycaemic control of patients with diabetes.However,despite decades of research,a consensus on the precise mechanisms of glucose regulation of glucagon secretion is yet to be reached.Second messengers are a group of small intracellular molecules that relay extracellular signals to the intracellular signalling cascade,modulating cellular functions.There is a growing body of evidence that second messengers,such as cAMP and Ca^(2+),play critical roles inα-cell glucose-sensing and glucagon secretion.In this review,we discuss the impact of second messengers onα-cell electrical activity,intracellular Ca^(2+)dynamics and cell exocytosis.We highlight the possibility that the interaction between different second messengers may play a key role in the glucose-regulation of glucagon secretion.
