Several studies have been reported on the in vitro expansion of stem cells from pancreatic islet (PI-SCs) cultures and on the differentiation of these SCs into multi-lineage cells. These mesenchymal-type cells which exhibit no hormone expression could then be induced to differentiate into hormone-expressing islet-like cell aggregates. It has been shown that human islet-derived precursor cells (hIPCs) were a type of mesenchymal stem cell (MSC). Newly we and some other research groups showed that nestin-positive progenitor/stem cells isolated from islets of human and murine pancreas have phenotypic markers identical to MSCs from bone marrow and that are able to proliferate and differentiate into insulin-producing cells in vitro . We also searched for the transcripts of Oct-4, Rex-1 and Sox-2, because these genes are generally known to be the master regulators of stem cell renewal and differentiation and were expressed by rat pancreatic islet-derived progenitor/stem cells. Therefore, based on our positive outcomes we called them as pancreatic islet-derived stem cells (PI-SCs). We showed by RT-PCR that the nestin-positive cells in the pancreatic islets express neither the hormones insulin, glucagon, somatostatin, or pancreatic polypeptide, nor the markers of embryonic development of endocrine pancreas. Recent studies also recommend that MSCs possess the dual ability to suppress and/or activate the immune responses depending on stimulus to which they are exposed. In addition, MSCs was shown to induce the production of T reg and it was suggested that they could play a potential role in treatment of autoimmune diseases. We studied the protective role of islet derived stem cells in the apoptosis of beta cells. After co-culture of damaged pancreatic islets with pancreatic islet derived stem cells, the expression of regulatory proteins in apoptosis, like Bcl3, TNIP1 (TNFAIP3 interacting protein 1) and MAPKAPK2, were increased under stress in pancreatic islets (unpublished data). The number of viable cells and insulin secretion capacity were preserved in the co culture with stem cells, whereas necrotic bodies were formed in the absence of the stem cells. Under the light of all these findings, SCs of islets like BM-MSCs might have the immunosuppressive and immunomodulatory roles, anti-apoptotic effects and a key function in the evolvement of type 1 diabetes. Therefore, strategies targeting the islet derived MSCs for the correction of the β-cell loss in type 1 diabetes should be established to prevent the destruction of β-cells.
{"title":"Immunosuppressive and Anti-apoptotic Properties of Pancreatic Islet Derived Stem Cells","authors":"E. Karaoz","doi":"10.6092/1590-8577/2786","DOIUrl":"https://doi.org/10.6092/1590-8577/2786","url":null,"abstract":"Several studies have been reported on the in vitro expansion of stem cells from pancreatic islet (PI-SCs) cultures and on the differentiation of these SCs into multi-lineage cells. These mesenchymal-type cells which exhibit no hormone expression could then be induced to differentiate into hormone-expressing islet-like cell aggregates. It has been shown that human islet-derived precursor cells (hIPCs) were a type of mesenchymal stem cell (MSC). Newly we and some other research groups showed that nestin-positive progenitor/stem cells isolated from islets of human and murine pancreas have phenotypic markers identical to MSCs from bone marrow and that are able to proliferate and differentiate into insulin-producing cells in vitro . We also searched for the transcripts of Oct-4, Rex-1 and Sox-2, because these genes are generally known to be the master regulators of stem cell renewal and differentiation and were expressed by rat pancreatic islet-derived progenitor/stem cells. Therefore, based on our positive outcomes we called them as pancreatic islet-derived stem cells (PI-SCs). We showed by RT-PCR that the nestin-positive cells in the pancreatic islets express neither the hormones insulin, glucagon, somatostatin, or pancreatic polypeptide, nor the markers of embryonic development of endocrine pancreas. Recent studies also recommend that MSCs possess the dual ability to suppress and/or activate the immune responses depending on stimulus to which they are exposed. In addition, MSCs was shown to induce the production of T reg and it was suggested that they could play a potential role in treatment of autoimmune diseases. We studied the protective role of islet derived stem cells in the apoptosis of beta cells. After co-culture of damaged pancreatic islets with pancreatic islet derived stem cells, the expression of regulatory proteins in apoptosis, like Bcl3, TNIP1 (TNFAIP3 interacting protein 1) and MAPKAPK2, were increased under stress in pancreatic islets (unpublished data). The number of viable cells and insulin secretion capacity were preserved in the co culture with stem cells, whereas necrotic bodies were formed in the absence of the stem cells. Under the light of all these findings, SCs of islets like BM-MSCs might have the immunosuppressive and immunomodulatory roles, anti-apoptotic effects and a key function in the evolvement of type 1 diabetes. Therefore, strategies targeting the islet derived MSCs for the correction of the β-cell loss in type 1 diabetes should be established to prevent the destruction of β-cells.","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"15 1","pages":"536-536"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TNF-related apoptosis-inducing ligand (TRAIL) is a TNF superfamily member, defined by its high homology to CD95L/FasL and TNF-alpha. It is known for its strong selective apoptotic effect on many transformed cell lines and tumor cells but not in most normal cell types. TRAIL appears to be a more complex molecule than predicted, with a higher therapeutic potential than previously anticipated. This is mainly because it has 5 different receptors that it can bind to in contrast to other TNF family members with one or two receptors; it is expressed widely in human tissues; and it has anti-inflammatory effects. For instance, type 1 diabetes (T1D) development was exacarbated in non-obese diabetic (NOD) mice when TRAIL function was blocked, and TRAIL -/- C57BL/6 mice developed T1D at a much earlier stage following streptozotocin (STZ) injection, compared to mice which displayed normal TRAIL expression. Furthermore, TRAIL displayed a pro-angiogenic effect in primary human vascular endothelial cells. It also induced survival against the apoptosis triggered by pro-inflammatory cytokines in vascular smooth muscle cells, as well as promoting migration and proliferation. Results from studies aiming to clear out the role of TRAIL in diabetes development suggest a protective role for this molecule on beta cells. TRAIL generally does not induce beta cell apoptosis, plays a protective role in these cells against the apoptotic effects of cytokines such as FasL and TNF-alpha, and its receptors are expressed at a significant level in the pancreatic islets. While TRAIL’s role or potential use in diabetes is investigated in various cell and animal systems by many reasearch groups including ours, it is still not clearly identified. Our previous and current results, which mainly support a protective role for TRAIL, will be discussed comparatively with similar and contradictory results of other groups.
{"title":"Role and Potential Therapeutic Use of TRAIL in Diabetes","authors":"A. Şanlioğlu","doi":"10.6092/1590-8577/2784","DOIUrl":"https://doi.org/10.6092/1590-8577/2784","url":null,"abstract":"TNF-related apoptosis-inducing ligand (TRAIL) is a TNF superfamily member, defined by its high homology to CD95L/FasL and TNF-alpha. It is known for its strong selective apoptotic effect on many transformed cell lines and tumor cells but not in most normal cell types. TRAIL appears to be a more complex molecule than predicted, with a higher therapeutic potential than previously anticipated. This is mainly because it has 5 different receptors that it can bind to in contrast to other TNF family members with one or two receptors; it is expressed widely in human tissues; and it has anti-inflammatory effects. For instance, type 1 diabetes (T1D) development was exacarbated in non-obese diabetic (NOD) mice when TRAIL function was blocked, and TRAIL -/- C57BL/6 mice developed T1D at a much earlier stage following streptozotocin (STZ) injection, compared to mice which displayed normal TRAIL expression. Furthermore, TRAIL displayed a pro-angiogenic effect in primary human vascular endothelial cells. It also induced survival against the apoptosis triggered by pro-inflammatory cytokines in vascular smooth muscle cells, as well as promoting migration and proliferation. Results from studies aiming to clear out the role of TRAIL in diabetes development suggest a protective role for this molecule on beta cells. TRAIL generally does not induce beta cell apoptosis, plays a protective role in these cells against the apoptotic effects of cytokines such as FasL and TNF-alpha, and its receptors are expressed at a significant level in the pancreatic islets. While TRAIL’s role or potential use in diabetes is investigated in various cell and animal systems by many reasearch groups including ours, it is still not clearly identified. Our previous and current results, which mainly support a protective role for TRAIL, will be discussed comparatively with similar and contradictory results of other groups.","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"15 1","pages":"535-535"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We recently demonstrated that cells arrested by glucose deprivation proceed into S phase when glucose is replenished only in the presence of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3) – an allosteric activator of phosphofructokinase 1 (PFK1), indicating the necessity to upregulate glycolysis at this stage of the cell cycle. PFKFB3 is expressed only transiently in G1, following a decrease in the activity of the ubiquitin ligase APC/C-Cdh1, implicated in PFKFB3 degradation. In the present study we investigate the functional significance of glycolysis in G1 to S transition. First, we established that PFKFB3 and glycolysis are necessary for the G1 to S phase transition in the cell cycle, since RNAi-mediated silencing of PFKFB3 or inhibition of glucose uptake by 2-deoxyglucose (2-DOG) induced accumulation of cells with DNA content indicative of G1. Next, we observed a strong correlation between PFKFB3 expression, the peak of lactate formation and the appearance of predominantly fused mitochondria at G1 to S transition in synchronized primary human fibroblasts (IMR90) or cancer (HCT 116) cells. The mitochondrial fusion at G1/S was dependent on PFKFB3 and glycolysis since RNAi-mediated silencing of PFKFB3 or inhibition of glucose uptake by 2-DOG abolished mitochondrial fusion, leading to fragmentation of mitochondria. Mdivi-1 prevents mitochondrial fission by inhibiting dynamin-related protein (Drp1). We have observed that this compound induces PFKFB3 expression, mitochondrial fusion and S phase entry (as judged by increased cellular DNA content, the expression of cyclin E and cyclin A and the accumulation of geminin). PFKFB3-silencing or 2-DOG treatment abolished the lactate generation and glycolysis and prevented the mitochondrial fusion and S phase entry induced by Mdivi-1. This could be reversed by overexpression of the glycolytic enzyme phosphofructokinase 1 (PFK1). We have found that increased glycolysis, rather than mitochondrial fusion, is important for initiating S phase, since ectopic expression of PFK1 stimulated starved G0 accumulated cells to enter S phase. S phase entry following the enhancement of glycolysis was accompanied by nuclear exclusion of Foxo3a. This was in turn followed by downregulation of its transcriptional target p27, an inhibitor of CDK2. The reduction in the nuclear levels of Foxo3a was associated with the activation of the IGF-R/Akt axis as shown by the phosphorylation of these proteins upstream of Foxo3a. These results suggest that transient glycolysis is important in the initiation of the S phase through the IGF-1/Akt-dependent nuclear exclusion of Foxo3a, an event which occurs concomitantly with the fusion of mitochondria, both of which are needed for cell cycle progression beyond the G1 phase. Upregulation of glycolytic enzymes was demonstrated in the blood of diabetic patients and shift to glycolysis was demonstrated in diabetes in some organs like heart and pancreas with recent evidence of glucose
{"title":"Transient Glycolysis Enables Mitochondrial Fusion and Stimulates S Phase Entry: The Role of FoxO3a","authors":"Slavica Tudzarova-Trajkovska, S. Moncada","doi":"10.6092/1590-8577/2780","DOIUrl":"https://doi.org/10.6092/1590-8577/2780","url":null,"abstract":"We recently demonstrated that cells arrested by glucose deprivation proceed into S phase when glucose is replenished only in the presence of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3) – an allosteric activator of phosphofructokinase 1 (PFK1), indicating the necessity to upregulate glycolysis at this stage of the cell cycle. PFKFB3 is expressed only transiently in G1, following a decrease in the activity of the ubiquitin ligase APC/C-Cdh1, implicated in PFKFB3 degradation. In the present study we investigate the functional significance of glycolysis in G1 to S transition. First, we established that PFKFB3 and glycolysis are necessary for the G1 to S phase transition in the cell cycle, since RNAi-mediated silencing of PFKFB3 or inhibition of glucose uptake by 2-deoxyglucose (2-DOG) induced accumulation of cells with DNA content indicative of G1. Next, we observed a strong correlation between PFKFB3 expression, the peak of lactate formation and the appearance of predominantly fused mitochondria at G1 to S transition in synchronized primary human fibroblasts (IMR90) or cancer (HCT 116) cells. The mitochondrial fusion at G1/S was dependent on PFKFB3 and glycolysis since RNAi-mediated silencing of PFKFB3 or inhibition of glucose uptake by 2-DOG abolished mitochondrial fusion, leading to fragmentation of mitochondria. Mdivi-1 prevents mitochondrial fission by inhibiting dynamin-related protein (Drp1). We have observed that this compound induces PFKFB3 expression, mitochondrial fusion and S phase entry (as judged by increased cellular DNA content, the expression of cyclin E and cyclin A and the accumulation of geminin). PFKFB3-silencing or 2-DOG treatment abolished the lactate generation and glycolysis and prevented the mitochondrial fusion and S phase entry induced by Mdivi-1. This could be reversed by overexpression of the glycolytic enzyme phosphofructokinase 1 (PFK1). We have found that increased glycolysis, rather than mitochondrial fusion, is important for initiating S phase, since ectopic expression of PFK1 stimulated starved G0 accumulated cells to enter S phase. S phase entry following the enhancement of glycolysis was accompanied by nuclear exclusion of Foxo3a. This was in turn followed by downregulation of its transcriptional target p27, an inhibitor of CDK2. The reduction in the nuclear levels of Foxo3a was associated with the activation of the IGF-R/Akt axis as shown by the phosphorylation of these proteins upstream of Foxo3a. These results suggest that transient glycolysis is important in the initiation of the S phase through the IGF-1/Akt-dependent nuclear exclusion of Foxo3a, an event which occurs concomitantly with the fusion of mitochondria, both of which are needed for cell cycle progression beyond the G1 phase. Upregulation of glycolytic enzymes was demonstrated in the blood of diabetic patients and shift to glycolysis was demonstrated in diabetes in some organs like heart and pancreas with recent evidence of glucose","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"15 1","pages":"531-531"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Type 2 diabetes (T2DM) is characterized by a deficit in pancreatic beta cell mass with increased beta cell apoptosis. Abnormalities of the exocrine pancreas have also been reported in T2DM, including a decreased overall pancreas size and increased pancreatitis. A promising therapy for T2DM emerged from an old observation that ingested glucose enhances insulin secretion to a greater extent than intravenously infused glucose, an observation termed the incretin effect. The hormone glucagon like peptide one (GLP-1) released from endocrine cells in the gut in response to food ingestion was identified as one of the incretin factors. GLP-1 based therapy has been marked for treatment of T2DM, either as injected GLP-1 mimetics or as orally active inhibitors of the enzyme that degrades endogenously secreted GLP-1 (Dipeptidyl peptidase 4, DPP-4). DPP-4 inhibitors and GLP-1 mimetics are effective at lowering blood glucose in T2DM. The concern as regards the unintended actions of GLP-1 based therapy on the exocrine pancreas was first noted in case reports of pancreatitis in individuals treated with the GLP-1 mimetic exenatide, and this was followed by a caution from the Federal Drug Administration (FDA) based on increased reports of pancreatitis noted in the FDA adverse event reporting system (AERS). Subsequent reports of the actions of GLP-1 on the exocrine pancreas have been controversial. Some, but not all studies, have reported an increase in pancreatic size in animal treated with GLP-1 based therapies. In one human study (of brain dead organ donors) we reported an increase in pancreas weight and pancreatic dysplasia in individuals with T2DM exposed to prior therapy with GLP-1 based therapy (7 DPP-4 inhibitors, 1 GLP-1 mimetic). Others have contested those findings. It is our view that the matter is not resolved and that additional studies are required to establish the safety of this widely prescribed class of drugs. Image: Gila monster ( Heloderma suspectum ) venom contains a substance that shares much of its chemistry with human GLP-1. (Author: Blueag9 , Wikimedia Commons )
2型糖尿病(T2DM)的特点是胰腺β细胞数量减少，细胞凋亡增加。外分泌胰腺的异常在T2DM中也有报道，包括胰腺总尺寸减小和胰腺炎增加。一个有希望的治疗T2DM的方法来自于一个古老的观察，即摄入葡萄糖比静脉输注葡萄糖更能促进胰岛素分泌，这一观察结果被称为肠促胰岛素效应。胰高血糖素样肽1 (glucagon like peptide one, GLP-1)是肠道内分泌细胞对食物摄取反应所释放的激素之一。基于GLP-1的治疗已被标记为治疗T2DM，无论是作为注射GLP-1模拟物，还是作为降解内源性分泌GLP-1(二肽基肽酶4,DPP-4)的酶的口服活性抑制剂。DPP-4抑制剂和GLP-1模拟物可有效降低T2DM患者的血糖。关于基于GLP-1的治疗对外分泌胰腺的意外作用的担忧首先在使用GLP-1模拟艾塞那肽治疗的个体胰腺炎的病例报告中被注意到，随后联邦药物管理局(FDA)基于FDA不良事件报告系统(AERS)中胰腺炎报告的增加而发出警告。随后关于GLP-1对外分泌胰腺作用的报道一直存在争议。一些，但不是所有的研究都报道了GLP-1治疗动物胰腺大小的增加。在一项人类研究(脑死亡器官供体)中，我们报道了先前接受GLP-1治疗(7种DPP-4抑制剂，1种GLP-1模拟物)的T2DM患者胰腺重量增加和胰腺发育不良。其他人对这些发现提出了质疑。我们认为，问题尚未解决，需要进一步的研究来确定这类广泛使用的药物的安全性。图片:吉拉怪物(Heloderma susectum)的毒液含有一种与人类GLP-1化学成分相似的物质。(作者:Blueag9，维基共享资源)
{"title":"GLP-1 Based Therapy and the Exocrine Pancreas: Accelerated Dysplasia and Cancer?","authors":"P. Butler","doi":"10.6092/1590-8577/2775","DOIUrl":"https://doi.org/10.6092/1590-8577/2775","url":null,"abstract":"Type 2 diabetes (T2DM) is characterized by a deficit in pancreatic beta cell mass with increased beta cell apoptosis. Abnormalities of the exocrine pancreas have also been reported in T2DM, including a decreased overall pancreas size and increased pancreatitis. A promising therapy for T2DM emerged from an old observation that ingested glucose enhances insulin secretion to a greater extent than intravenously infused glucose, an observation termed the incretin effect. The hormone glucagon like peptide one (GLP-1) released from endocrine cells in the gut in response to food ingestion was identified as one of the incretin factors. GLP-1 based therapy has been marked for treatment of T2DM, either as injected GLP-1 mimetics or as orally active inhibitors of the enzyme that degrades endogenously secreted GLP-1 (Dipeptidyl peptidase 4, DPP-4). DPP-4 inhibitors and GLP-1 mimetics are effective at lowering blood glucose in T2DM. The concern as regards the unintended actions of GLP-1 based therapy on the exocrine pancreas was first noted in case reports of pancreatitis in individuals treated with the GLP-1 mimetic exenatide, and this was followed by a caution from the Federal Drug Administration (FDA) based on increased reports of pancreatitis noted in the FDA adverse event reporting system (AERS). Subsequent reports of the actions of GLP-1 on the exocrine pancreas have been controversial. Some, but not all studies, have reported an increase in pancreatic size in animal treated with GLP-1 based therapies. In one human study (of brain dead organ donors) we reported an increase in pancreas weight and pancreatic dysplasia in individuals with T2DM exposed to prior therapy with GLP-1 based therapy (7 DPP-4 inhibitors, 1 GLP-1 mimetic). Others have contested those findings. It is our view that the matter is not resolved and that additional studies are required to establish the safety of this widely prescribed class of drugs. Image: Gila monster ( Heloderma suspectum ) venom contains a substance that shares much of its chemistry with human GLP-1. (Author: Blueag9 , Wikimedia Commons )","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"15 1","pages":"527-527"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
While long-standing diabetes (DM) modestly increases the risk of pancreatic ductal adenocarcinoma (PC), there is growing evidence that PC frequently causes DM. Up to 85% of PC patients have DM or hyperglycemia, which frequently manifests in the 2 to 3 years preceding the diagnosis of cancer. Conversely, subjects with new-onset DM have a high probability (5-8 folds higher than the population) of being diagnosed with PC within 1-3 years of DM onset. Resection of the PC leads to amelioration of DM. Type 2 DM occurs due to beta cell failure following decades of obesity-associated insulin resistance. As in type 2 DM, beta cell dysfunction and peripheral insulin resistance are seen in PC-induced DM (PC-DM). However, in contrast to type 2 DM, onset and progression of glucose intolerance in PC-DM occur in the face of ongoing, often profound, weight loss. The weight loss precedes the development of DM in PC and occurs months before the onset of cancer cachexia. Studies show that PC is associated with profound insulin resistance that resolves following PC resection. However, the very high frequency of DM suggests that there is associated beta cell dysfunction. There are many hypotheses for how PC might cause DM: a) Is PC-DM simply type 2 DM? Canonical risk factors for DM (age, BMI and family history of DM) are also risk factors for PCDM. However, the fact that new-onset DM and hyperglycemia occur in 85% of PC suggest a PC-specific stressor that profoundly and consistently decompensates glucose homeostasis. b) Could PCDM be a consequence of profound cachexia seen in PC? Cachexia is associated with insulin resistance which could potentially decompensate glues homeostasis, especially in the elderly. This is unlikely to explain PCDM as. c) Could obstruction of the pancreatic duct and consequent pancreatic atrophy cause PCDM? PC is frequently associated with obstructive pancreatitis and distal atrophy. However, onset of DM occurs at a time when CT does not even show a mass. Additionally, insulin levels would be expected to be low in patients with DM due to destruction of islet mass. Insulin levels are relatively high in PCDM, reflecting insulin resistance. d) The most likely explanation for the frequent occurrence of DM in PC is that it is a paraneoplastic phenomenon caused by tumor secreted products. Apart from the clinical and epidemiological evidence noted above, this notion is supported by laboratory data that supernatant from PC cell lines inhibit insulin secretion. Although much remains to be learned, new insights on the pathogenesis of these metabolic alterations in PC have recently emerged. Adrenomedullin, which is over-expressed in PC, was identified as a potential mediator of beta-cell dysfunction in PCDM. Adrenomedullin is a pluripotent hormone with homology semblance to amylin. In the pancreas, its receptors are found on beta cells and its expression is seen specifically in the F cells of the islets. Inhibition of insulin secretion in beta cells ind
{"title":"Mechanism(s) of Pancreatic Cancer-induced Diabetes","authors":"S. Chari","doi":"10.6092/1590-8577/2777","DOIUrl":"https://doi.org/10.6092/1590-8577/2777","url":null,"abstract":"While long-standing diabetes (DM) modestly increases the risk of pancreatic ductal adenocarcinoma (PC), there is growing evidence that PC frequently causes DM. Up to 85% of PC patients have DM or hyperglycemia, which frequently manifests in the 2 to 3 years preceding the diagnosis of cancer. Conversely, subjects with new-onset DM have a high probability (5-8 folds higher than the population) of being diagnosed with PC within 1-3 years of DM onset. Resection of the PC leads to amelioration of DM. Type 2 DM occurs due to beta cell failure following decades of obesity-associated insulin resistance. As in type 2 DM, beta cell dysfunction and peripheral insulin resistance are seen in PC-induced DM (PC-DM). However, in contrast to type 2 DM, onset and progression of glucose intolerance in PC-DM occur in the face of ongoing, often profound, weight loss. The weight loss precedes the development of DM in PC and occurs months before the onset of cancer cachexia. Studies show that PC is associated with profound insulin resistance that resolves following PC resection. However, the very high frequency of DM suggests that there is associated beta cell dysfunction. There are many hypotheses for how PC might cause DM: a) Is PC-DM simply type 2 DM? Canonical risk factors for DM (age, BMI and family history of DM) are also risk factors for PCDM. However, the fact that new-onset DM and hyperglycemia occur in 85% of PC suggest a PC-specific stressor that profoundly and consistently decompensates glucose homeostasis. b) Could PCDM be a consequence of profound cachexia seen in PC? Cachexia is associated with insulin resistance which could potentially decompensate glues homeostasis, especially in the elderly. This is unlikely to explain PCDM as. c) Could obstruction of the pancreatic duct and consequent pancreatic atrophy cause PCDM? PC is frequently associated with obstructive pancreatitis and distal atrophy. However, onset of DM occurs at a time when CT does not even show a mass. Additionally, insulin levels would be expected to be low in patients with DM due to destruction of islet mass. Insulin levels are relatively high in PCDM, reflecting insulin resistance. d) The most likely explanation for the frequent occurrence of DM in PC is that it is a paraneoplastic phenomenon caused by tumor secreted products. Apart from the clinical and epidemiological evidence noted above, this notion is supported by laboratory data that supernatant from PC cell lines inhibit insulin secretion. Although much remains to be learned, new insights on the pathogenesis of these metabolic alterations in PC have recently emerged. Adrenomedullin, which is over-expressed in PC, was identified as a potential mediator of beta-cell dysfunction in PCDM. Adrenomedullin is a pluripotent hormone with homology semblance to amylin. In the pancreas, its receptors are found on beta cells and its expression is seen specifically in the F cells of the islets. Inhibition of insulin secretion in beta cells ind","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"15 1","pages":"528-528"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pancreatic cancer is the tenth most common cancer diagnosis; however, it is the fourth most common cause of death due to cancer. Recent estimates suggest that by 2020 pancreatic cancer will become the second most common cause of cancer death in the US. The 5-year survival rate in all patients is only ~5% and has not changed significantly over the past five decades. Though the relationship between diabetes mellitus and pancreatic cancer has been known for over 125 years, it still remains to be fully understood. The complex relationship between the two diseases has been the subject of numerous clinical, epidemiological, laboratory and experimental studies. Epidemiologic studies suggest that long-standing type 2 diabetes is a modest risk factor for the development of pancreatic cancer. Meta-analysis of multiple cohort and case-control studies show that the risk of pancreatic cancer in those with diabetes for >5 years is 1.5 to 2.0 fold higher. This s not fully explained by shared risk factors between the two diseases such as obesity. There is also strong clinical, epidemiological and experimental evidence to show that pancreatic cancer causes diabetes. Hyperglycemia and diabetes mellitus occur in ~85% of pancreatic cancer subjects, with diabetes being present in 45% to 67% of pancreatic cancer patients depending on how diabetes is ascertained. Majority (~75%) of diabetes in pancreatic cancer is new-onset, i.e., less than 3 years in duration. The new-onset diabetes often resolves with resection of cancer. The notion that new-onset diabetes in pancreatic cancer is a paraneoplastic phenomenon caused by tumor secreted products was strengthened by a recent study that proposed adrenomedullin, a 52 amino-acid polypeptide, as a strong candidate for mediator of diabetes in pancreatic cancer. In previous studies adrenomedullin has been shown not only to promote pancreatic cancer aggressiveness, but also inhibits insulin exocytosis from beta cells. In the aforementioned study pancreatic cancer cell lines overexpressing adrenomedullin were shown to inhibit insulin secretion, an effect that was reversed by silencing adrenomedullin. Adrenomedullin was also shown to be overexpressed in human pancreatic cancer and plasma levels of adrenomedullin were also increased in pancreatic cancer patients, especially those with diabetes. New-onset diabetes appears to be the only clue to the presence of asymptomatic sporadic pancreatic cancer. Nearly 25% of patients with pancreatic cancer are diagnosed with diabetes 6 months to 36 months before the diagnosis of pancreatic cancer. Conversely, subjects with new-onset diabetes over age 50 years have an 8-fold higher risk for having pancreatic cancer. Thus new-onset diabetes may be a clue to the early diagnosis of the cancer. However, the success of the strategy to use new-onset diabetes as a marker of pancreatic cancer will depend on our ability to distinguish pancreatic cancer-associate diabetes from the more common type 2 diabe
{"title":"New-onset Diabetes: A Clue to the Early Diagnosis of Pancreatic Cancer","authors":"S. Chari","doi":"10.6092/1590-8577/2778","DOIUrl":"https://doi.org/10.6092/1590-8577/2778","url":null,"abstract":"Pancreatic cancer is the tenth most common cancer diagnosis; however, it is the fourth most common cause of death due to cancer. Recent estimates suggest that by 2020 pancreatic cancer will become the second most common cause of cancer death in the US. The 5-year survival rate in all patients is only ~5% and has not changed significantly over the past five decades. Though the relationship between diabetes mellitus and pancreatic cancer has been known for over 125 years, it still remains to be fully understood. The complex relationship between the two diseases has been the subject of numerous clinical, epidemiological, laboratory and experimental studies. Epidemiologic studies suggest that long-standing type 2 diabetes is a modest risk factor for the development of pancreatic cancer. Meta-analysis of multiple cohort and case-control studies show that the risk of pancreatic cancer in those with diabetes for >5 years is 1.5 to 2.0 fold higher. This s not fully explained by shared risk factors between the two diseases such as obesity. There is also strong clinical, epidemiological and experimental evidence to show that pancreatic cancer causes diabetes. Hyperglycemia and diabetes mellitus occur in ~85% of pancreatic cancer subjects, with diabetes being present in 45% to 67% of pancreatic cancer patients depending on how diabetes is ascertained. Majority (~75%) of diabetes in pancreatic cancer is new-onset, i.e., less than 3 years in duration. The new-onset diabetes often resolves with resection of cancer. The notion that new-onset diabetes in pancreatic cancer is a paraneoplastic phenomenon caused by tumor secreted products was strengthened by a recent study that proposed adrenomedullin, a 52 amino-acid polypeptide, as a strong candidate for mediator of diabetes in pancreatic cancer. In previous studies adrenomedullin has been shown not only to promote pancreatic cancer aggressiveness, but also inhibits insulin exocytosis from beta cells. In the aforementioned study pancreatic cancer cell lines overexpressing adrenomedullin were shown to inhibit insulin secretion, an effect that was reversed by silencing adrenomedullin. Adrenomedullin was also shown to be overexpressed in human pancreatic cancer and plasma levels of adrenomedullin were also increased in pancreatic cancer patients, especially those with diabetes. New-onset diabetes appears to be the only clue to the presence of asymptomatic sporadic pancreatic cancer. Nearly 25% of patients with pancreatic cancer are diagnosed with diabetes 6 months to 36 months before the diagnosis of pancreatic cancer. Conversely, subjects with new-onset diabetes over age 50 years have an 8-fold higher risk for having pancreatic cancer. Thus new-onset diabetes may be a clue to the early diagnosis of the cancer. However, the success of the strategy to use new-onset diabetes as a marker of pancreatic cancer will depend on our ability to distinguish pancreatic cancer-associate diabetes from the more common type 2 diabe","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"15 1","pages":"529-529"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Several epidemiology studies have observed that there is a higher than expected association between diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDAC). However, because no plausible mechanistic link exists between high glucose levels and carcinogenesis, additional risk factors are likely involved. Evaluating these epidemiologic data has been confounded by difficulty in identifying appropriate control populations and in replicating the demographics and risk found in previous studies. Furthermore, a significant subset of patients developed DM up to 2 years before the detection of cancer, suggesting that the glucose intolerance in these patients is a paraneoplastic syndrome linked to factors released from the tumor rather than typical type 1 or type 2 DM. Indeed, DM is a major co-morbidity of PDAC and is often reversed following resection of the cancer and a major part of the pancreas, while in other cases, pancreatic resection leads to DM. Finally, the DM may be associated with previous acute pancreatitis and/or subclinical chronic pancreatitis, so that the diagnosis of pancreatitis is often missed. The pancreatitis factor is important since the link between pancreatitis and pancreatic cancer is well established and a close temporal link between pancreatitis and diabetes in known. In these cases the primary epidemiology association is between DM and pancreatitis rather, and secondarily, there is a mechanistic association between pancreatitis and PDAC. To date, though, pancreatitis and pancreatogenic DM (Type 3c) has not been adequately assessed in a major epidemiology study. These observations indicate that glucose intolerance is non-specific, that PDAC can cause DM, and that pancreatitis may be an important missing link between DM and PDAC. Thus, new carefully controlled studies are needed to better understand the underlying cause of the association of PDAC with DM.
{"title":"Diabetes and Cancer: The Problem of Reverse Causality and Missing Links","authors":"D. Whitcomb","doi":"10.6092/1590-8577/2772","DOIUrl":"https://doi.org/10.6092/1590-8577/2772","url":null,"abstract":"Several epidemiology studies have observed that there is a higher than expected association between diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDAC). However, because no plausible mechanistic link exists between high glucose levels and carcinogenesis, additional risk factors are likely involved. Evaluating these epidemiologic data has been confounded by difficulty in identifying appropriate control populations and in replicating the demographics and risk found in previous studies. Furthermore, a significant subset of patients developed DM up to 2 years before the detection of cancer, suggesting that the glucose intolerance in these patients is a paraneoplastic syndrome linked to factors released from the tumor rather than typical type 1 or type 2 DM. Indeed, DM is a major co-morbidity of PDAC and is often reversed following resection of the cancer and a major part of the pancreas, while in other cases, pancreatic resection leads to DM. Finally, the DM may be associated with previous acute pancreatitis and/or subclinical chronic pancreatitis, so that the diagnosis of pancreatitis is often missed. The pancreatitis factor is important since the link between pancreatitis and pancreatic cancer is well established and a close temporal link between pancreatitis and diabetes in known. In these cases the primary epidemiology association is between DM and pancreatitis rather, and secondarily, there is a mechanistic association between pancreatitis and PDAC. To date, though, pancreatitis and pancreatogenic DM (Type 3c) has not been adequately assessed in a major epidemiology study. These observations indicate that glucose intolerance is non-specific, that PDAC can cause DM, and that pancreatitis may be an important missing link between DM and PDAC. Thus, new carefully controlled studies are needed to better understand the underlying cause of the association of PDAC with DM.","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"15 1","pages":"524-524"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Epidemiological studies revealed a connection between several types of cancer and type 2 diabetes (T2D), and suggested that T2D is both a symptom and a risk factor of pancreatic cancer. High level of circulating insulin (hyperinsulinemia) associated with obesity has been implicated in promoting aggressive types of cancers. Peripheral insulin resistance, a symptom/risk factor of T2D, pressures pancreatic b-cells to increase insulin secretion, which results in hyperinsulinemia. This in turn, is believed to lead to a poorly understood gradual loss of functional b-cell mass, thus suggesting the existence of a fine-balance and interplay between b-cell function and mass. While the mechanisms of these connections are unclear, the mammalian target of rapamycin complex 1 (mTORC1) pathway has been implicated in controlling b-cell function and mass, and mediating a link between cancer and T2D. However, the mechanism by which the mTOR pathway does so remains unclear. Moreover, incomplete understating of how the pathway is regulated and how it integrates body metabolism has hindered its efficacy as a clinical target. The IQ motif containing GTPase-activating protein 1 (IQGAP1) is a growth factor- and nutrient-sensor that couples cell growth and division, and regulates glucose-stimulated insulin secretion from b-cells. Dysregulation of IQGAP1 is associated in humans with several carcinomas and with T2D. Here we discuss how IQGAP1, through differential interactions with Rho-type of small guanosine triphosphatases (GTPases), acts as a rheostat that fine-tunes the mTORC1 and the mitogen-activated protein kinase (MAPK) signals, and potentially integrates b-cell function and mass with insulin action. Dysfunction of IQGAP1 provides a plausible molecular mechanism for understanding cancer initiation in diabetes, and a potential clinical target for treating both cancer and diabetes with high selectivity.
{"title":"Role of Signal Dynamics in the Link Between Type 2 Diabetes and Cancer","authors":"Mahasin A. Osman","doi":"10.6092/1590-8577/2779","DOIUrl":"https://doi.org/10.6092/1590-8577/2779","url":null,"abstract":"Epidemiological studies revealed a connection between several types of cancer and type 2 diabetes (T2D), and suggested that T2D is both a symptom and a risk factor of pancreatic cancer. High level of circulating insulin (hyperinsulinemia) associated with obesity has been implicated in promoting aggressive types of cancers. Peripheral insulin resistance, a symptom/risk factor of T2D, pressures pancreatic b-cells to increase insulin secretion, which results in hyperinsulinemia. This in turn, is believed to lead to a poorly understood gradual loss of functional b-cell mass, thus suggesting the existence of a fine-balance and interplay between b-cell function and mass. While the mechanisms of these connections are unclear, the mammalian target of rapamycin complex 1 (mTORC1) pathway has been implicated in controlling b-cell function and mass, and mediating a link between cancer and T2D. However, the mechanism by which the mTOR pathway does so remains unclear. Moreover, incomplete understating of how the pathway is regulated and how it integrates body metabolism has hindered its efficacy as a clinical target. The IQ motif containing GTPase-activating protein 1 (IQGAP1) is a growth factor- and nutrient-sensor that couples cell growth and division, and regulates glucose-stimulated insulin secretion from b-cells. Dysregulation of IQGAP1 is associated in humans with several carcinomas and with T2D. Here we discuss how IQGAP1, through differential interactions with Rho-type of small guanosine triphosphatases (GTPases), acts as a rheostat that fine-tunes the mTORC1 and the mitogen-activated protein kinase (MAPK) signals, and potentially integrates b-cell function and mass with insulin action. Dysfunction of IQGAP1 provides a plausible molecular mechanism for understanding cancer initiation in diabetes, and a potential clinical target for treating both cancer and diabetes with high selectivity.","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"10 3 1","pages":"530-530"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Beta cell loss/impairment of function appears as a significant problem in both type 1 and type 2 diabetes. TRAIL (TNF-related apoptosis-inducing ligand) was recently correlated with both types of diabetes with a proposed protective effect. TRAIL was also shown to promote survival and proliferation in different cells such as vascular smooth muscle cells and human vascular endothelial cells. Recently, TRAIL was claimed to protect pancreatic beta cells against cytokine-related harm. We hypothesized a proliferative effect for TRAIL on beta cells, and used Min6 mouse pancreatic beta cell line to test our hypothesis. Min6 cells were treated with various doses of (0, 0.1, 1, 10, 100 ng/mL) soluble TRAIL molecule (sTRAIL) for 24, 48, and 72 hours. Survival and proliferation tests (WST-1 and Ki67, respectively) were performed. Phosphorylation levels of intracellular ERK, p38, and Akt molecules were studied by western blotting. We found that sTRAIL did not lead to apoptosis in Min6 cells, but increased survival and induced proliferation at 10 ng/mL dose. ERK and p38 phosphorylation was induced substantially, and Akt was phosphorylated at a lower degree in these cells. Our results suggest that sTRAIL increases cell survival and proliferation in Min6 mouse pancreatic beta cell line. These findings, while requiring further investigation, support a possible therapeutic role for TRAIL in diabetes. Acknowledgements This study was supported by grants from Tubitak, Ankara, Turkey (112S450), and Akdeniz University research fund 2012.03.0122.003 Image: Structure of the TNFSF10 protein. Based on PyMOL rendering of PDB 1d0g (Author: Emw , Wikimedia Commons )
{"title":"Proliferative Effect of sTRAIL on Mouse Pancreatic Beta Cells","authors":"S. Kahraman, E. Dirice, H. Altunbas, A. Şanlioğlu","doi":"10.6092/1590-8577/2790","DOIUrl":"https://doi.org/10.6092/1590-8577/2790","url":null,"abstract":"Beta cell loss/impairment of function appears as a significant problem in both type 1 and type 2 diabetes. TRAIL (TNF-related apoptosis-inducing ligand) was recently correlated with both types of diabetes with a proposed protective effect. TRAIL was also shown to promote survival and proliferation in different cells such as vascular smooth muscle cells and human vascular endothelial cells. Recently, TRAIL was claimed to protect pancreatic beta cells against cytokine-related harm. We hypothesized a proliferative effect for TRAIL on beta cells, and used Min6 mouse pancreatic beta cell line to test our hypothesis. Min6 cells were treated with various doses of (0, 0.1, 1, 10, 100 ng/mL) soluble TRAIL molecule (sTRAIL) for 24, 48, and 72 hours. Survival and proliferation tests (WST-1 and Ki67, respectively) were performed. Phosphorylation levels of intracellular ERK, p38, and Akt molecules were studied by western blotting. We found that sTRAIL did not lead to apoptosis in Min6 cells, but increased survival and induced proliferation at 10 ng/mL dose. ERK and p38 phosphorylation was induced substantially, and Akt was phosphorylated at a lower degree in these cells. Our results suggest that sTRAIL increases cell survival and proliferation in Min6 mouse pancreatic beta cell line. These findings, while requiring further investigation, support a possible therapeutic role for TRAIL in diabetes. Acknowledgements This study was supported by grants from Tubitak, Ankara, Turkey (112S450), and Akdeniz University research fund 2012.03.0122.003 Image: Structure of the TNFSF10 protein. Based on PyMOL rendering of PDB 1d0g (Author: Emw , Wikimedia Commons )","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"15 1","pages":"540-540"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
All patients with type 1 diabetes (T1DM) and most patients with type 2 diabetes (T2DM) become insulin dependent due to the progressive nature of the disease, eventually leading to beta-cell loss. The increase in apoptosis, but not the decrease in new islet formation or beta-cell replication, is blamed for the loss of beta-cell mass observed in patients with T2DM. Thus, therapeutic approaches that either interfere with apoptosis of beta cells and/or increase beta-cell mass have the potential not only for managing hyperglycemia but also for reversing disease progression. Vasoactive intestinal peptide (VIP) is a neuropeptide of the secretin family just like GLP1 and PACAP with equipotent insulinotropic effects. More importantly, it is an effective anti-inflammatory agent involved in suppression of Th1 immune response and activation of regulatory T cells for inducing immune tolerance. For this reason, VIP is now considered to be an emerging therapeutic agent for autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, multiple sclerosis, and T1DM. Despite all these advantages, VIP is extremely sensitive to peptidases (DPP-4) present in most tissues. Thus, multiple injections of VIP at high doses are required to observe any therapeutic effect. Contrary to using peptide forms of therapeutic agents, some gene therapy vectors can provide long-term and stable gene expression. Thus, viral and non-viral VIP gene delivery methods have been under development. Despite the successful results obtained from these studies, especially against autoimmune diseases, some limitations of using gene therapy vectors were revealed in recent studies. For example, the clinical efficacy of plasmid DNA transfer is low. Adenoviral vectors only provide transient gene expression due to the antigenic character of adenoviral epitopes. AAV has limited cargo capacity and low transduction efficiency. Compared with other gene therapy vectors, lentiviral vectors appear to be the vector of choice when considering long-term gene expression, transduction efficacy, and safety. Consequently, the testing of the efficacy of lentivirus-mediated VIP gene delivery against diabetes became an essential issue to discuss in experimental animal model of diabetes.
{"title":"Vasoactive Intestinal Peptide-mediated Gene Therapy for Diabetes","authors":"S. Sanlioglu","doi":"10.6092/1590-8577/2783","DOIUrl":"https://doi.org/10.6092/1590-8577/2783","url":null,"abstract":"All patients with type 1 diabetes (T1DM) and most patients with type 2 diabetes (T2DM) become insulin dependent due to the progressive nature of the disease, eventually leading to beta-cell loss. The increase in apoptosis, but not the decrease in new islet formation or beta-cell replication, is blamed for the loss of beta-cell mass observed in patients with T2DM. Thus, therapeutic approaches that either interfere with apoptosis of beta cells and/or increase beta-cell mass have the potential not only for managing hyperglycemia but also for reversing disease progression. Vasoactive intestinal peptide (VIP) is a neuropeptide of the secretin family just like GLP1 and PACAP with equipotent insulinotropic effects. More importantly, it is an effective anti-inflammatory agent involved in suppression of Th1 immune response and activation of regulatory T cells for inducing immune tolerance. For this reason, VIP is now considered to be an emerging therapeutic agent for autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, multiple sclerosis, and T1DM. Despite all these advantages, VIP is extremely sensitive to peptidases (DPP-4) present in most tissues. Thus, multiple injections of VIP at high doses are required to observe any therapeutic effect. Contrary to using peptide forms of therapeutic agents, some gene therapy vectors can provide long-term and stable gene expression. Thus, viral and non-viral VIP gene delivery methods have been under development. Despite the successful results obtained from these studies, especially against autoimmune diseases, some limitations of using gene therapy vectors were revealed in recent studies. For example, the clinical efficacy of plasmid DNA transfer is low. Adenoviral vectors only provide transient gene expression due to the antigenic character of adenoviral epitopes. AAV has limited cargo capacity and low transduction efficiency. Compared with other gene therapy vectors, lentiviral vectors appear to be the vector of choice when considering long-term gene expression, transduction efficacy, and safety. Consequently, the testing of the efficacy of lentivirus-mediated VIP gene delivery against diabetes became an essential issue to discuss in experimental animal model of diabetes.","PeriodicalId":47280,"journal":{"name":"Journal of the Pancreas","volume":"15 1","pages":"534-534"},"PeriodicalIF":0.2,"publicationDate":"2014-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71234680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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