Experimental Diabetes Research最新文献

{"title":"Vascular stem and progenitor cells in diabetic complications.","authors":"Gian Paolo Fadini, Paolo Madeddu, Johannes Waltenberger, Paolo Fiorina","doi":"10.1155/2012/580343","DOIUrl":"https://doi.org/10.1155/2012/580343","url":null,"abstract":"Hyperglycemia and its associated biochemical abnormalities damage vascular wall cells, especially the endothelium, leading to an increased risk of cardiovascular events and disease, as well as microangiopathy and end-organ complications. In the last decade, accumulating data suggest that vascular repair mechanisms are important to maintain normal homeostasis of the arterial wall and to prevent development of pathologic processes, such as atherosclerosis, restenosis, and microvascular disease. \u0000 \u0000Diabetes mellitus, through the impairment of vascular stem and progenitor cells, entails a defective repair of the injured endothelium. The biochemical and cellular mechanisms that account for reduced or functionally impaired vascular progenitor cells in diabetes are not fully elucidated, and this is an intense area of research. Additionally, therapeutic approaches to modulate the endogenous reparative/regenerative processes are of particular interest in the setting of experimental and clinical diabetes research. \u0000 \u0000For this special issue of Experimental Diabetes Research, we invited investigators to contribute with original research articles and review articles that stimulate the continuing efforts to understand the molecular and cellular aspects underlying defective vascular repair by means of stem/progenitor cells in diabetes, as well as the development of interventions to reverse it. \u0000 \u0000The journal has received a variety of valuable submissions spanning the pathophysiological and therapeutic implications of vascular stem/progenitor cells. \u0000 \u0000The pathophysiological implications are herein described in the setting of both diabetes and the metabolic syndrome. S. Devaraj and I. Jialal report how number and/or functionality of endothelial progenitor cells (EPCs) could emerge as a novel cellular biomarker of endothelial/vascular dysfunction and cardiovascular disease (CVD) risk in patients with the metabolic syndrome. In the setting of diabetes, a focus review highlights the central contribution played by bone-marrow-derived progenitor cells in the development and progression of chronic complications. Not only are EPCs reduced and dysfunctional in diabetes, but they also appear to have a deranged differentiation capacity, which is shifted toward a procalcific phenotype that may have a negative impact on ectopic calcification and atherosclerosis. Of note, circulating progenitor cell phenotypes are not limited to EPC, but may include a variety of lineage-committed cells relevant for the pathobiology of diabetic complications. As an example, the level of pericyte progenitor cells (PPCs) in type 2 diabetes appears to be related to microangiopathy in response to glucose-lowering therapy. Among disparate complications, retinopathy has received a special attention: while G. Tremolada and colleagues provide a comprehensive analysis of the mechanisms of neoangiogenesis in the diabetic retina, R. Longeras et al. show how pigment-epithelium-derived-factor- (PEDF-) 34 ","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":" ","pages":"580343"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/580343","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39971751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dysfunction and β-cell failure in type 2 diabetes mellitus.","authors":"Zhongmin Alex Ma,&nbsp;Zhengshan Zhao,&nbsp;John Turk","doi":"10.1155/2012/703538","DOIUrl":"https://doi.org/10.1155/2012/703538","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is the most common human endocrine disease and is characterized by peripheral insulin resistance and pancreatic islet β-cell failure. Accumulating evidence indicates that mitochondrial dysfunction is a central contributor to β-cell failure in the evolution of T2DM. As reviewed elsewhere, reactive oxygen species (ROS) produced by β-cell mitochondria as a result of metabolic stress activate several stress-response pathways. This paper focuses on mechanisms whereby ROS affect mitochondrial structure and function and lead to β-cell failure. ROS activate UCP2, which results in proton leak across the mitochondrial inner membrane, and this leads to reduced β-cell ATP synthesis and content, which is a critical parameter in regulating glucose-stimulated insulin secretion. In addition, ROS oxidize polyunsaturated fatty acids in mitochondrial cardiolipin and other phospholipids, and this impairs membrane integrity and leads to cytochrome c release into cytosol and apoptosis. Group VIA phospholipase A₂ (iPLA₂β) appears to be a component of a mechanism for repairing mitochondrial phospholipids that contain oxidized fatty acid substituents, and genetic or acquired iPLA₂β-deficiency increases β-cell mitochondrial susceptibility to injury from ROS and predisposes to developing T2DM. Interventions that attenuate ROS effects on β-cell mitochondrial phospholipids might prevent or retard development of T2DM.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"703538"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/703538","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30132348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of aldose reductase activates hepatic peroxisome proliferator-activated receptor-α and ameliorates hepatosteatosis in diabetic db/db mice.","authors":"Longxin Qiu,&nbsp;Jianhui Lin,&nbsp;Fangui Xu,&nbsp;Yuehong Gao,&nbsp;Cuilin Zhang,&nbsp;Ying Liu,&nbsp;Yu Luo,&nbsp;James Y Yang","doi":"10.1155/2012/789730","DOIUrl":"https://doi.org/10.1155/2012/789730","url":null,"abstract":"<p><p>We previously demonstrated in streptozotocin-induced diabetic mice that deficiency or inhibition of aldose reductase (AR) caused significant dephosphorylation of hepatic transcriptional factor PPARα, leading to its activation and significant reductions in serum lipid levels. Herein, we report that inhibition of AR by zopolrestat or by a short-hairpin RNA (shRNA) against AR caused a significant reduction in serum and hepatic triglycerides levels in 10-week old diabetic db/db mice. Meanwhile, hyperglycemia-induced phosphorylation of hepatic ERK1/2 and PPARα was significantly attenuated in db/db mice treated with zopolrestat or AR shRNA. Further, in comparison with the untreated db/db mice, the hepatic mRNA expression of Aco and ApoA5, two target genes for PPARα, was increased by 93% (P < 0.05) and 73% (P < 0.05) in zopolrestat-treated mice, respectively. Together, these data indicate that inhibition of AR might lead to significant amelioration in hyperglycemia-induced dyslipidemia and nonalcoholic fatty liver disease.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"789730"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/789730","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30132349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac insulin resistance and microRNA modulators.","authors":"Lakshmi Pulakat,&nbsp;Annayya R Aroor,&nbsp;Rukhsana Gul,&nbsp;James R Sowers","doi":"10.1155/2012/654904","DOIUrl":"https://doi.org/10.1155/2012/654904","url":null,"abstract":"<p><p>Cardiac insulin resistance is a metabolic and functional disorder that is often associated with obesity and/or the cardiorenal metabolic syndrome (CRS), and this disorder may be accentuated by chronic alcohol consumption. In conditions of over-nutrition, increased insulin (INS) and angiotensin II (Ang II) activate mammalian target for rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2), it also renders cardioprotection via increased Ang II receptor 2 (AT2R) upregulation and adaptive hypertrophy. In the INS-resistant and hyperinsulinemic Zucker obese (ZO) rat, a rodent model for CRS, activation of mTOR/S6K1signaling in cardiac tissue is regulated by protective feed-back mechanisms involving mTOR↔AT2R signaling loop and profile changes of microRNA that target S6K1. Such regulation may play a role in attenuating progressive heart failure. Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"654904"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/654904","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30190267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of metformin in the management of NAFLD.","authors":"Angela Mazza,&nbsp;Barbara Fruci,&nbsp;Giorgia Anna Garinis,&nbsp;Stefania Giuliano,&nbsp;Roberta Malaguarnera,&nbsp;Antonino Belfiore","doi":"10.1155/2012/716404","DOIUrl":"https://doi.org/10.1155/2012/716404","url":null,"abstract":"<p><p>Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Its prevalence ranges 10-24% in the general population, reaching 60-95% and 28-55% in obese and diabetic patients, respectively. Although the etiology of NAFLD is still unclear, several lines of evidences have indicated a pathogenetic role of insulin resistance in this disorder. This concept has stimulated several clinical studies where antidiabetic drugs, such as insulin sensitizers including metformin, have been evaluated in insulin-resistant, NAFLD patients. These studies indicate that metformin might be of benefit in the treatment of NAFLD, also in nondiabetic patients, when associated to hypocaloric diet and weight control. However, the heterogeneity of these studies still prevents us from reaching firm conclusions about treatment guidelines. Moreover, metformin could have beneficial tissue-specific effects in NAFLD patients irrespective of its effects as insulin sensitizer.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"716404"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/716404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30346064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic aerobic exercise induces baroreflex improvement in diabetic rats.","authors":"Luciana Jorge,&nbsp;Demilto Y da Pureza,&nbsp;Danielle da Silva Dias,&nbsp;Filipe Fernandes Conti,&nbsp;Maria-Cláudia Irigoyen,&nbsp;Kátia De Angelis","doi":"10.1155/2012/108680","DOIUrl":"https://doi.org/10.1155/2012/108680","url":null,"abstract":"<p><p>The objective of the present study was to investigate the effects of an acute aerobic exercise on arterial pressure (AP), heart rate (HR), and baroreflex sensitivity (BRS) in STZ-induced diabetic rats. Male Wistar rats were divided into control (n = 8) and diabetic (n = 8) groups. AP, HR, and BRS, which were measured by tachycardic and bradycardic (BR) responses to AP changes, were evaluated at rest (R) and postexercise session (PE) on a treadmill. At rest, STZ diabetes induced AP and HR reductions, associated with BR impairment. Attenuation in resting diabetes-induced AP (R: 103 ± 2 versus PE: 111 ± 3 mmHg) and HR (R: 290 ± 7 versus PE: 328 ± 10 bpm) reductions and BR dysfunction (R: -0.70 ± 0.06 versus PE: -1.21 ± 0.09 bpm/mmHg) was observed in the postexercise period. In conclusion, the hemodynamic and arterial baro-mediated control of circulation improvement in the postexercise period reinforces the role of exercise in the management of cardiovascular risk in diabetes.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"108680"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/108680","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30353510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time-dependent alterations in rat macrovessels with type 1 diabetes.","authors":"Yvonne Searls,&nbsp;Irina V Smirnova,&nbsp;Lisa Vanhoose,&nbsp;Barbara Fegley,&nbsp;Rajprasad Loganathan,&nbsp;Lisa Stehno-Bittel","doi":"10.1155/2012/278620","DOIUrl":"https://doi.org/10.1155/2012/278620","url":null,"abstract":"<p><p>Vascular complications are associated with the progressive severity of diabetes, resulting in significant morbidity and mortality. This study quantifies functional vascular parameters and macrovascular structure in a rat model of type 1 diabetes. While there was no difference in the systemic arterial elastance (Ea) with 50 days of diabetes, changes were noted in the aorta and femoral artery including increased tunica media extracellular matrix content, decreased width of both the media and individual smooth muscle cell layers, and increased incidence of damaged mitochondria. Extracellular matrix proteins and elastin levels were significantly greater in the aorta of diabetic animals. These differences correlated with diminished matrix metalloprotease activity in the aorta of the diabetic animals. In conclusion, diabetes significantly altered the structure and ultrastructure of the aorta and femoral artery before systemic changes in arterial elastance could be detected.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"278620"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/278620","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30443590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial dysfunction in diabetes mellitus: possible involvement of endoplasmic reticulum stress?","authors":"Basma Basha,&nbsp;Samson Mathews Samuel,&nbsp;Chris R Triggle,&nbsp;Hong Ding","doi":"10.1155/2012/481840","DOIUrl":"https://doi.org/10.1155/2012/481840","url":null,"abstract":"<p><p>The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"481840"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/481840","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30551524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of apoptosis pathways by oxidative stress and autophagy in β cells.","authors":"Maorong Wang,&nbsp;Mia Crager,&nbsp;Subbiah Pugazhenthi","doi":"10.1155/2012/647914","DOIUrl":"https://doi.org/10.1155/2012/647914","url":null,"abstract":"<p><p>Human islets isolated for transplantation are exposed to multiple stresses including oxidative stress and hypoxia resulting in significant loss of functional β cell mass. In this study we examined the modulation of apoptosis pathway genes in islets exposed to hydrogen peroxide, peroxynitrite, hypoxia, and cytokines. We observed parallel induction of pro- and antiapoptotic pathways and identified several novel genes including BFAR, CARD8, BNIP3, and CIDE-A. As BNIP3 is an inducer of autophagy, we examined this pathway in MIN6 cells, a mouse beta cell line and in human islets. Culture of MIN6 cells under low serum conditions increased the levels of several proteins in autophagy pathway, including ATG4, Beclin 1, LAMP-2, and UVRAG. Amino acid deprivation led to induction of autophagy in human islets. Preconditioning of islets with inducers of autophagy protected them from hypoxia-induced apoptosis. However, induction of autophagy during hypoxia exacerbated apoptotic cell death. ER stress led to induction of autophagy and apoptosis in β cells. Overexpression of MnSOD, an enzyme that scavenges free radicals, resulted in protection of MIN6 cells from cytokine-induced apoptosis. Ceramide, a mediator of cytokine-induced injury, reduced the active phosphorylated form of Akt and downregulated the promoter activity of the antiapoptotic gene bcl-2. Furthermore, cytokine-stimulated JNK pathway downregulated the bcl-2 promoter activity which was reversed by preincubation with SP600125, a JNK inhibitor. Our findings suggest that β cell apoptosis by multiple stresses in islets isolated for transplantation is the result of orchestrated gene expression in apoptosis pathway.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"647914"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/647914","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30551528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms.","authors":"Biagio Arcidiacono,&nbsp;Stefania Iiritano,&nbsp;Aurora Nocera,&nbsp;Katiuscia Possidente,&nbsp;Maria T Nevolo,&nbsp;Valeria Ventura,&nbsp;Daniela Foti,&nbsp;Eusebio Chiefari,&nbsp;Antonio Brunetti","doi":"10.1155/2012/789174","DOIUrl":"https://doi.org/10.1155/2012/789174","url":null,"abstract":"<p><p>Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"789174"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/789174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30693547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}