The direct effects of tacrolimus and cyclosporin A on isolated human islets: A functional, survival and gene expression study

Bugliani, Marco; Masini, Matilde; Liechti, Robin; Marselli, Lorella; Xénarios, Ioannis; Boggi, Ugo; Filipponi, Franco; Masiello, Pellegrino; Marchetti, Piero

doi:10.4161/isl.1.2.9142

Cited by 34 publications

(28 citation statements)

References 28 publications

(43 reference statements)

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“…CsA is a diabetogenic agent when its use is prolonged [36] Indeed, posttransplant diabetes mellitus (PTDM) induced by CsA treatment is a frequent and serious complication after solid organ transplantation, and is considered to be a type of secondary diabetes mellitus involving impaired insulin secretion and insulin resistance [2]. Although information about this condition is increasing, the ultimate mechanisms underlying CsA-induced diabetes and related complications are not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Oral Administration of Ginseng Ameliorates Cyclosporine-Induced Pancreatic Injury in an Experimental Mouse Model

et al. 2013

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BackgroundThis study was performed to investigate whether ginseng has a protective effect in an experimental mouse model of cyclosporine-induced pancreatic injury.MethodsMice were treated with cyclosporine (30 mg/kg/day, subcutaneously) and Korean red ginseng extract (0.2 or 0.4 g/kg/day, oral gavage) for 4 weeks while on a 0.01% salt diet. The effect of ginseng on cyclosporine-induced pancreatic islet dysfunction was investigated by an intraperitoneal glucose tolerance test and measurements of serum insulin level, β cell area, macrophage infiltration, and apoptosis. Using an in vitro model, we further examined the effect of ginseng on a cyclosporine-treated insulin-secreting cell line. Oxidative stress was measured by the concentration of 8-hydroxy-2′-deoxyguanosine in serum, tissue sections, and culture media.ResultsFour weeks of cyclosporine treatment increased blood glucose levels and decreased insulin levels, but cotreatment with ginseng ameliorated the cyclosporine-induced glucose intolerance and hyperglycemia. Pancreatic β cell area was also greater with ginseng cotreatment compared with cyclosporine monotherapy. The production of proinflammatory molecules, such as induced nitric oxide synthase and cytokines, and the level of apoptotic cell death also decreased in pancreatic β cell with ginseng treatment. Consistent with the in vivo results, the in vitro study showed that the addition of ginseng protected against cyclosporine-induced cytotoxicity, inflammation, and apoptotic cell death. These in vivo and in vitro changes were accompanied by decreases in the levels of 8-hydroxy-2′-deoxyguanosine in pancreatic β cell in tissue section, serum, and culture media during cotreatment of ginseng with cyclosporine.ConclusionsThe results of our in vivo and in vitro studies demonstrate that ginseng has a protective effect against cyclosporine-induced pancreatic β cell injury via reducing oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Oral Administration of Ginseng Ameliorates Cyclosporine-Induced Pancreatic Injury in an Experimental Mouse Model

et al. 2013

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“…Ex vivo insulin secretion from human islets The details of these experiments have been provided elsewhere [24][25][26]. Briefly, islet samples were kept for 45 min at 37°C in KRB, 0.5% (vol./vol.)…”

Section: Methodsmentioning

confidence: 99%

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

et al. 2013

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Aims/hypothesis Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes. Methods We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabetic patients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells. Results SIRT3 expression was markedly decreased in islets isolated from type 2 diabetes patients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on proinflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β. Conclusions/interpretation Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.

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“…We also found increased mRNAs encoding other possible targets of calcineurin/NFAT signaling (Figure 3, E-G) thought to promote cell proliferation, includ- (26,27,37,38). To unravel signaling links between Ex-4/GLP-1R and calcineurin/NFAT pathways in human islets, we first measured human islet mRNAs encoding all NFAT members and found that NFATC2 and NFATC3 were most abundant (Supplemental Figure 4, A and B).…”

Section: Ink4bmentioning

confidence: 99%

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

Dai

Hang

Shostak

et al. 2017

Journal of Clinical Investigation

127

143

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The direct effects of tacrolimus and cyclosporin A on isolated human islets: A functional, survival and gene expression study

Cited by 34 publications

References 28 publications

Oral Administration of Ginseng Ameliorates Cyclosporine-Induced Pancreatic Injury in an Experimental Mouse Model

Oral Administration of Ginseng Ameliorates Cyclosporine-Induced Pancreatic Injury in an Experimental Mouse Model

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

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