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John D Betteridge - One of the best experts on this subject based on the ideXlab platform.
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Diabetogenic action of statins mechanisms
Current Atherosclerosis Reports, 2019Co-Authors: Rafael Carmena, John D BetteridgeAbstract:Purpose of review Observational studies and meta-analyses of randomized clinical trials data have revealed a 10-12% increased risk of new-onset diabetes (NOD) associated with statin therapy; the risk is increased with intensive treatment regimens and in people with features of the metabolic syndrome or prediabetes. The purpose of this review is to provide an updated summary of what is known about the potential mechanisms for the Diabetogenic effect of statins. Recent findings Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of HMGCoAR. In vitro and in vivo data indicate that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, leading to impaired β-cell function and decreased insulin sensitivity and insulin release. While this effect has been thought to be a drug class effect, recent insights suggest that pravastatin and pitavastatin could exhibit neutral effects on glycaemic parameters in patients with and without diabetes mellitus. The mechanisms by which statins might lead to the development of NOD are unclear. The inhibition of HMGCoAR activity by statins appears to be a key mechanism. It is difficult to offer a comprehensive view regarding the Diabetogenic effect of statins because our understanding of the most widely recognized potential mechanisms, i.e. underlying statin-induced reduction of insulin sensitivity and/or insulin secretion, is still far from complete. The existence of this dual mechanism is supported by the results of a study in a large group of non-diabetic men, showing that a 46% higher risk of NOD in statin users compared to non-users was accompanied by a significant 12% reduction in insulin secretion and a 24.3% increase in insulin resistance. Although statin therapy is associated with a modest increase in the risk of NOD (about one per thousand patient-years), patients should be reassured that the benefits of statins in preventing cardiovascular disease (CVD) events far outweigh the potential risk from elevation in plasma glucose.
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the Diabetogenic action of statins mechanisms and clinical implications
Nature Reviews Endocrinology, 2016Co-Authors: John D Betteridge, Rafael CarmenaAbstract:Treatment with statins has transformed primary and secondary prevention of cardiovascular disease (CVD), including thrombotic stroke. Evidence-based data demonstrate the benefits and safety of statin therapy and help to guide clinicians in the management of populations at high risk of CVD. Nevertheless, clinical trials, meta-analyses and observational studies highlight a 10-12% increase in new-onset diabetes mellitus (NODM) among patients receiving statins. The risk further increases with intensive therapy and among individuals with known risk factors for NODM. Mechanisms underpinning this effect are not yet fully understood; however, Mendelian randomization studies suggest that they are related to lowered activity of HMG-CoA reductase, the target of statin therapy. In vitro research indicates that statins potentially impair β-cell function and decrease insulin sensitivity but how these findings relate to patients is unknown. In the clinic, statins should be prescribed on the basis of CVD risk and individual patient characteristics. In addition, diet and lifestyle interventions should be emphasized to help mitigate the risk of NODM. Individuals who develop NODM while taking statins do not exhibit increased microvascular disease, which is reassuring. In diabetes mellitus of long duration, the effect of statins on glycaemic control is small and unlikely to be clinically important.
Rafael Carmena - One of the best experts on this subject based on the ideXlab platform.
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Diabetogenic action of statins mechanisms
Current Atherosclerosis Reports, 2019Co-Authors: Rafael Carmena, John D BetteridgeAbstract:Purpose of review Observational studies and meta-analyses of randomized clinical trials data have revealed a 10-12% increased risk of new-onset diabetes (NOD) associated with statin therapy; the risk is increased with intensive treatment regimens and in people with features of the metabolic syndrome or prediabetes. The purpose of this review is to provide an updated summary of what is known about the potential mechanisms for the Diabetogenic effect of statins. Recent findings Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of HMGCoAR. In vitro and in vivo data indicate that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, leading to impaired β-cell function and decreased insulin sensitivity and insulin release. While this effect has been thought to be a drug class effect, recent insights suggest that pravastatin and pitavastatin could exhibit neutral effects on glycaemic parameters in patients with and without diabetes mellitus. The mechanisms by which statins might lead to the development of NOD are unclear. The inhibition of HMGCoAR activity by statins appears to be a key mechanism. It is difficult to offer a comprehensive view regarding the Diabetogenic effect of statins because our understanding of the most widely recognized potential mechanisms, i.e. underlying statin-induced reduction of insulin sensitivity and/or insulin secretion, is still far from complete. The existence of this dual mechanism is supported by the results of a study in a large group of non-diabetic men, showing that a 46% higher risk of NOD in statin users compared to non-users was accompanied by a significant 12% reduction in insulin secretion and a 24.3% increase in insulin resistance. Although statin therapy is associated with a modest increase in the risk of NOD (about one per thousand patient-years), patients should be reassured that the benefits of statins in preventing cardiovascular disease (CVD) events far outweigh the potential risk from elevation in plasma glucose.
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the Diabetogenic action of statins mechanisms and clinical implications
Nature Reviews Endocrinology, 2016Co-Authors: John D Betteridge, Rafael CarmenaAbstract:Treatment with statins has transformed primary and secondary prevention of cardiovascular disease (CVD), including thrombotic stroke. Evidence-based data demonstrate the benefits and safety of statin therapy and help to guide clinicians in the management of populations at high risk of CVD. Nevertheless, clinical trials, meta-analyses and observational studies highlight a 10-12% increase in new-onset diabetes mellitus (NODM) among patients receiving statins. The risk further increases with intensive therapy and among individuals with known risk factors for NODM. Mechanisms underpinning this effect are not yet fully understood; however, Mendelian randomization studies suggest that they are related to lowered activity of HMG-CoA reductase, the target of statin therapy. In vitro research indicates that statins potentially impair β-cell function and decrease insulin sensitivity but how these findings relate to patients is unknown. In the clinic, statins should be prescribed on the basis of CVD risk and individual patient characteristics. In addition, diet and lifestyle interventions should be emphasized to help mitigate the risk of NODM. Individuals who develop NODM while taking statins do not exhibit increased microvascular disease, which is reassuring. In diabetes mellitus of long duration, the effect of statins on glycaemic control is small and unlikely to be clinically important.
Jan P Dutz - One of the best experts on this subject based on the ideXlab platform.
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prolonged antibiotic treatment induces a Diabetogenic intestinal microbiome that accelerates diabetes in nod mice
The ISME Journal, 2016Co-Authors: Kirsty Brown, Yiqun Zhang, Artem Godovannyi, Zahra Ahmadivand, Chaunbin Dai, Monika A Gorzelak, Yeekwan Chan, Justin M Chan, Arion Lochner, Jan P DutzAbstract:Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer's patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is Diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The Diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the Diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their Diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a Diabetogenic microbiome.
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tlr9 blockade inhibits activation of Diabetogenic cd8 t cells and delays autoimmune diabetes
Journal of Immunology, 2010Co-Authors: Yiqun Zhang, Andrew Lee, Afshin Shameli, Xuan Geng, Diane T Finegood, Pere Santamaria, Jan P DutzAbstract:Diabetogenic CD8(+) T cells are primed in the pancreatic lymph nodes (PLNs) by dendritic cells (DCs) carrying islet cell Ags. TLR signaling modifies DC function. The goal of this study was to determine the effect of TLR9 signaling on Diabetogenic CD8(+) T cell activation and the course of type 1 diabetes. We explored the effects of CpG oligonucleotide, TLR9 antagonists, and genetic TLR9 deficiency on the activation of Diabetogenic CD8(+) T cells. NOD bone marrow-derived DCs pulsed with freeze-thawed insulinoma cells in the presence of TLR9 agonist CpG and CD40 agonist induced Diabetogenic CD8(+) T cell activation. The addition of TLR9 antagonist oligodeoxynucleotide or chloroquine inhibited bone marrow-derived DCs activation and CD8(+) T cell priming in response to CpG. CpG alone or with CD40 agonist induced CTL activity that triggered diabetes development in 8.3-TCR transgenic NOD mice. Oligodeoxynucleotide treatment of 8.3-TCR transgenic NOD mice delayed spontaneous diabetes development. Chloroquine treatment delayed the spontaneous onset of diabetes in NOD mice, coincident with the decreased activation of PLN DCs. TLR9(-/-) NOD mice had delayed onset of diabetes compared with TLR9(-/+) NOD littermates. TLR9(-/-) NOD mice had lower levels of IFN-alpha in PLNs and decreased frequencies of plasmacytoid DCs and Diabetogenic CD8(+) T cells compared with NOD mice. We propose that TLR9 activation contributes to the spontaneous onset of diabetes in NOD mice by increasing IFN-alpha and promoting Diabetogenic CD8 T cell activation.
Terry L Delovitch - One of the best experts on this subject based on the ideXlab platform.
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blockade of tumor necrosis factor related apoptosis inducing ligand exacerbates type 1 diabetes in nod mice
Diabetes, 2003Co-Authors: Salah Eddine Lamhamedicherradi, Konstantin V Salojin, Li Zhou, Marsha Grattan, Craig Meagher, Peter Zucker, Youhai H Chen, James W Nagle, Dennis D Taub, Terry L DelovitchAbstract:Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is expressed in different tissues and cells, including pancreas and lymphocytes, and can induce apoptosis in various tumor cells but not in most normal cells. The specific roles of TRAIL in health and disease remain unclear. Here we show by cDNA array analyses that TRAIL gene expression is upregulated in pancreatic islets during the development of autoimmune type 1 diabetes in nonobese diabetic (NOD) mice and in Min6 islet β-cells activated by TNF-α + interferon-γ. However, stimulation of freshly isolated pancreatic islets or Min6 cells with TRAIL did not induce their apoptosis. TRAIL blockade exacerbates the onset of type 1 diabetes in NOD. Scid recipients of transferred Diabetogenic T-cells and in cyclophosphamide-treated NOD mice. TRAIL inhibits the proliferation of NOD Diabetogenic T-cells by suppressing interleukin (IL)-2 production and cell cycle progression, and this inhibition can be rescued in the presence of exogenous IL-2. cDNA array and Western blot analyses indicate that TRAIL upregulates the expression of the cdk inhibitor p27 kip1 . Our data suggest that TRAIL is an important immune regulator of the development of type 1 diabetes.
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insulin b chain reactive cd4 regulatory t cells induced by oral insulin treatment protect from type 1 diabetes by blocking the cytokine secretion and pancreatic infiltration of Diabetogenic effector t cells
Diabetes, 1999Co-Authors: Isabelle Bergerot, G A Arreaza, Mark J Cameron, Marie D Burdick, Robert M Strieter, S W Chensue, Subrata Chakrabarti, Terry L DelovitchAbstract:The mechanism of protection from type 1 diabetes conferred by regulatory T-cells induced by oral insulin treatment of NOD mice is not well understood. We demonstrate that oral insulin feeding of NOD mice induces the function of insulin B-chain reactive CD4+ regulatory T-cells, which compete with Diabetogenic effector T-cells for the recognition of insulin in NOD.Scid recipient mice. These effector T-cells become deprived of interleukin (IL)-2 and interferon (IFN)-gamma and are unable to expand and migrate to the pancreas. Type 1 diabetes-protective splenic regulatory T-cells secrete relatively little transforming growth factor (TGF)-beta1, suggesting that TGF-beta may not contribute to the inactivation of effector T-cells in NOD.Scid recipients. The observed preferential infiltration of insulin-reactive regulatory T-cells rather than effector T-cells in the pancreas results in a nondestructive insulitis that correlates with an increased intrapancreatic expression of macrophage inflammatory protein-1beta. Thus, oral insulin therapy overcomes a deficiency in regulatory T-cells and protects against type 1 diabetes by inducing insulin B-chain reactive regulatory T-cells to block cytokine secretion and migration of Diabetogenic effector T-cells to the pancreas. Our data emphasize that continuous oral insulin feeding over a prolonged period is required to prevent type 1 diabetes.
Barak Blum - One of the best experts on this subject based on the ideXlab platform.
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the anna karenina model of β cell maturation in development and their dedifferentiation in type 1 and type 2 diabetes
Diabetes, 2021Co-Authors: Sutichot D Nimkulrat, Matthew N Bernstein, Jared Brown, Christina Kendziorski, Barak BlumAbstract:Loss of mature β cell function and identity, or β cell dedifferentiation, is seen in both type 1 and type 2 diabetes. Two competing models explain β cell dedifferentiation in diabetes. In the first model, β cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated β cells resemble β cell progenitors. In the second model, β cell dedifferentiation depends on the type of Diabetogenic stress. This model, which we call the “Anna Karenina” model, predicts that in each type of diabetes, β cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular Diabetogenic stress. We directly tested the two models using a β cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of β cell transcriptional trajectories during the normal course of β cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated β cells, β cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes.
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the anna karenina model of beta cell maturation in development and their dedifferentiation in type 1 and type 2 diabetes
bioRxiv, 2021Co-Authors: Sutichot D Nimkulrat, Jared Brown, Christina Kendziorski, Barak BlumAbstract:Loss of mature {beta} cell function and identity, or {beta} cell dedifferentiation, is seen in all types of diabetes mellitus. Two competing models explain {beta} cell dedifferentiation in diabetes. In the first model, {beta} cells dedifferentiate in the reverse order of their developmental ontogeny. This model predicts that dedifferentiated {beta} cells resemble {beta} cell progenitors. In the second model, {beta} cell dedifferentiation depends on the type of Diabetogenic stress. This model, which we call the "Anna Karenina" model, predicts that in each type of diabetes, {beta} cells dedifferentiate in their own way, depending on how their mature identity is disrupted by any particular Diabetogenic stress. We directly tested the two models using a {beta} cell-specific lineage-tracing system coupled with RNA-sequencing in mice. We constructed a multidimensional map of {beta} cell transcriptional trajectories during the normal course of {beta} cell postnatal development and during their dedifferentiation in models of both type 1 diabetes (NOD) and type 2 diabetes (BTBR-Lepob/ob). Using this unbiased approach, we show here that despite some similarities between immature and dedifferentiated {beta} cells, {beta} cells dedifferentiation in the two mouse models is not a reversal of developmental ontogeny and is different between different types of diabetes.