Marc Y Donath

Universitätsspital Basel, Bâle, Basel-City, Switzerland

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Publications (132)1133.24 Total impact

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    ABSTRACT: Exercise increases muscle derived Interleukin–6 (IL–6) leading to insulin secretion via glucagon-like peptide–1. IL–1 antagonism improves glycemia and decreases systemic inflammation including IL–6 in patients with type 2 diabetes. However, it is not known whether physiological, exercise-induced muscle-derived IL–6 is also regulated by the IL–1 system. Therefore we conducted a double blind, crossover study in 17 healthy male subjects randomized to receive either the IL–1 receptor antagonist IL-1Ra (anakinra) or placebo prior to an acute treadmill exercise. Muscle activity led to a 2–3 fold increase in serum IL–6 concentrations but anakinra had no effect on this exercise-induced IL–6. Furthermore, the IL–1 responsive inflammatory markers CRP, cortisol and MCP–1 remained largely unaffected by exercise and anakinra. We conclude that the beneficial effect of muscle-induced IL–6 is not meaningfully affected by IL–1 antagonism.
    PLoS ONE 10/2015; 10(10):e0139662. DOI:10.1371/journal.pone.0139662 · 3.23 Impact Factor
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    ABSTRACT: Patients with type 2 diabetes (T2D) exhibit chronic activation of the innate immune system in pancreatic islets, in insulin-sensitive tissues, and at sites of diabetic complications. This results from a pathological response to overnutrition and physical inactivity seen in genetically predisposed individuals. Processes mediated by the proinflammatory cytokine interleukin-1 (IL-1) link obesity and dyslipidemia and have implicated IL-1β in T2D and related cardiovascular complications. Epidemiological, molecular, and animal studies have now assigned a central role for IL-1β in driving tissue inflammation during metabolic stress. Proof-of-concept clinical studies have validated IL-1β as a target to improve insulin production and action in patients with T2D. Large ongoing clinical trials will address the potential of IL-1 antagonism to prevent cardiovascular and other related complications. Epidemiological studies showed activation of the IL-1 system more than a decade before the onset of T2D and CVD. The rising concentration of IL-1Ra probably reflects a futile attempt to counteract IL-1.Multiple factors induce IL-1 activity in patients with a metabolic syndrome including glucose, lipids, TLR-2 and -4 ligands, endocannabinoids, ER and oxidative stress, angiotensin II, and, in islets, amyloid polypeptide. Clinical studies have validated IL-1β as a target to improve insulin secretion and action and glycemic control. Evidence indicates an atherogenic role for IL-1 cytokines, but the individual contributions of IL-1α and IL-1β in the different stages of CVD need further clarification. Inflammation in T2D is by far not limited to the IL-1 system.
    Trends in Endocrinology and Metabolism 10/2015; 26(10):551-563. DOI:10.1016/j.tem.2015.08.001 · 9.39 Impact Factor
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    ABSTRACT: The role of the IL-1 system in development of type 2 diabetes is well established. Using an IL-1 receptor antagonist, which blocks IL-1alpha and -beta activity, or by specifically neutralizing IL-1beta, several clinical studies have demonstrated improvement in insulin secretion and glycaemia. However, the role of IL-1alpha remains to be investigated. We evaluated the safety and preliminary efficacy of a neutralizing true human™ monoclonal antibody against IL-1alpha (MABp1) in an open label trial in patients with type 2 diabetes. Seven patients between 50 to 66years with type 2 diabetes mellitus were enrolled in the study. The study subjects received four biweekly intravenous infusions of MABp1 at 1.25mg/kg body weight up to day 60 and were followed up for a total of 90days. Compared to baseline, after the 60-day period of treatment HbA1c was numerically reduced by 0.14±0.21% (p=0.15), fasting C-peptide was increased by 88% (p=0.03), pro-insulin by 48% (p=0.03) and insulin numerically increased by 74% (p=0.11). Systolic blood pressure numerically decreased by 11mmHg (p=0.2). Both HbA1c and blood pressure rebounded to baseline levels thirty days after the end of MABp1 application. Treatment with MABp1 was well tolerated, and no adverse events occurred during the study. The results point to a role of IL-1alpha in type 2 diabetes and encourage further investigations. ( number NCT01427699). Copyright © 2015. Published by Elsevier Inc.
    Journal of Diabetes and its Complications 06/2015; 29(7). DOI:10.1016/j.jdiacomp.2015.05.019 · 3.01 Impact Factor
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    ABSTRACT: We study here the influence of different patients and the influence of different devices with the same patients on the signals and modeling of data from measurements from a noninvasive Multisensor glucose monitoring system in patients with type 1 diabetes. The Multisensor includes several sensors for biophysical monitoring of skin and underlying tissue integrated on a single substrate. Two Multisensors were worn simultaneously, 1 on the upper left and 1 on the upper right arm by 4 patients during 16 study visits. Glucose was administered orally to induce 2 consecutive hyperglycemic excursions. For the analysis, global (valid for a population of patients), personal (tailored to a specific patient), and device-specific multiple linear regression models were derived. We find that adjustments of the model to the patients improves the performance of the glucose estimation with an MARD of 17.8% for personalized model versus a MARD of 21.1% for the global model. At the same time the effect of the measurement side is negligible. The device can equally well measure on the left or right arm. We also see that devices are equal in the linear modeling. Thus hardware calibration of the sensors is seen to be sufficient to eliminate interdevice differences in the measured signals. We demonstrate that the hardware of the 2 devices worn on the left and right arms are consistent yielding similar measured signals and thus glucose estimation results with a global model. The 2 devices also return similar values of glucose errors. These errors are mainly due to nonstationarities in the measured signals that are not solved by the linear model, thus suggesting for more sophisticated modeling approaches. © 2015 Diabetes Technology Society.
    Journal of diabetes science and technology 04/2015; 9(4). DOI:10.1177/1932296815579459
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    Christian Herder · Marc Y Donath ·

    The Lancet Diabetes & Endocrinology 02/2015; 117(4). DOI:10.1016/S2213-8587(15)00035-2 · 9.19 Impact Factor
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    Jan A Ehses · Marc Y Donath ·
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    ABSTRACT: Inflammation is a pathological feature of the pancreatic islet in type 1 and 2 diabetes, contributing to islet endocrine cell failure and the onset of hyperglycaemia in both diseases. Indeed, numerous immune targets have recently been found to be altered in type 2 diabetes, but few have yet to be translated to the clinic. Taylor-Fishwick and colleagues aimed to change this by performing proof-of-concept studies investigating the efficacy of small molecule inhibitors of 12-lipoxygenase in rodent and human beta cells exposed to proinflammatory cytokines. The results of these studies, published in this issue of Diabetologia (DOI: 10.1007/s00125-014-3452-0 ), build on a wealth of preclinical data that have implicated 12-lipoxygenase in rodent models of type 1 and 2 diabetes. While there remain some unanswered mechanistic questions regarding how cytokines regulate 12-lipoxygenase activation and the downstream consequences of activation, it is hoped that future studies with newly identified selective inhibitors may overcome the in vitro limitations of this study and allow for the eventual clinical translation of these highly interesting findings.
    Diabetologia 12/2014; 58(3). DOI:10.1007/s00125-014-3482-7 · 6.67 Impact Factor
  • Elise Dalmas · Marc Y Donath ·
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    ABSTRACT: Increasing evidence points to a role for the immune system in the regulation of metabolism. Two new studies in mice indicate treatment with interleukin-22 restores mucosal immunity in diabetes and alleviates metabolic disease, resulting in improved glycemic control.
    Nature Medicine 11/2014; 20(12). DOI:10.1038/nm.3748 · 27.36 Impact Factor
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    ABSTRACT: Pathological activation of the renin-angiotensin system (RAS) is associated with the metabolic syndrome, and new-onset of type 2 diabetes can be delayed by RAS inhibition. In animal models of type 2 diabetes, inhibition of the RAS improves insulin secretion. However, the direct effects of angiotensin II on islet function and underlying mechanisms independent of changes in blood pressure remain unclear. Here we show that exposure of human and mouse islets to angiotensin II induces IL-1-dependent expression of IL-6 and MCP-1, β-cell apoptosis, and impairs mitochondrial function and insulin secretion. In vivo, high fat fed mice treated with angiotensin II and the vasodilator hydralazine to prevent hypertension, showed defective glucose-stimulated insulin secretion and deteriorated glucose tolerance. Application of an anti-IL-1β antibody reduced the deleterious effects of angiotensin II on islet inflammation, restored insulin secretion and improved glycaemia. We conclude that angiotensin II leads to islet dysfunction via induction of inflammation and independent of vasoconstriction. Our findings reveal a novel role for the renin-angiotensin system and an additional rationale for the treatment of type 2 diabetes patients with an IL-1β antagonist.
    Diabetes 10/2014; 64(4). DOI:10.2337/db14-1282 · 8.10 Impact Factor
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    ABSTRACT: Objective We have previously shown the existence of a muscle-pancreas intercommunication axis in which CX3CL1 (fractalkine), a CX3C chemokine produced by skeletal muscle cells, could be implicated. It has recently been shown that the fractalkine system modulates murine β-cell function. However, the impact of CX3CL1 on human islet cells especially regarding a protective role against cytokine-induced apoptosis remains to be investigated. Methods Gene expression was determined using RNA sequencing in human islets, sorted β - and non β -cells. Glucose-stimulated insulin secretion (GSIS) and glucagon secretion from human islets was measured following 24 h exposure to 1-50 ng/ml CX3CL1. GSIS and specific protein phosphorylation were measured in rat sorted β-cells exposed to CX3CL1 for 48 h alone or in the presence of TNFα (20ng/ml). Rat and human β-cell apoptosis (TUNEL) and rat β-cell proliferation (BrdU incorporation) were assessed after 24 h treatment with increasing concentrations of CX3CL1. Results Both CX3CL1 and its receptor CX3CR1 are expressed in human islets. However, CX3CL1 is more expressed in non- β cells than in β-cells while its receptor is more expressed in β-cells. CX3CL1 decreased human (but not rat) β-cell apoptosis. CX3CL1 inhibited human islet glucagon secretion stimulated by low glucose but did not impact human islet and rat sorted β-cell GSIS. However, CX3CL1 completely prevented the adverse effect of TNFα on GSIS and on molecular mechanisms involved in insulin granule trafficking by restoring the phosphorylation (Akt, AS160, paxillin) and expression (IRS2, ICAM-1, Sorcin, PCSK1) of key proteins involved in these processes. Conclusions We demonstrate for the first time that human islets express and secrete CX3CL1 and CX3CL1 impacts them by decreasing glucagon secretion without affecting insulin secretion. Moreover, CX3CL1 decreases basal apoptosis of human β-cells. We further demonstrate that CX3CL1 protects β-cells from the adverse effects of TNFα on their function by restoring the expression and phosphorylation of key proteins of the insulin secretion pathway.
    Molecular Metabolism 10/2014; 3(7). DOI:10.1016/j.molmet.2014.07.007
  • Marc Y Donath ·
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    ABSTRACT: The role of inflammation in the pathogenesis of type 2 diabetes and associated complications is now well established. Several conditions that are driven by inflammatory processes are also associated with diabetes, including rheumatoid arthritis, gout, psoriasis and Crohn's disease, and various anti-inflammatory drugs have been approved or are in late stages of development for the treatment of these conditions. This Review discusses the rationale for the use of some of these anti-inflammatory treatments in patients with diabetes and what we could expect from their use. Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.
    Nature Reviews Drug Discovery 05/2014; 13(6). DOI:10.1038/nrd4275 · 41.91 Impact Factor
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    ABSTRACT: Contracting muscle releases interleukin-6 (IL-6) enabling the metabolic switch from carbohydrate to fat utilization. Similarly, metabolism is switched during transition from fed to fasting state. Herein, we examined a putative role for IL-6 in the metabolic adaptation to normal fasting. In lean C57BL/6J mice, 6 hours of food withdrawal increased gene transcription levels of IL-6 in skeletal muscle but not in white adipose tissue. Concomitantly, circulating IL-6 and free fatty acid (FFA) levels were significantly increased, whereas respiratory quotient (RQ) was reduced in 6-hour fasted mice. In white adipose tissue, phosphorylation of hormone-sensitive lipase (HSL) was increased upon fasting, indicating increased lipolysis. Intriguingly, fasting-induced increase in circulating IL-6 levels and parallel rise in FFA concentration were absent in obese and glucose intolerant mice. A causative role for IL-6 in the physiological adaptation to fasting was further supported by the fact that fasting-induced increase in circulating FFA levels was significantly blunted in lean IL-6 knockout (KO) and lean C57BL/6J mice treated with neutralizing IL-6 antibody. Consistently, phosphorylation of HSL was significantly reduced in adipose tissue of IL-6 depleted mice. Hence, our findings suggest a novel role for IL-6 in energy supply during early fasting.
    AJP Regulatory Integrative and Comparative Physiology 04/2014; 306(11). DOI:10.1152/ajpregu.00533.2013 · 3.11 Impact Factor
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    Marc Y Donath · Christoph Hess · Ed Palmer ·
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    ABSTRACT: Despite tremendous research efforts, type 1 diabetes is one of the few remaining autoimmune diseases without any approved immunological treatment. This observation compels us to reconsider the role of autoimmunity in the pathogenesis of this disease. In this commentary, we will review solely human data in an attempt to appreciate, in an unbiased manner, the importance and relevance of the immunological alterations in patients with type 1 diabetes. The aim of this paper is to generate reflection on this topic, rather than a controversy.
    Diabetologia 01/2014; 57(4). DOI:10.1007/s00125-013-3153-0 · 6.67 Impact Factor
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    M. Y. Donath ·
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    ABSTRACT: Islets of patients with type 2 diabetes display the typical features of an inflammatory process characterized by the presence of cytokines, chemokines, immune cell infiltration, impaired function and tissue destruction with fibrotic areas. Functional studies have shown that targeting inflammation may improve insulin secretion and sensitivity. In particular clinical proof of concept studies using modulators of the interleukin‐1β (IL‐1β)—nuclear factor‐κB (NF‐κB) pathway demonstrated the role of the innate immune system in type 2 diabetes. This programme has now entered the phase 3 of clinical development. Other targets such as tumour necrosis factor α (TNFα) may be equally important but have been neglected based on poorly designed studies. In this article we discuss the mechanisms of islet inflammation in type 2 diabetes and review the opportunity of clinical translation.
    Diabetes Obesity and Metabolism 09/2013; 15(s3). DOI:10.1111/dom.12172 · 6.36 Impact Factor
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    Marc Y. Donath · Rémy Burcelin ·

    Diabetes Care 07/2013; 36(Supplement_2):S145-S148. DOI:10.2337/dcS13-2015 · 8.42 Impact Factor
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    Katharina Timper · Petr Hruz · Christoph Beglinger · Marc Y Donath ·

    Diabetes care 07/2013; 36(7):e90-e91. DOI:10.2337/dc13-0199 · 8.42 Impact Factor
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    ABSTRACT: The role of the immune system is to restore functionality in response to stress. Increasing evidence shows that this function is not limited to insults by infection or injury and plays a role in response to overnutrition. Initially, this metabolic activation of the immune system is a physiological response, but it may become deleterious with time. Therefore, therapeutic interventions should aim at modulating the immune system rather than simply damping it. In this article, we describe the physiology and pathology of the immune system during obesity and diabetes with a focus on islet inflammation, the IL-1β pathway, and clinical translation.
    Cell metabolism 06/2013; 17(6):860-72. DOI:10.1016/j.cmet.2013.05.001 · 17.57 Impact Factor
  • Marc Y Donath ·
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    ABSTRACT: Obesity induces metabolic stress and is associated with inflammation. A cellular pathway now links SIRT2, a deacetylase involved in metabolic processes, to cytoskeleton remodelling and activation of the NLRP3 inflammasome.
    Nature Immunology 04/2013; 14(5):421-422. DOI:10.1038/ni.2591 · 20.00 Impact Factor
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    ABSTRACT: BACKGROUND: Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. METHODS: We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. FINDINGS: Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. INTERPRETATION: Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. FUNDING: National Institutes of Health and Juvenile Diabetes Research Foundation.
    The Lancet 04/2013; DOI:10.1016/S0140-6736(13)60023-9 · 45.22 Impact Factor
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    ABSTRACT: Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.
    Cell metabolism 03/2013; 17(3):448-55. DOI:10.1016/j.cmet.2013.02.001 · 17.57 Impact Factor
  • Marc Y. Donath ·
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    ABSTRACT: Type 2 diabetes occurs when the pancreatic islet beta-cell fails to adapt to the increased insulin demand caused by obesity-associated insulin resistance. Islets of patients with type 2 diabetes display an inflammatory process characterized by the presence of cytokines, immune cells, beta-cell apoptosis, amyloid deposits and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. Therefore, impaired insulin secretion observed in patients with type 2 diabetes can be treated by anti-inflammatory approaches. Copyright (C) 2013 S. Karger AG, Basel
    01/2013: pages 80-85;

Publication Stats

9k Citations
1,133.24 Total Impact Points


  • 2010-2015
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
    • University of Colorado
      • Department of Medicine
      Denver, CO, United States
  • 1999-2015
    • Hebrew University of Jerusalem
      • • Department of Applied Physics
      • • Hadassah Medical School
      Yerushalayim, Jerusalem, Israel
  • 2014
    • Universität Basel
      Bâle, Basel-City, Switzerland
  • 1994-2012
    • University of Zurich
      • • Center for Integrative Human Physiology
      • • Internal Medicine Unit
      Zürich, Zurich, Switzerland
  • 2009
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 1997-2009
    • University Hospital Zürich
      Zürich, Zurich, Switzerland
  • 2008
    • Université Montpellier
      Montpelhièr, Languedoc-Roussillon, France
  • 2007
    • Lund University
      Lund, Skåne, Sweden
  • 2006
    • University of Illinois at Chicago
      • Division of Transplantation
      Chicago, Illinois, United States
  • 2004
    • Novo Nordisk
      København, Capital Region, Denmark
  • 2000
    • Hadassah Medical Center
      • Department of Endocrinology and Metabolism
      Yerushalayim, Jerusalem District, Israel