Marc Y Donath

Universitätsspital Basel, Bâle, Basel-City, Switzerland

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Publications (124)1028.89 Total impact

  • [Show abstract] [Hide abstract]
    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; DOI:10.1177/1932296815579459
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    Christian Herder, Marc Y Donath
    02/2015; 117(4). DOI:10.1016/S2213-8587(15)00035-2
  • 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 · 6.88 Impact Factor
  • Elise Dalmas, Marc Y Donath
    Nature Medicine 11/2014; DOI:10.1038/nm.3748 · 28.05 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; DOI:10.2337/db14-1282 · 8.47 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.
    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.
    dressNature Reviews Drug Discovery 05/2014; 13(6). DOI:10.1038/nrd4275 · 37.23 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; DOI:10.1152/ajpregu.00533.2013 · 3.53 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 · 6.88 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. DOI:10.1111/dom.12172 · 5.46 Impact Factor
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    Diabetes care 07/2013; 36(7):e90-e91. DOI:10.2337/dc13-0199 · 8.57 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 · 16.75 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 · 24.97 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 · 39.21 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 · 16.75 Impact Factor
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    ABSTRACT: β-Cell lipotoxicity is thought to play an important role in the development of type 2 diabetes. However, no study has examined its role in type 1 diabetes, which could be clinically relevant for slow-onset type 1 diabetes. Reports of enhanced cytokine toxicity in fat-laden islets are consistent with the hypothesis that lipid and cytokine toxicity may be synergistic. Thus, β-cell lipotoxicity could be enhanced in models of autoimmune diabetes. To determine this, we examined the effects of prolonged free fatty acids elevation on β-cell secretory function in the prediabetic diabetes-prone BioBreeding (dp-BB) rat, its diabetes-resistant BioBreeding (dr-BB) control, and normal Wistar-Furth (WF) rats. Rats received a 48-h iv infusion of saline or Intralipid plus heparin (IH) (to elevate free fatty acid levels 2-fold) followed by hyperglycemic clamp or islet secretion studies ex vivo. IH significantly decreased β-cell function, assessed both by the disposition index (insulin secretion corrected for IH-induced insulin resistance) and in isolated islets, in dp-BB, but not in dr-BB or WF, rats, and the effect of IH was inhibited by the antioxidant N-acetylcysteine. Furthermore, IH significantly increased islet cytokine mRNA and plasma cytokine levels (monocyte chemoattractant protein-1 and IL-10) in dp-BB, but not in dr-BB or WF, rats. All dp-BB rats had mononuclear infiltration of islets, which was absent in dr-BB and WF rats. In conclusion, the presence of insulitis was permissive for IH-induced β-cell dysfunction in the BB rat, which suggests a link between β-cell lipotoxicity and islet inflammation.
    Endocrinology 11/2012; 154(1). DOI:10.1210/en.2012-1720 · 4.64 Impact Factor
  • Katharina Timper, Marc Y Donath
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    ABSTRACT: Already 600 years before Christ, type 2 diabetes was known as a disease of elevated blood sugar levels associated with obesity. Since then, it appears, our understanding of the disease has not changed much, aside from the replacement of tasting the patients' urine by the measurement of plasma glucose and glycated haemoglobin levels (HbA1c) for its diagnosis and the discovery of some new drugs. Already, in those old days a physician from India named Sushrut described diabetes mellitus as a disease characterised by the passage of large amounts of urine and its "honey-like" taste and, noteworthy, as a disease that is mainly associated with obesity and a sedentary lifestyle, recommending physical activity as the primary treatment option. Although these milestone observations remain valid, major progress in the underlying pathogenesis of type 2 diabetes has been achieved showing a new face of this old disease and opening doors for novel treatment options. This review will highlight recent pathophysiological aspects of type 2 diabetes, actual diagnostic and treatment guidelines and discuss some possible upcoming new therapeutic strategies.
    Schweizerische medizinische Wochenschrift 07/2012; 142:w13635. DOI:10.4414/smw.2012.13635 · 1.88 Impact Factor
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    ABSTRACT: Metabolic activation of the innate immune system governed by interleukin (IL)-1β contributes to β-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti-IL-1β antibody. We evaluated the safety and biological activity of gevokizumab in patients with type 2 diabetes. In a placebo-controlled, dose-escalation study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to evaluate the safety profile of gevokizumab in type 2 diabetes. The secondary objectives were to assess pharmacokinetics for different dose levels, routes of administration, and regimens and to assess biological activity. The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG(2), with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1, 2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines. This novel IL-1β-neutralizing antibody improved glycemia, possibly via restored insulin production and action, and reduced inflammation in patients with type 2 diabetes. This therapeutic agent may be able to be used on a once-every-month or longer schedule.
    Diabetes care 06/2012; 35(8):1654-62. DOI:10.2337/dc11-2219 · 8.57 Impact Factor
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    Diabetes care 06/2012; 35(6):e41. DOI:10.2337/dc12-0115 · 8.57 Impact Factor
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    ABSTRACT: A decrease in functional beta-cell mass is a key feature of type 2 diabetes. Glucagon-like peptide 1 (GLP-1) analogues induce proliferation of rodent beta-cells. However, the proliferative capacity of human beta-cells and its modulation by GLP-1 analogues remain to be fully investigated. We therefore sought to quantify adult human beta-cell proliferation in vitro and whether this is affected by the GLP-1 analogue liraglutide. Human islets from 7 adult cadaveric organ donors were dispersed into single cells. Beta-cells were purified by FACS. Non-sorted cells and the beta-cell enriched (“beta-cells”) population were plated on extracellular matrix from rat (804G) and human bladder carcinoma cells (HTB9) or bovine corneal endothelial ECM (BCEC). Cells were maintained in culture+/−liraglutide for 4 days in the presence of BrdU. Rare human beta-cell proliferation could be observed either in the purified beta-cell population (0.051±0.020%; 22 beta-cells proliferating out of 84'283 beta-cells counted) or in the non-sorted cell population (0.055±0.011%; 104 proliferating beta-cells out of 232'826 beta-cells counted), independently of the matrix or the culture conditions. Liraglutide increased human beta-cell proliferation on BCEC in the non-sorted cell population (0.082±0.034% proliferating beta-cells vs. 0.017±0.008% in control, p<0.05). These results indicate that adult human beta-cell proliferation can occur in vitro but remains an extremely rare event with these donors and particular culture conditions. Liraglutide increases beta-cell proliferation only in the non-sorted cell population and only on BCEC. However, it cannot be excluded that human beta-cells may proliferate to a greater extent in situ in response to natural stimuli.
    PLoS ONE 04/2012; 7(4):e35801. DOI:10.1371/journal.pone.0035801 · 3.53 Impact Factor

Publication Stats

8k Citations
1,028.89 Total Impact Points


  • 2010–2015
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
    • University of Colorado
      • Department of Medicine
      Denver, CO, United States
  • 2014
    • Universität Basel
      Bâle, Basel-City, Switzerland
  • 1997–2012
    • University of Zurich
      • • Center for Integrative Human Physiology
      • • Internal Medicine Unit
      Zürich, Zurich, Switzerland
  • 2007–2009
    • Steno Diabetes Center
      Gjentofte, Capital Region, Denmark
    • Lund University
      Lund, Skåne, Sweden
  • 1997–2009
    • University Hospital Zürich
      Zürich, Zurich, Switzerland
  • 2006
    • University of Illinois at Chicago
      • Division of Transplantation
      Chicago, Illinois, United States
  • 2004
    • Novo Nordisk
      København, Capital Region, Denmark
  • 1999–2001
    • Hebrew University of Jerusalem
      • Hadassah Medical School
      Jerusalem, Jerusalem District, Israel
  • 2000
    • Hadassah Medical Center
      • Department of Endocrinology and Metabolism
      Yerushalayim, Jerusalem District, Israel