Prof. Dr. med. Marc Donath Department of Clinical Research Profiles & Affiliations OverviewResearch Publications Projects & Collaborations Projects & Collaborations OverviewResearch Publications Projects & Collaborations Profiles & Affiliations Projects & Collaborations 14 foundShow per page10 10 20 50 Immune-neuro-metabolic regulation of the distribution of cellular nutrients and its functional consequences. Research Project | 1 Project MembersImported from Grants Tool 4701538 Immune-mediated regulation of insulin processing in the development of obesity and impaired glucose metabolism Research Project | 1 Project MembersNo Description available Early Interception of Inflammatory-mediated Type 2 Diabetes Research Project | 1 Project MembersNo Description available Mechanisms and treatments of beta-cell dysfunction in patients with prediabetes Research Project | 1 Project MembersNo Description available Canakinumab in patients with COVID-19 and Type 2 Diabetes: A Multicentre Randomized, Double-Blind, Placebo-Controlled Trial Research Project | 1 Project MembersPatients with a metabolic syndrome (overweight, diabetes, hypertension) have a particularly bad outcome if infected with covid-19. This may be explained by an over-activation of the IL-1beta System. Indeed, metabolic stress (increased glucose and lipid levels) induces NLRP3-mediated IL-1beta secretion. Covid-19 also activates NLRP3. Therefore we hypothesize that metabolic stress in patients with overweight and diabetes potentiates covid-19 induced hyper-inflammatory syndrome leading to excess mortality in these vulnerable patients.Backrgoung:Activation of the innate immune system by IL-1 is apparent at all stages of the development of obesity associated type 2 diabetes and its complications. This includes impaired insulin secretion and sensitivity, cardiovascular diseases and heart failure. Accordingly, IL-1 antagonism has been shown to improve glycaemia, cardiovascular complications, and to reduce hospitalization for heart failure and heart failure-related mortality. The latter is of particular importance in the context of Covid-19, because patients with type 2 diabetes per se are at high risk to develop heart failure with a high mortality rate. Several studies have shown that the corona virus stimulates the NLRP3 inflammasome leading to a severe inflammatory response by the IL-1beta pathway, as reflected by CRP and IL-6 increase. In obese diabetic individuals, metabolic stress also promotes the IL-1ß pathway. Thus we hypothesize that both mechanisms will synergize leading to a deleterious hyper-inflammation as often observed in obese diabetic patients affected by Covid-19.Our hypothesis is supported by several recent studies. Indeed, in a cohort of >7'000 Covid-19 patients, type 2 diabetes was associated with a higher death rate. Supporting our hypothesis that glucose-induced IL-1ß will amplify Covid-19 hyper-inflammation, hyperglycemia correlated with a worse outcome. Most importantly, in a retrospective cohort study of patients with Covid-19, treatment with the IL-1 receptor antagonist IL-1Ra was safe and associated with clinical improvement in 72% of patients.Method:This is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in hospitalized patients with COVID-19 infection and type 2 diabetes.A total of 116 patients will be randomized using a 1:1 allocation ratio of which 58 subjects will receive a single intravenous canakinumab infusion and 58 patients will receive a single placebo infusion. IL-1-receptor antagonist during cephalic phase of insulin secretion in health and type 2 diabetes - The Cephalira Study Research Project | 2 Project MembersNo Description available Immune-mediated response to nutrition in physiology and pathology Research Project | 6 Project MembersWe and others have demonstrated a pathologic role of chronic inflammation in metabolism. More recently, other studies point to a physiological role of the immune system in the regulation of metabolism. Indeed, we have shown that IL-6 enhances insulin secretion via GLP-1, that macrophage-derived IL-1ß potentiates postprandial insulin secretion, and that IL-33-activated islet-resident innate lymphoid cells promote insulin secretion. These processes hint towards a role of the immune system in the endocrine regulation of metabolism. Overall objectives: While the role of the immune system in metabolism has been extensively investigated in pancreatic islets and insulin sensitive tissues, little attention has been given to a potential role of the innate immune system in 3 additional circumstances influencing metabolism, namely (i) the cephalic phase of insulin secretion, which enhances insulin secretion not only while anticipating food, but also during its resorption; (ii) pregnancy, which often leads to gestational diabetes; and (iii) the immune cell infiltration of the exocrine pancreas which occurs in patients with type 2 diabetes.Impact: Understanding the physiology and pathophysiology of the role of the immune system in metabolism is critical for guiding the clinical development of immune treatment of type 2 diabetes and its complications. Physiology of pro-inflammatory cytokines and islet resident immune cells in insulin secretion Research Project | 1 Project MembersThe deleterious role of chronic activation of the innate immune system in type 2 diabetes is well documented. However, little attention has been paid to a possible physiological role of the immune system in metabolism. The general objective of the present project is to uncover mechanisms on how the innate immune system contributes to the adaption of pancreatic islet function under various physiological and stressful (obesity and diabetes) situations. Understanding the PROtectiVe Inflammation in DiabEtes Research Project | 1 Project MembersType-2 diabetes (T2D) is promoted by multiple mechanisms that underlie a defect in insulin secretion and reduced response to insulin-stimulated glucose uptake in liver, muscle and adipose tissues, known as insulin resistance. These mechanisms include glucotoxicity, lipotoxicity, oxidative stress, endoplasmic reticulum stress and alterations of the gut microbiota. Interestingly, all of these mechanisms are associated with inflammatory response. Clinical studies have demonstrated that anti-inflammatory treatments including IL-1- antagonism, salsalate and probably TNF-antagonism improve glucose metabolism. Some anti-inflammatory treatments may be more effective at improving insulin secretion, while others primarily enhance insulinsensitivity. Furthermore, there are different mechanisms that engage different branches of immune response during the course of diabetes. Given the heterogeneity of the disease and the complexity of the inflammatory response, optimal anti-inflammatory strategies are a challenge and studies in humans have yielded variable results. However, inflammation is not in itself a disease but a manifestation of a disease. It may have beneficial effects allowing for adaptation to the metabolic stress. Increasing evidence suggests physiological and beneficial effects of the inflammation (called protective immune response) in the adaptive process of increased insulin secretion and reduced insulin resistance. A metabolic inflammatory response consists of four components: inflammatory inducers (such as nutrients), cell sensors (such as macrophages, dendritic cells), inflammatory mediators (such as T cells) and the target tissues (adipose tissue, liver and pancreas) that are affected by inflammatory mediators. The time line of events and the molecular mechanisms that integrate the inflammatory response with metabolic homeostasis at the tissue and systemic levels are still to be characterized in T2D. Recently, we discovered that inflammatory pathways controlled by Interferon Regulatory Factor 5 (IRF5) in macrophages (the sensor cells) orchestrate the immune response towards a pro-diabetogenic program (Dalmas et al. Nature Medicine in press). Interfering with IRF5 pathways (IRF5 macrophage specific KO mice) lead to modification of the innate and adaptive response leading to a healthier metabolic status. Extensive characterisation of the IRF5-dependent immune response is required for a better understanding of physiological (protective) versus pathological immune programs involved in T2D (mouse studies). These immune programs will also be validated in different clinical situations (human studies) ie: weight loss, exercise and immune-therapy (IL-6 modulation) known to improve diabetes and reduce inflammation. The overall objective of the proposed project is to reveal the physiologic role of inflammation dependent of IRF5 pathways in the adaptation to metabolic stress linked to T2D. Understanding the physiological and the pathological role of the immune system may allow designing personalized treatments promoting a beneficial immune status in patients with T2D. Immunologic consequences of time-graded exposure to an 'obesity-diabetes milieu' Research Project | 3 Project MembersTraditionellerweise werden Metabolismus und Immunität als zwei verschiedene Entitäten mit verschiedenen Funktionen wahrgenommen: der Metabolismus reguliert die Nahrungsverteilung, die Immunität ist für die Abwehr zuständig. Dieses Konzept hat zu verschiedenen spezialisierten Forschungsgebieten mit wenig Interaktionen geführt. In den letzten Jahren hat sich jedoch gezeigt, dass bei übergewichtigen Patienten und Patienten mit Typ 2-Diabetes eine pathologische Aktivierung des Immunsystems stattfindet. Diese führt zu Versagen der Insulinproduktion und Aktionen. Aus diesem Grund wird heute der Typ 2-Diabetes auch als eine inflammatorische Erkrankung betrachtet. Neben diesen pathologischen Aspekten scheint das Immunsystem auch eine Rolle in der Physiologie des Metabolismus eine Rolle zu spielen. Andererseits scheint auch der Metabolismus die Immunzellen zu regulieren. In den vorgeschlagenen Experimenten sollen nun der Zusammenhang zwischen Metabolismus (Marc Donath), Immunologie (Christoph Hess) und Epigenetik (Renato Parro) untersucht werden, um die Hypothese zu testen, dass Übergewicht und Diabetes einen Einfluss haben auf Zellen des Immunsystems, die auch epigenetisch fixieren können. Wir planen zu untersuchen, wie akut sowie chronisch ein metabolischer Stress, charakterisiert durch ein Überangebot an Nährstoffen, sich auf die metabolische Antwort, Funktion und Epigenetik von Zellen von angeborenem und adaptivem Immunsystem auswirkt. Die Mechanismen sowie auch die Reversibilität sollen untersucht werden. 12 12 OverviewResearch Publications Projects & Collaborations
Projects & Collaborations 14 foundShow per page10 10 20 50 Immune-neuro-metabolic regulation of the distribution of cellular nutrients and its functional consequences. Research Project | 1 Project MembersImported from Grants Tool 4701538 Immune-mediated regulation of insulin processing in the development of obesity and impaired glucose metabolism Research Project | 1 Project MembersNo Description available Early Interception of Inflammatory-mediated Type 2 Diabetes Research Project | 1 Project MembersNo Description available Mechanisms and treatments of beta-cell dysfunction in patients with prediabetes Research Project | 1 Project MembersNo Description available Canakinumab in patients with COVID-19 and Type 2 Diabetes: A Multicentre Randomized, Double-Blind, Placebo-Controlled Trial Research Project | 1 Project MembersPatients with a metabolic syndrome (overweight, diabetes, hypertension) have a particularly bad outcome if infected with covid-19. This may be explained by an over-activation of the IL-1beta System. Indeed, metabolic stress (increased glucose and lipid levels) induces NLRP3-mediated IL-1beta secretion. Covid-19 also activates NLRP3. Therefore we hypothesize that metabolic stress in patients with overweight and diabetes potentiates covid-19 induced hyper-inflammatory syndrome leading to excess mortality in these vulnerable patients.Backrgoung:Activation of the innate immune system by IL-1 is apparent at all stages of the development of obesity associated type 2 diabetes and its complications. This includes impaired insulin secretion and sensitivity, cardiovascular diseases and heart failure. Accordingly, IL-1 antagonism has been shown to improve glycaemia, cardiovascular complications, and to reduce hospitalization for heart failure and heart failure-related mortality. The latter is of particular importance in the context of Covid-19, because patients with type 2 diabetes per se are at high risk to develop heart failure with a high mortality rate. Several studies have shown that the corona virus stimulates the NLRP3 inflammasome leading to a severe inflammatory response by the IL-1beta pathway, as reflected by CRP and IL-6 increase. In obese diabetic individuals, metabolic stress also promotes the IL-1ß pathway. Thus we hypothesize that both mechanisms will synergize leading to a deleterious hyper-inflammation as often observed in obese diabetic patients affected by Covid-19.Our hypothesis is supported by several recent studies. Indeed, in a cohort of >7'000 Covid-19 patients, type 2 diabetes was associated with a higher death rate. Supporting our hypothesis that glucose-induced IL-1ß will amplify Covid-19 hyper-inflammation, hyperglycemia correlated with a worse outcome. Most importantly, in a retrospective cohort study of patients with Covid-19, treatment with the IL-1 receptor antagonist IL-1Ra was safe and associated with clinical improvement in 72% of patients.Method:This is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in hospitalized patients with COVID-19 infection and type 2 diabetes.A total of 116 patients will be randomized using a 1:1 allocation ratio of which 58 subjects will receive a single intravenous canakinumab infusion and 58 patients will receive a single placebo infusion. IL-1-receptor antagonist during cephalic phase of insulin secretion in health and type 2 diabetes - The Cephalira Study Research Project | 2 Project MembersNo Description available Immune-mediated response to nutrition in physiology and pathology Research Project | 6 Project MembersWe and others have demonstrated a pathologic role of chronic inflammation in metabolism. More recently, other studies point to a physiological role of the immune system in the regulation of metabolism. Indeed, we have shown that IL-6 enhances insulin secretion via GLP-1, that macrophage-derived IL-1ß potentiates postprandial insulin secretion, and that IL-33-activated islet-resident innate lymphoid cells promote insulin secretion. These processes hint towards a role of the immune system in the endocrine regulation of metabolism. Overall objectives: While the role of the immune system in metabolism has been extensively investigated in pancreatic islets and insulin sensitive tissues, little attention has been given to a potential role of the innate immune system in 3 additional circumstances influencing metabolism, namely (i) the cephalic phase of insulin secretion, which enhances insulin secretion not only while anticipating food, but also during its resorption; (ii) pregnancy, which often leads to gestational diabetes; and (iii) the immune cell infiltration of the exocrine pancreas which occurs in patients with type 2 diabetes.Impact: Understanding the physiology and pathophysiology of the role of the immune system in metabolism is critical for guiding the clinical development of immune treatment of type 2 diabetes and its complications. Physiology of pro-inflammatory cytokines and islet resident immune cells in insulin secretion Research Project | 1 Project MembersThe deleterious role of chronic activation of the innate immune system in type 2 diabetes is well documented. However, little attention has been paid to a possible physiological role of the immune system in metabolism. The general objective of the present project is to uncover mechanisms on how the innate immune system contributes to the adaption of pancreatic islet function under various physiological and stressful (obesity and diabetes) situations. Understanding the PROtectiVe Inflammation in DiabEtes Research Project | 1 Project MembersType-2 diabetes (T2D) is promoted by multiple mechanisms that underlie a defect in insulin secretion and reduced response to insulin-stimulated glucose uptake in liver, muscle and adipose tissues, known as insulin resistance. These mechanisms include glucotoxicity, lipotoxicity, oxidative stress, endoplasmic reticulum stress and alterations of the gut microbiota. Interestingly, all of these mechanisms are associated with inflammatory response. Clinical studies have demonstrated that anti-inflammatory treatments including IL-1- antagonism, salsalate and probably TNF-antagonism improve glucose metabolism. Some anti-inflammatory treatments may be more effective at improving insulin secretion, while others primarily enhance insulinsensitivity. Furthermore, there are different mechanisms that engage different branches of immune response during the course of diabetes. Given the heterogeneity of the disease and the complexity of the inflammatory response, optimal anti-inflammatory strategies are a challenge and studies in humans have yielded variable results. However, inflammation is not in itself a disease but a manifestation of a disease. It may have beneficial effects allowing for adaptation to the metabolic stress. Increasing evidence suggests physiological and beneficial effects of the inflammation (called protective immune response) in the adaptive process of increased insulin secretion and reduced insulin resistance. A metabolic inflammatory response consists of four components: inflammatory inducers (such as nutrients), cell sensors (such as macrophages, dendritic cells), inflammatory mediators (such as T cells) and the target tissues (adipose tissue, liver and pancreas) that are affected by inflammatory mediators. The time line of events and the molecular mechanisms that integrate the inflammatory response with metabolic homeostasis at the tissue and systemic levels are still to be characterized in T2D. Recently, we discovered that inflammatory pathways controlled by Interferon Regulatory Factor 5 (IRF5) in macrophages (the sensor cells) orchestrate the immune response towards a pro-diabetogenic program (Dalmas et al. Nature Medicine in press). Interfering with IRF5 pathways (IRF5 macrophage specific KO mice) lead to modification of the innate and adaptive response leading to a healthier metabolic status. Extensive characterisation of the IRF5-dependent immune response is required for a better understanding of physiological (protective) versus pathological immune programs involved in T2D (mouse studies). These immune programs will also be validated in different clinical situations (human studies) ie: weight loss, exercise and immune-therapy (IL-6 modulation) known to improve diabetes and reduce inflammation. The overall objective of the proposed project is to reveal the physiologic role of inflammation dependent of IRF5 pathways in the adaptation to metabolic stress linked to T2D. Understanding the physiological and the pathological role of the immune system may allow designing personalized treatments promoting a beneficial immune status in patients with T2D. Immunologic consequences of time-graded exposure to an 'obesity-diabetes milieu' Research Project | 3 Project MembersTraditionellerweise werden Metabolismus und Immunität als zwei verschiedene Entitäten mit verschiedenen Funktionen wahrgenommen: der Metabolismus reguliert die Nahrungsverteilung, die Immunität ist für die Abwehr zuständig. Dieses Konzept hat zu verschiedenen spezialisierten Forschungsgebieten mit wenig Interaktionen geführt. In den letzten Jahren hat sich jedoch gezeigt, dass bei übergewichtigen Patienten und Patienten mit Typ 2-Diabetes eine pathologische Aktivierung des Immunsystems stattfindet. Diese führt zu Versagen der Insulinproduktion und Aktionen. Aus diesem Grund wird heute der Typ 2-Diabetes auch als eine inflammatorische Erkrankung betrachtet. Neben diesen pathologischen Aspekten scheint das Immunsystem auch eine Rolle in der Physiologie des Metabolismus eine Rolle zu spielen. Andererseits scheint auch der Metabolismus die Immunzellen zu regulieren. In den vorgeschlagenen Experimenten sollen nun der Zusammenhang zwischen Metabolismus (Marc Donath), Immunologie (Christoph Hess) und Epigenetik (Renato Parro) untersucht werden, um die Hypothese zu testen, dass Übergewicht und Diabetes einen Einfluss haben auf Zellen des Immunsystems, die auch epigenetisch fixieren können. Wir planen zu untersuchen, wie akut sowie chronisch ein metabolischer Stress, charakterisiert durch ein Überangebot an Nährstoffen, sich auf die metabolische Antwort, Funktion und Epigenetik von Zellen von angeborenem und adaptivem Immunsystem auswirkt. Die Mechanismen sowie auch die Reversibilität sollen untersucht werden. 12 12
Immune-neuro-metabolic regulation of the distribution of cellular nutrients and its functional consequences. Research Project | 1 Project MembersImported from Grants Tool 4701538
Immune-mediated regulation of insulin processing in the development of obesity and impaired glucose metabolism Research Project | 1 Project MembersNo Description available
Early Interception of Inflammatory-mediated Type 2 Diabetes Research Project | 1 Project MembersNo Description available
Mechanisms and treatments of beta-cell dysfunction in patients with prediabetes Research Project | 1 Project MembersNo Description available
Canakinumab in patients with COVID-19 and Type 2 Diabetes: A Multicentre Randomized, Double-Blind, Placebo-Controlled Trial Research Project | 1 Project MembersPatients with a metabolic syndrome (overweight, diabetes, hypertension) have a particularly bad outcome if infected with covid-19. This may be explained by an over-activation of the IL-1beta System. Indeed, metabolic stress (increased glucose and lipid levels) induces NLRP3-mediated IL-1beta secretion. Covid-19 also activates NLRP3. Therefore we hypothesize that metabolic stress in patients with overweight and diabetes potentiates covid-19 induced hyper-inflammatory syndrome leading to excess mortality in these vulnerable patients.Backrgoung:Activation of the innate immune system by IL-1 is apparent at all stages of the development of obesity associated type 2 diabetes and its complications. This includes impaired insulin secretion and sensitivity, cardiovascular diseases and heart failure. Accordingly, IL-1 antagonism has been shown to improve glycaemia, cardiovascular complications, and to reduce hospitalization for heart failure and heart failure-related mortality. The latter is of particular importance in the context of Covid-19, because patients with type 2 diabetes per se are at high risk to develop heart failure with a high mortality rate. Several studies have shown that the corona virus stimulates the NLRP3 inflammasome leading to a severe inflammatory response by the IL-1beta pathway, as reflected by CRP and IL-6 increase. In obese diabetic individuals, metabolic stress also promotes the IL-1ß pathway. Thus we hypothesize that both mechanisms will synergize leading to a deleterious hyper-inflammation as often observed in obese diabetic patients affected by Covid-19.Our hypothesis is supported by several recent studies. Indeed, in a cohort of >7'000 Covid-19 patients, type 2 diabetes was associated with a higher death rate. Supporting our hypothesis that glucose-induced IL-1ß will amplify Covid-19 hyper-inflammation, hyperglycemia correlated with a worse outcome. Most importantly, in a retrospective cohort study of patients with Covid-19, treatment with the IL-1 receptor antagonist IL-1Ra was safe and associated with clinical improvement in 72% of patients.Method:This is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in hospitalized patients with COVID-19 infection and type 2 diabetes.A total of 116 patients will be randomized using a 1:1 allocation ratio of which 58 subjects will receive a single intravenous canakinumab infusion and 58 patients will receive a single placebo infusion.
IL-1-receptor antagonist during cephalic phase of insulin secretion in health and type 2 diabetes - The Cephalira Study Research Project | 2 Project MembersNo Description available
Immune-mediated response to nutrition in physiology and pathology Research Project | 6 Project MembersWe and others have demonstrated a pathologic role of chronic inflammation in metabolism. More recently, other studies point to a physiological role of the immune system in the regulation of metabolism. Indeed, we have shown that IL-6 enhances insulin secretion via GLP-1, that macrophage-derived IL-1ß potentiates postprandial insulin secretion, and that IL-33-activated islet-resident innate lymphoid cells promote insulin secretion. These processes hint towards a role of the immune system in the endocrine regulation of metabolism. Overall objectives: While the role of the immune system in metabolism has been extensively investigated in pancreatic islets and insulin sensitive tissues, little attention has been given to a potential role of the innate immune system in 3 additional circumstances influencing metabolism, namely (i) the cephalic phase of insulin secretion, which enhances insulin secretion not only while anticipating food, but also during its resorption; (ii) pregnancy, which often leads to gestational diabetes; and (iii) the immune cell infiltration of the exocrine pancreas which occurs in patients with type 2 diabetes.Impact: Understanding the physiology and pathophysiology of the role of the immune system in metabolism is critical for guiding the clinical development of immune treatment of type 2 diabetes and its complications.
Physiology of pro-inflammatory cytokines and islet resident immune cells in insulin secretion Research Project | 1 Project MembersThe deleterious role of chronic activation of the innate immune system in type 2 diabetes is well documented. However, little attention has been paid to a possible physiological role of the immune system in metabolism. The general objective of the present project is to uncover mechanisms on how the innate immune system contributes to the adaption of pancreatic islet function under various physiological and stressful (obesity and diabetes) situations.
Understanding the PROtectiVe Inflammation in DiabEtes Research Project | 1 Project MembersType-2 diabetes (T2D) is promoted by multiple mechanisms that underlie a defect in insulin secretion and reduced response to insulin-stimulated glucose uptake in liver, muscle and adipose tissues, known as insulin resistance. These mechanisms include glucotoxicity, lipotoxicity, oxidative stress, endoplasmic reticulum stress and alterations of the gut microbiota. Interestingly, all of these mechanisms are associated with inflammatory response. Clinical studies have demonstrated that anti-inflammatory treatments including IL-1- antagonism, salsalate and probably TNF-antagonism improve glucose metabolism. Some anti-inflammatory treatments may be more effective at improving insulin secretion, while others primarily enhance insulinsensitivity. Furthermore, there are different mechanisms that engage different branches of immune response during the course of diabetes. Given the heterogeneity of the disease and the complexity of the inflammatory response, optimal anti-inflammatory strategies are a challenge and studies in humans have yielded variable results. However, inflammation is not in itself a disease but a manifestation of a disease. It may have beneficial effects allowing for adaptation to the metabolic stress. Increasing evidence suggests physiological and beneficial effects of the inflammation (called protective immune response) in the adaptive process of increased insulin secretion and reduced insulin resistance. A metabolic inflammatory response consists of four components: inflammatory inducers (such as nutrients), cell sensors (such as macrophages, dendritic cells), inflammatory mediators (such as T cells) and the target tissues (adipose tissue, liver and pancreas) that are affected by inflammatory mediators. The time line of events and the molecular mechanisms that integrate the inflammatory response with metabolic homeostasis at the tissue and systemic levels are still to be characterized in T2D. Recently, we discovered that inflammatory pathways controlled by Interferon Regulatory Factor 5 (IRF5) in macrophages (the sensor cells) orchestrate the immune response towards a pro-diabetogenic program (Dalmas et al. Nature Medicine in press). Interfering with IRF5 pathways (IRF5 macrophage specific KO mice) lead to modification of the innate and adaptive response leading to a healthier metabolic status. Extensive characterisation of the IRF5-dependent immune response is required for a better understanding of physiological (protective) versus pathological immune programs involved in T2D (mouse studies). These immune programs will also be validated in different clinical situations (human studies) ie: weight loss, exercise and immune-therapy (IL-6 modulation) known to improve diabetes and reduce inflammation. The overall objective of the proposed project is to reveal the physiologic role of inflammation dependent of IRF5 pathways in the adaptation to metabolic stress linked to T2D. Understanding the physiological and the pathological role of the immune system may allow designing personalized treatments promoting a beneficial immune status in patients with T2D.
Immunologic consequences of time-graded exposure to an 'obesity-diabetes milieu' Research Project | 3 Project MembersTraditionellerweise werden Metabolismus und Immunität als zwei verschiedene Entitäten mit verschiedenen Funktionen wahrgenommen: der Metabolismus reguliert die Nahrungsverteilung, die Immunität ist für die Abwehr zuständig. Dieses Konzept hat zu verschiedenen spezialisierten Forschungsgebieten mit wenig Interaktionen geführt. In den letzten Jahren hat sich jedoch gezeigt, dass bei übergewichtigen Patienten und Patienten mit Typ 2-Diabetes eine pathologische Aktivierung des Immunsystems stattfindet. Diese führt zu Versagen der Insulinproduktion und Aktionen. Aus diesem Grund wird heute der Typ 2-Diabetes auch als eine inflammatorische Erkrankung betrachtet. Neben diesen pathologischen Aspekten scheint das Immunsystem auch eine Rolle in der Physiologie des Metabolismus eine Rolle zu spielen. Andererseits scheint auch der Metabolismus die Immunzellen zu regulieren. In den vorgeschlagenen Experimenten sollen nun der Zusammenhang zwischen Metabolismus (Marc Donath), Immunologie (Christoph Hess) und Epigenetik (Renato Parro) untersucht werden, um die Hypothese zu testen, dass Übergewicht und Diabetes einen Einfluss haben auf Zellen des Immunsystems, die auch epigenetisch fixieren können. Wir planen zu untersuchen, wie akut sowie chronisch ein metabolischer Stress, charakterisiert durch ein Überangebot an Nährstoffen, sich auf die metabolische Antwort, Funktion und Epigenetik von Zellen von angeborenem und adaptivem Immunsystem auswirkt. Die Mechanismen sowie auch die Reversibilität sollen untersucht werden.
