Projects & Collaborations 9 foundShow per page10 10 20 50 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. 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. Anti-inflammatory regulators in pancreatic islets: role in physiology and diabetes Research Project | 3 Project MembersObesity and type 2 diabetes are associated with a state of chronic low-grade inflammation characterized by proinflammatory immune infiltrates in the endocrine organs, including pancreatic islets. While extensive research has focused of the role of inflammation in the development of metabolic complications, rare studies highlighted the role of benign resident immune cells in tissue physiology during leanness and/or health. Resident immune cells are able to react to changes in physiology and allow the host to restore homeostasis to the tissue. To our knowledge, no comprehensive analysis of pancreatic islet resident immune cells and their potential role in islet function has been reported yet. Therefore, our project will help to identify the resident immune cells of the pancreatic islets and how they influence pancreatic islet function in physiology and during inflammation induced by metabolic stress such as type 2 diabetes. Our preliminary data strongly support the hypothesis that enhancement of type 2 immunity is likely to improve islet function and mediate protection against obesityinduced metabolic stress. We will phenotype the resident immune cells within islets and then we will assess which factors promote immune cell residency and whether pancreatic islets express endogenous mediators to sustain type 2 immunity. Our project will provide insights into new defence mechanisms that might protect pancreatic islets to cope with mild but regular stress, opening new avenues to the conception of novel antiinflammatory immunotherapies in the field of metabolic diseases. Role of the innate immune system in type 2 diabetes Research Project | 1 Project MembersOur research focuses on the mechanisms of decreased insulin production in type 2 diabetes. We have described an inflammatory process underlying the defect of insulin production in this condition. On the basis of this we conducted clinical studies. This program has now entered the phase 3 of clinical development. The objective of the present project is to uncover additional roles of the immune system in the regulation of insulin secretion during adaptation to obesity and its contribution to diabetes Role of SIRT1 in type 1 diabetes Research Project | 1 Project MembersRecently we identified a family carrying a mutation in the SIRT1 gene, in which affected members display not only the classical features of type 1 diabetes, but also insulin resistance. At the time of diagnosis, a 26-year-old lean man presented signs of type 1 diabetes, including auto-antibodies to ƒÒ-cell antigens and a rapid dependence on insulin. Intriguingly, several of the patients¡¦ family members were also affected. Given the hereditary nature of the phenotype, genomic sequencing was performed in order to identify possible DNA mutations associated with the disease. Analysis of the SIRT1 gene revealed the presence of a T to C exchange in exon 1 of a single allele, corresponding to a Leucine-Proline mutation at residue 107 in the protein. Expression of SIRT1-L107P in the £]-cell line Min6 resulted in NF-ƒÛB hyperacetylation (p65 acetyl K3109) and overproduction of inducible nitric oxide, cytokines, and chemokines, relative to an equal expression of the wild-type protein. These observations underscore the importance of SIRT1 in glucose metabolism in humans and identify a novel role for SIRT1 in auto-immunity. Furthermore these results unveil the first monogenic form of type 1 diabetes with intersecting symptoms of type 2 diabetes. Our data provide evidence that SIRT1 activators may prevent or treat this condition in humans. Islet inflammation in type 2 diabetes: pathogenesis and therapy Research Project | 1 Project MembersOur research focuses on the mechanisms and therapy of decreased insulin production by the pancreatic islets in the obesity associated type 2 diabetes. In previous studies we demonstrated that the metabolic stress evoked by high glucose and saturated fatty acids (contained in animal fat) may induce death of the insulin producing beta-cells of the islets. Subsequently we identified a factor termed interleukin 1 beta (IL-1b) as a key mediator of these deleterious effects and showed that it is produce by human beta-cells in type 2 diabetes. More recently we published several additional studies supporting the concept that this mechanism leads to an inflammatory process and underlies the failure to produce sufficient amount of insulin in type 2 diabetes. On the basis of this we initiated clinical trials in patients with type 2 diabetes that vindicates this hypothesis and opens the way for a causative treatment. The overall goal of the present project aims at understanding the precise role and regulation of the uncovered islet inflammation in type 2 diabetes and test therapeutic intervention at early stages of the disease. In particular, we propose the following aims: Aim 1: To study the mechanism of nutrient induced islet inflammation: We have shown that metabolic stress (increased glucose and free fatty acids levels) induces islet derived IL-1b production leading to islet inflammation. However, the underlying mechanism remains unclear. We hypothesize that this involves a group of proteins termed inflammasome. Aim 2: To investigate the role of IL-6 in regulating glucagon-like peptide 1. Plasma IL-6 levels are chronically elevated in obese and type 2 diabetic individuals and predict disease progression. In recent studies we observed that IL-6 regulates a hormone termed GLP-1. GLP-1 may increase the mass and capacity of the beta-cells to produce insulin. We aim to investigate the mechanisms and precise consequences of IL-6 regulated GLP-1. Aim 3: To determine the effect of IL-1b antagonism on insulin secretion and action in obese subjects at risk to develop type 2 diabetes. We have shown that he blockade of IL-1 improved type 2 diabetes and insulin secrtion. However, the consequence of IL-1 antagonism in individuals at risk to develop diabetes has not been studied. The overall objective of this study is therefore to determine in obese subjects whether blocking IL-1b improves insulin secretion and action. We will conduct a placebo-controlled, double-blind study in obese subjects with impaired glucose metabolism. We will assess whether IL-1b antagonism is associated with changes in insulin secretion and thus diabetes prevention 1 1
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.
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.
Anti-inflammatory regulators in pancreatic islets: role in physiology and diabetes Research Project | 3 Project MembersObesity and type 2 diabetes are associated with a state of chronic low-grade inflammation characterized by proinflammatory immune infiltrates in the endocrine organs, including pancreatic islets. While extensive research has focused of the role of inflammation in the development of metabolic complications, rare studies highlighted the role of benign resident immune cells in tissue physiology during leanness and/or health. Resident immune cells are able to react to changes in physiology and allow the host to restore homeostasis to the tissue. To our knowledge, no comprehensive analysis of pancreatic islet resident immune cells and their potential role in islet function has been reported yet. Therefore, our project will help to identify the resident immune cells of the pancreatic islets and how they influence pancreatic islet function in physiology and during inflammation induced by metabolic stress such as type 2 diabetes. Our preliminary data strongly support the hypothesis that enhancement of type 2 immunity is likely to improve islet function and mediate protection against obesityinduced metabolic stress. We will phenotype the resident immune cells within islets and then we will assess which factors promote immune cell residency and whether pancreatic islets express endogenous mediators to sustain type 2 immunity. Our project will provide insights into new defence mechanisms that might protect pancreatic islets to cope with mild but regular stress, opening new avenues to the conception of novel antiinflammatory immunotherapies in the field of metabolic diseases.
Role of the innate immune system in type 2 diabetes Research Project | 1 Project MembersOur research focuses on the mechanisms of decreased insulin production in type 2 diabetes. We have described an inflammatory process underlying the defect of insulin production in this condition. On the basis of this we conducted clinical studies. This program has now entered the phase 3 of clinical development. The objective of the present project is to uncover additional roles of the immune system in the regulation of insulin secretion during adaptation to obesity and its contribution to diabetes
Role of SIRT1 in type 1 diabetes Research Project | 1 Project MembersRecently we identified a family carrying a mutation in the SIRT1 gene, in which affected members display not only the classical features of type 1 diabetes, but also insulin resistance. At the time of diagnosis, a 26-year-old lean man presented signs of type 1 diabetes, including auto-antibodies to ƒÒ-cell antigens and a rapid dependence on insulin. Intriguingly, several of the patients¡¦ family members were also affected. Given the hereditary nature of the phenotype, genomic sequencing was performed in order to identify possible DNA mutations associated with the disease. Analysis of the SIRT1 gene revealed the presence of a T to C exchange in exon 1 of a single allele, corresponding to a Leucine-Proline mutation at residue 107 in the protein. Expression of SIRT1-L107P in the £]-cell line Min6 resulted in NF-ƒÛB hyperacetylation (p65 acetyl K3109) and overproduction of inducible nitric oxide, cytokines, and chemokines, relative to an equal expression of the wild-type protein. These observations underscore the importance of SIRT1 in glucose metabolism in humans and identify a novel role for SIRT1 in auto-immunity. Furthermore these results unveil the first monogenic form of type 1 diabetes with intersecting symptoms of type 2 diabetes. Our data provide evidence that SIRT1 activators may prevent or treat this condition in humans.
Islet inflammation in type 2 diabetes: pathogenesis and therapy Research Project | 1 Project MembersOur research focuses on the mechanisms and therapy of decreased insulin production by the pancreatic islets in the obesity associated type 2 diabetes. In previous studies we demonstrated that the metabolic stress evoked by high glucose and saturated fatty acids (contained in animal fat) may induce death of the insulin producing beta-cells of the islets. Subsequently we identified a factor termed interleukin 1 beta (IL-1b) as a key mediator of these deleterious effects and showed that it is produce by human beta-cells in type 2 diabetes. More recently we published several additional studies supporting the concept that this mechanism leads to an inflammatory process and underlies the failure to produce sufficient amount of insulin in type 2 diabetes. On the basis of this we initiated clinical trials in patients with type 2 diabetes that vindicates this hypothesis and opens the way for a causative treatment. The overall goal of the present project aims at understanding the precise role and regulation of the uncovered islet inflammation in type 2 diabetes and test therapeutic intervention at early stages of the disease. In particular, we propose the following aims: Aim 1: To study the mechanism of nutrient induced islet inflammation: We have shown that metabolic stress (increased glucose and free fatty acids levels) induces islet derived IL-1b production leading to islet inflammation. However, the underlying mechanism remains unclear. We hypothesize that this involves a group of proteins termed inflammasome. Aim 2: To investigate the role of IL-6 in regulating glucagon-like peptide 1. Plasma IL-6 levels are chronically elevated in obese and type 2 diabetic individuals and predict disease progression. In recent studies we observed that IL-6 regulates a hormone termed GLP-1. GLP-1 may increase the mass and capacity of the beta-cells to produce insulin. We aim to investigate the mechanisms and precise consequences of IL-6 regulated GLP-1. Aim 3: To determine the effect of IL-1b antagonism on insulin secretion and action in obese subjects at risk to develop type 2 diabetes. We have shown that he blockade of IL-1 improved type 2 diabetes and insulin secrtion. However, the consequence of IL-1 antagonism in individuals at risk to develop diabetes has not been studied. The overall objective of this study is therefore to determine in obese subjects whether blocking IL-1b improves insulin secretion and action. We will conduct a placebo-controlled, double-blind study in obese subjects with impaired glucose metabolism. We will assess whether IL-1b antagonism is associated with changes in insulin secretion and thus diabetes prevention
