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Islet inflammation in type 2 diabetes: pathogenesis and therapy

Applicant Donath Marc Yves
Number 130008
Funding scheme Project funding (Div. I-III)
Research institution Abteilung Endokrinologie, Diabetologie und Metabolismus Universitätsspital Basel
Institution of higher education University of Zurich - ZH
Main discipline Clinical Endocrinology
Start/End 01.04.2010 - 31.03.2013
Approved amount 537'000.00
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All Disciplines (2)

Discipline
Clinical Endocrinology
Pathophysiology

Keywords (6)

Diabetes; Inflammation; insulin; glucose; IL-1; IL-6

Lay Summary (English)

Lead
Lay summary
Our 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
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
In vitro proliferation of adult human Beta-cells.
Rutti Sabine, Sauter Nadine S, Bouzakri Karim, Prazak Richard, Halban Philippe A, Donath Marc Y (2012), In vitro proliferation of adult human Beta-cells., in PloS one, 7(4), 35801-35801.
Cannabis exposure associated with weight reduction and β-cell protection in an obese rat model.
Levendal R-A, Schumann D, Donath M, Frost C L (2012), Cannabis exposure associated with weight reduction and β-cell protection in an obese rat model., in Phytomedicine : international journal of phytotherapy and phytopharmacology, 19(7), 575-82.
How biologics targeting the IL-1 system are being considered for the treatment of type 2 diabetes.
Böni-Schnetzler Marianne, Donath Marc Y (2012), How biologics targeting the IL-1 system are being considered for the treatment of type 2 diabetes., in British journal of clinical pharmacology, .(.), .-..
ARTD1 deletion causes increased hepatic lipid accumulation in mice fed a high-fat diet and impairs adipocyte function and differentiation.
Erener Süheda, Mirsaidi Ali, Hesse Mareike, Tiaden André N, Ellingsgaard Helga, Kostadinova Radina, Donath Marc Y, Richards Peter J, Hottiger Michael O (2012), ARTD1 deletion causes increased hepatic lipid accumulation in mice fed a high-fat diet and impairs adipocyte function and differentiation., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, .(.), .-..
Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells.
Ellingsgaard Helga, Hauselmann Irina, Schuler Beat, Habib Abdella M, Baggio Laurie L, Meier Daniel T, Eppler Elisabeth, Bouzakri Karim, Wueest Stephan, Muller Yannick D, Hansen Ann Maria Kruse, Reinecke Manfred, Konrad Daniel, Gassmann Max, Reimann Frank, Halban Philippe A, Gromada Jesper, Drucker Daniel J, Gribble Fiona M, Ehses Jan A, Donath Marc Y (2011), Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells., in Nature medicine, 17(11), 1481-9.
Subacute bilateral visual loss in methylmalonic acidemia.
Traber Ghislaine, Baumgartner Matthias R, Schwarz Urs, Pangalu Athina, Donath Marc Y, Landau Klara (2011), Subacute bilateral visual loss in methylmalonic acidemia., in Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Soci, 31(4), 344-6.
Inflammation as a sensor of metabolic stress in obesity and type 2 diabetes.
Donath Marc Y (2011), Inflammation as a sensor of metabolic stress in obesity and type 2 diabetes., in Endocrinology, 152(11), 4005-6.
Inhibition of IL-1beta improves fatigue in type 2 diabetes.
Cavelti-Weder Claudia, Furrer Romana, Keller Cornelia, Babians-Brunner Andrea, Solinger Alan M, Gast H, Fontana A, Donath Marc Y, Penner Iris K (2011), Inhibition of IL-1beta improves fatigue in type 2 diabetes., in Diabetes care, 34(10), 158-158.
Increased IL-1β activation, the culprit not only for defective insulin secretion but also for insulin resistance?
Böni-Schnetzler Marianne, Donath Marc Y (2011), Increased IL-1β activation, the culprit not only for defective insulin secretion but also for insulin resistance?, in Cell research, 21(7), 995-7.
Bimodal effect on pancreatic β-cells of secretory products from normal or insulin-resistant human skeletal muscle.
Bouzakri Karim, Plomgaard Peter, Berney Thierry, Donath Marc Y, Pedersen Bente Karlund, Halban Philippe A (2011), Bimodal effect on pancreatic β-cells of secretory products from normal or insulin-resistant human skeletal muscle., in Diabetes, 60(4), 1111-21.
Characteristics of a multisensor system for non invasive glucose monitoring with external validation and prospective evaluation.
Caduff Andreas, Mueller Martin, Megej Alexander, Dewarrat Francois, Suri Roland E, Klisic Jelena, Donath Marc, Zakharov Pavel, Schaub Dominik, Stahel Werner A, Talary Mark S (2011), Characteristics of a multisensor system for non invasive glucose monitoring with external validation and prospective evaluation., in Biosensors & bioelectronics, .(.), .-..

Associated projects

Number Title Start Funding scheme
146840 Role of the innate immune system in the regulation of pancreatic islet function 01.04.2013 Project funding (Div. I-III)
116701 Islet inflammation in diabetes: from adaptation to failure 01.04.2007 Project funding (Div. I-III)

Abstract

Our research focuses on the mechanisms and therapy of decreased insulin production in type 2 diabetes. In previous studies we demonstrated that the metabolic stress evoked by hyperglycaemia and saturated fatty acids may induce death of the insulin producing ß-cells. Subsequently we identified IL-1ß as a key mediator of these deleterious effects and showed that it is produce by human ß-cells in response to metabolic stress in type 2 diabetes. More recently we published several additional studies supporting the concept that this islet derived IL-1ß leads to an inflammatory process and underlies ß-cell failure and apoptosis in the pathogenesis of 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 insulitis 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-1ß production leading to islet inflammation. However, the underlying mechanism remains unclear. Since insoluble materials such as uric acid crystals and neuronal amyloid-ß activate the inflammasome (which is required for the secretion of active IL-1ß), we hypothesize that free fatty acids and/or human islet amyloid polypeptide activate the inflammasome in pancreatic islets, an effect which could be potentiated by high glucose and IL-1ß auto-stimulation.Aim 2: To investigate the role of IL-6 in regulating a- and L-cell turnover, function and proglucagon derived peptides. 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 pancreatic a-cell mass expansion along with a switch of proglucagon processing from glucagon to glucagon-like peptide 1 (GLP-1) production. We aim to investigate (2a) whether IL-6 regulates a- and L-cell derived GLP-1 through an upregulation of prohormone convertase (PC) 1/3, (2b) whether metabolic stress (elevated glucose and free fatty acid levels) induces expression of proglucagon and PC1/3 in the a-cell and subsequent GLP-1 release, and whether IL-6 is involved in this regulation, and (2c) whether IL-6 regulated a- and L-cell derived GLP-1 is biologically relevant for maintaining ß-cell function during high fat feeding.Aim 3: To determine the effect of IL-1ß 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 glycemia and ß-cell secretory function and reduced markers of systemic inflammation in patients with type 2 diabetes. 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-1ß 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-1ß antagonism is associated with changes in ß-cell function, insulin sensitivity, plasma levels of glucagon, incretines, adipokines, inflammatory markers, lipid profile, hepatic steatosis, fat cell size, macrophage infiltration in adipose tissue, and adipose tissue gene expression.
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