Disease
ULB CENTER FOR DIABETES RESEARCH
The disease and our approach
Disease
Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia that can lead to chronic complications such as cardiovascular disease, blindness and kidney failure. Loss of functional β-cell mass is the key mechanism leading to the two main forms of diabetes mellitus, type 1 and type 2 diabetes. In order to prevent or revert diabetes, it is critical to understand the mechanisms behind β-cell failure, and this is one of the main objectives of the UCDR. There are basic pathogenic differences in the two forms of diabetes, i.e. immune-mediated in type 1 diabetes and metabolic in type 2 diabetes, which differentially impact early β-cell dysfunction and eventual fate.
In recent years there have been major advances in the field, mostly delivered by studies on β-cells in human disease. These include studies of islet morphology and human β-cell gene expression in type 1 and type 2 diabetes, the identification and characterization of the role of diabetes candidate genes at the β-cell level, and endoplasmic reticulum stress signaling that contributes to β-cell failure in both forms of diabetes. Current therapies consist of insulin administration or drugs that increase insulin secretion or insulin sensitivity, but unfortunately none of them prevent the progressive loss of functional β-cell mass. Thus, research to develop novel treatment strategies to protect pancreatic b-cells in diabetes is urgently needed. The two most frequent types of diabetes are type 1 and type 2 diabetes:
Type 1 diabetes
Type 1 diabetes accounts for 10-15% of cases of diabetes. The prevalence of type 1 diabetes in children is doubling every 25 years, and still today causes an average loss of 11-12 years of life expectancy. Type 1 diabetes is caused by autoimmune-mediated β-cell dysfunction and apoptosis, leading to the lifelong need for exogenous insulin therapy. The disease is the consequence of a complex âdialogueâ involving on the one hand invading or resident immune cells, which release chemokines and cytokines in the islet micro-environment and deliver cell-to-cell pro-apoptotic signals, and on the other hand signals generated by stressed, injured or dying β-cells that attract and activate immune cells to the islets. This dialogue is determined by the host genetic background, age and environmental factors such as viral infections, diet etc. It may trigger local inflammation (insulitis) and progressive β-cell dysfunction and death, mainly via apoptosis, or be arrested by protective mechanisms that dampen the immune response and restore physiology.Â
Researchers at the UCDR are dedicated to finding new tools for effective detection, prevention and treatment strategies for the disease. This is based on basic and clinical research studies, using adult human β-cells or induced pluripotent stem cell-derived β-cells to characterize the causes and mechanisms of the disease and, based on this information, to identify novel therapies to protect β-cells and arrest or delay the autoimmune assault.
Type 2 diabetes
Type 2 diabetes represents the bulk (80%) of all cases of diabetes. Relative insulin deficiency due to β-cell dysfunction, often coexisting with insulin resistance, is key for disease development. Type 2 diabetes remains an ill-defined form of diabetes and a diagnosis of exclusion: no specific diagnostic criteria exist for type 2 diabetes. Obesity, energy-dense âWesternâ diets, older age and sedentary lifestyle are key risk factors for type 2 diabetes that have driven a 4-fold increase in the number of cases over the last 40 years. These risk factors may precipitate both β-cell failure and insulin resistance. Even if chronic complication rates have improved over time, type 2 diabetes remains associated with significant morbidity and mortality. It shortens life span by 6 years on average, but the loss in life expectancy reaches 12 years in people who develop type 2 diabetes at a younger age. While a large number of drug classes exist to treat type 2 diabetes, none has been convincingly shown to modify the progressive decline in β-cell function over time.
Researchers at the UCDR are developing novel experimental models to study the disease and its therapy, using adult human β-cells, induced pluripotent stem cell-derived β-cells and transgenic and humanized mouse models. The ultimate aim is to characterize the causes and mechanisms of progressive β-cell failure in type 2 diabetes and, based on this information, to propose novel therapies to preserve and/or restore β-cell function.
Monogenic forms of diabetes
While much less common than type 1 or type 2 diabetes, monogenic forms of diabetes are important to recognize and study. They can be viewed as experiments of nature that provide important insight into molecules and pathways that are crucial to develop and maintain human β-cell function and mass. Variants in monogenic diabetes genes are associated with type 1 and type 2 diabetes. These monogenic forms of diabetes can therefore be studied as âhuman knockout modelsâ that provide compelling genetic evidence for key aspects of β-cell biology and glucose homeostasis. The study of monogenic diseases can also provide insight for drug discovery: understanding the phenotypic effects of gain- or loss-of-function mutations provides information on the putative beneficial or deleterious consequences of changes in expression or function of a gene product. In clinic, uncommon diseases are underdiagnosed and often blindly treated based on guidelines for common forms of diabetes. Even when recognized, rare diseases are less likely to benefit from serendipitous observations of specific therapeutic responses, and it is more difficult to recruit sufficient numbers of patients into clinical trials.Â
Patientsâ induced pluripotent stem cell-derived β-cells provide an exciting model to study monogenic forms of diabetes. First, they can shed light on disease mechanisms and, second, provide preclinical proof for therapeutic efficacy of drugs in highly relevant disease-in-a-dish and humanized mouse models, thereby enabling rapid translation to clinical testing. By using gene silencing or overexpression approaches in adult human β-cells, inducible pluripotent cells-derived β-cells and neurons from monogenic diabetes patients (some of these forms of diabetes are associated with neurodevelopmental or neurodegenerative features) and transgenic mouse models, researchers at the UCDR are studying the molecular mechanisms underlying these pathologies and testing potential therapeutic opportunities for β-cell and neuronal preservation.
Visit us
The UCDR has several teams of established and young researchers, working together to better understand and cure diabetes.
You are welcome to visit our Center to learn about our ongoing research and see how the scientists are working to improve the health of people with diabetes. You are also welcome to explore job opportunities.
