Modeling Monogenic Diabetes – MDM

Type 2 diabetes (T2D) affecting 300 million individuals worldwide and responsible for severe co-morbidities and early mortality, is a main health challenge of the 21st century. Whilst the environment is the key contributing factor at the population level, genetic factors are the major determinants of the individual response to the Westernized lifestyle. Our understanding of the physiology of common T2D has recently improved through genome-wide association studies (GWAS), although the 70 confirmed T2D loci identified so far explain no more than 10% of T2D inheritance. Familial forms of non-autoimmune early-onset diabetes such as Maturity-Onset Diabetes of the Young (MODY) are thought to be monogenic. These forms of T2D are due to primary dysfunction of pancreatic ß-cells resulting in severe insulin secretion defects. Elucidating the genetic bases of familial T2D has brought much insight in the last 15 years and should bring again new breakthroughs in the physiopathology of glucose homeostasis.
In the present project, we aim to perform whole-exome sequencing (WES) in large multigenerational unelucidated MODY-X pedigrees, followed by 1/ innovative cellular analyses using induced pluripotent stem cells (iPSCs) generated from blood samples or primary fibroblasts of MODY-X patients and their potential to differentiate into human functional pancreatic ß-cells; and 2/ extensive metabolic characterization of novel diabetes gene function, in order to further elucidate the molecular bases of T2D.
The main objectives of MDM are:
1/ To identify the genetic causes of 12 unresolved early-onset diabetes MODY-X families using WES analysis for diabetes gene discovery (Task 2, Partner 1). WES has been fully optimized and is routinely used in the Partner 1 laboratory. A staged proprietary mutation filter process will be used for the identification of putatively causative non synonymous mutations co-segregating with MODY. The contribution of novel MODY genes in European families will subsequently be assessed.
2/ To produce functional human pancreatic ß-cells from MODY patient’s iPS cell line and to characterize their phenotype and function. We will first validate the model in MODY-3 patients (with a known mutation in HNF1A) before to extend the model to the mutations discovered in Task 2 (Task 3, Partners 2 and 1).
3/ To elucidate the cellular mechanisms leading to primary human pancreatic ß-cell function defects due to the mutations identified in Task 2 (Task 4, Partners 1 and 2).
4/ To explore the metabolic consequences of the newly identified MODY mutations on insulin secretion, in human carriers of these genetic defects (Task 5, Partners 3 and 1). This will be achieved further by using glucose clamp methods in carrier subjects.
The overall goal of MDM is to take the opportunity of our unique collection of well phenotyped families with early-onset diabetes and of the emerging WES potential for the discovery of new susceptibility genes to elucidate novel genetic aetiologies of diabetes and related defects on insulin secretion, using cutting edge iPSC strategy. Importantly, the new findings should lead to a better treatment to MODY patients, as previously shown for several MODY genes. Furthermore, it may identify specific molecular targets for new drug treatments for common T2D (as evidenced for glucokinase activators). WES and iPSC modeling may be subsequently extended to other forms of familial T2D opening avenues to personalized diabetes medicine.