Diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose levels and increased risk of vascular complications. Currently 415 million people have diabetes globally, and that number is expected to rise to 642 million by 2040. Several subtypes of diabetes can be clinically distinguished, including polygenic/multifactorial, monogenic and secondary forms. The two most common forms of diabetes, type 1 (T1DM) and type 2 (T2DM) diabetes are polygenic and multifactorial. Reduced insulin signaling (be it due to insulin resistance or beta cell failure), results in decreased glucose uptake in target organs and increased release by the liver and kidney. The resulting chronic hyperglycemia in turn damages blood vessels and nerves, eventually leading to multi-organ damage.
The current standard of care for diabetes consists of exogenous insulin injections and/or oral glucose-modifying drugs. None of these therapies directly address the underlying beta cell deficit in most patients with diabetes. Beta-cell replacement therapies could effectively restore and protect the functional beta cell-mass. Transplantation of cadaveric human donor islets represents one promising approach for beta cell replacement. Shortage of donor islets however severely limits the more widespread clinical use of this alternative therapy. As such, the need for alternative supplies of human islet cells is evident. Insulin-producing cells can be generated by replication of pre-existing beta cells and/or by (trans)differentiation of non-beta cells.
The current project will identify the mechanisms regulating embryonic beta cell development, expand these mechanisms to in vivo mouse models for beta cell generation, generate a novel humanised mouse model to test beta cell regeneration and expand on the specific targeting of the therapy to human cells in vivo. Many of our prior studies were performed in mice. While mice remain a valuable tool for studying these processes in whole organism, and for preclinical tests of potential therapies, we aim to increasingly move studies into human tissues and ultimately into people.
The impact of the proposed model is potentially very high and can cause a paradigm shift in the field of beta cell regeneration. The current focus within the diabetes field is on generating sufficient functional beta cells that can improve cell therapeutic approaches. The current project proposes to develop a preclinical model representative for human diabetes to study a treatment that would omit the need for cell therapy and thus circumvent the problems associated with allograft rejection. If successful, this approach may lead to revolutionary therapies that alleviate the burden diabetes imposes on patients, with the highest incidence of type 1 diabetes observed in children between the age of 2 and 14 years old. Diabetes remains incurable, has a terrible impact on the quality of life and causes a massive socio-economical problem. Insulin-dependent patients, including young type 1 patients, can still only resort to daily injections of exogenous insulin to control disease progression.
