EXPLORING THE ROLE OF MELATONIN IN ISLET CELLS AND TYPE 2 DIABETES

Failure of pancreatic β-cells to release adequate amounts of insulin is the main culprit in type 2 diabetes (T2D). Efforts from us highlight melatonin, the circadian rhythm hormone, as a critical regulator of insulin release.

In fact, carriers of a common variant of the melatonin receptor 1B (MNTR1B) gene are at higher risk of developing T2D.This project aims to understand the pathological properties of melatonin signaling in islet cells.

We will use patient specific (MTNR1B risk variant) human induced pluripotent stem cells (hiPSCs) differentiated to α and β-like cells.

Single base genome editing to “repair” the disease variant and stable knock out lines of both melatonin receptors (MTNR1A and MTNR1B) by CRISPR/Cas9, will explain the diabetogenic phenotype in humans.

Cells will be assessed by live cell imaging to establish functional changes, due to disease variant correction or knock out of receptors.To comprehend the involvement of melatonin on glucose homeostasis, and islet function, α and β-cell specific knock out mice will be phenotyped in vivo and in vitro.

Collectively, this will deepen our understanding of how melatonin influence development of T2D.

Additionally, our models will allow for screening of pharmacological compounds targeting melatonin signaling, information that can be utilized to provide novel precision medicine tools and thus innovative therapeutic strategies.