Harnessing long non-coding RNAs (lncRNAs) to stimulate pancreatic islet regeneration

Pancreatic β-cells within islets of Langerhans release insulin in response to blood glucose levels. While glucose transporters such as GLUT1 permit basal glucose transport in the absence of insulin, the presence of insulin causes a greater uptake of circulating glucose. Insulin binds cell surface insulin receptors to stimulate translocation of intracellular GLUT4 transporters to the cell surface. This allows a large cellular influx of glucose, thereby clearing glucose in the blood to restore normoglycemia. Type 2 diabetes mellitus (T2D) is a condition that is characterised by a reduced capacity for blood glucose clearance, hyperglycemia, insulin resistance and β-cell dysfunction. Individuals that are predisposed to T2D enter a prediabetic phase whereby insulin resistance increases while β-cell mass and function gradually diminishes. The tipping point for T2D onset comes when β-cells can no longer compensate for large amounts of glucose in the blood, cellular stress causes loss of β-cell mass and function. Sustained hyperglycemia has toxic effects on the organs which cause the complications of T2D, such as increased risk of heart attack and stroke, neuropathy, retinopathy and kidney failure.

It is well known that human β-cells have a poor proliferation rate in adulthood. However, β-cell proliferation was shown to increase during pregnancy as an adaptive response the metabolic demand of a growing fetus. Delivery of glucose from the mother to the fetus is a passive process that depends on high maternal blood glucose and low fetal blood glucose. To maintain this gradient, the mother undergoes increased insulin resistance, stimulated by placental hormones, which prevents her cells taking up glucose and allows its direction to the fetus. β-cells proliferate in response to placental lactogens to compensate for the greater insulin demand. An aim of this project is to explore the molecular mechanism in increased β-cell proliferation, as stimulating proliferation could provide a potential therapeutic approach to treat T2D.

Long non-coding RNAs (lncRNAs) are relatively unstudied molecules whose functions have recently been established in vital cellular processes such as transcription, mRNA processing and protein stability. Preliminary research has identified >1100 lncRNAs that are differentially expressed in β-cells and have roles in their differentiation. This project aims to screen these lncRNAs to investigate their potential roles in enhanced β-cell proliferation. So far, initial attempts to knockdown lncRNAs by transfecting with CRISPRi were unsuccessful and needs more investigation.

Publications:

The role of long non-coding RNAs in the regulation of pancreatic beta cell identity.  M.E. Wilson, T.J. Pullen. Biochem Soc Trans. 2021:BST20210207.