T2D can be characterized by a reduction in insulin production, a reduction in the body’s response to insulin, or both. Insulin supply can be managed by drugs that boost production from the pancreatic islets of patients, but there has never been a clear understanding of why insulin production falls in the first place. Dr Patrick MacDonald changed that with research that identified a key mechanism for the elusive “dimmer switch”, postulated to exist as far back as 25 years ago.
MacDonald and his research team that included Drs Mourad Ferdaoussi, Xiaoqing Dai, Joceylyn Manning Fox, Kunimasa Suzuki, PhD student Catherine Hamjrle, undergraduate student Robert Wright, and lab specialists Gregory Plummer, Aliya Spigelman and Nancy Smith examined islet cells from 99 human organ donors and identified a new molecular pathway that manages the amount of insulin produced and adjusts how much of the hormone is secreted when blood sugar rises.
They focused on isocitrate and showed that the cytosolic enzyme isocitrate dehydrogenase (ICDc) produces signals that contributes to the amplification of insulin exocytosis via another enzyme that MacDonald has studied extensively – sentrin/SUMO-specific protease-1 (SENP1). Deletion of SENP1 in mice caused impaired glucose tolerance by reducing insulin secretion and activating this enzyme in islets from human donors with T2D rescued insulin production.
Together, these results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues ϐ-cell function in diabetes. Results of MacDonald’s research were published in The Journal of Clinical Investigation (125:3847-3860, 2015) and received considerable attention globally.