Congratulations to Naomi Berrie Diabetes Center scientist Utpal Pajvani, MD, PhD, who received a Roy and Diana Vagelos Precision Medicine inaugural Pilot Grant—a 2-year, $200,000 award intended to support groundbreaking research relevant to advancing the basic science of precision medicine.
Dr. Pajvani, the Herbert Irving Assistant Professor of Medicine, is an expert on a protein called Notch, which has been extensively studied in the context of cancer—but his lab has shown that Notch is also important to the development of metabolic diseases such as type 2 diabetes (T2D) and fatty liver. The title of this grant is NOTCH2 polymorphisms as predictors of low beta cells.
“A critical question in the pathogenesis of all types of diabetes is the mechanism by which the number of beta cells in the islets is determined,” explained Berrie Center Co-Director Rudolph Leibel, the Christopher J. Murphy Memorial Professor of Diabetes Research. “Larger beta cell mass, all other things being equal, can be protective against the development of diabetes. Dr. Pajvani is a longstanding student of the Notch signaling pathway that plays a role in the development of many tissues. In most tissues, the gene shuts off after early development. Dr. Pajvani has shown that reactivation of the Notch pathway in beta cells occurs in response to high-fat diets and elevated blood glucose. This reactivation is associated with impaired beta cell function. Dr. Pajvani proposes to use human stem cell-derived beta cells to determine the role of Notch in the proliferation and function of these cells.”
Dr. Pajvani’s team will be led by Alberto Bartolome, PhD, an Associate Research Scientist and prior recipient of the Berrie Frontiers Fellowship, who brings considerable expertise in beta cell biology. Key Berrie Center collaborators for the proposed studies include stem cell scientist, Dieter Egli, PhD, the Maimonides Assistant Professor of Developmental Cell Biology and Domenico Accili, MD, the Russell Berrie Foundation Professor of Diabetes, whose long-term contributions to the understanding of diabetes earned him the 2017 American Diabetes Association’s Banting Medal.
“What we hope to do,” continued Dr. Pajvani, who was an endocrine fellow in Dr. Accili’s lab from 2007 through 2011, “is to look at whether Notch could be influencing pancreatic beta cell biology in a way that is conferring risk to getting T2D. I’ve been thinking about this question for over ten years now, and it’s one of the reasons I started studying Notch. Now the technology has finally caught up to the questions I’ve been asking for all these years, and I feel like we can do this.”
Dr. Pajvani is mostly talking about the giant strides that have been made in pluripotent, or adult-generated, stem cell technology (including the work of Dr. Egli who is a pioneer in the field) without which this research would be impossible. “Using Dr. Egli’s protocols, we are looking at whether we can use human stem cells to model beta cell development and see whether we can do this using cells from people who have a NOTCH2 risk variant—a small change in their genetic signature that predisposes them to T2D.”
Hopefully, said Dr. Pajvani, his team will answer the academic question of how these NOTCH2 risk variants (or SNPs, Single Nucleotide Polymorphisms, pronounced “snips”) predispose to diabetes. But he is also excited about the possible clinical implications of this study down the road:
“We want to take advantage of our clinical expertise and the fact that this is a very, very common risk variant,” Dr. Pajvani said, “Maybe one in ten people with T2D who come to the Berrie Center have this SNP. Do these people end up needing insulin at a much earlier stage of disease? Do they have less beta cell mass? Do they need more of a stimulus to secrete insulin? Would they benefit from a certain class of medication? Eventually, this is where we want to take the study. We’re doing this work because it has clear clinical implications.”