Antonio Luis Cuesta-Muñoz, MD, PhD - Spain

Unfortunately, the primary goal of human islets transplantation to treat type 1 diabetes, long term insulin independency, has not yet been reached due to limitations such as low survival and function of the transplanted islets and the shortage of organs to treat the desired number of patients. Untill other alternatives to islets are clearly defined, success, in the context of islet transplantation, is likely to come from strategies aimed at “making every islet count”.

Glucokinase (GK) is located in pancreatic β, α and δ–cells. GK controls glucose homeostasis in humans and plays an important role in β-cell mass, proliferation and survival. Humans with severe activating mutations in the glucokinase gene (GCK) present large and highly efficient pancreatic islets and β-cell proliferation. In one patient with this type of activating mutation, who underwent 98% pancreatectomy, as little as the remaining 2% (20,000 islets) of such Highly Efficient Islets (HEI) were able to effectively maintain normal glycaemia for years with no treatment. Using lentiviral technology and ex vivo human islets, we have replicated “in vitro” these naturally occurring HEI with a significant increase in both glucose stimulated insulin secretion and capacity of proliferation.

Human HEI have a normal cytoarchitecture, survive for a long period of time, and exhibit enhanced proliferative capacity. The study of these spontaneously occurring GCK mutations has given us a precious model for the development of potential therapies for diabetes. Deconstructing this model allows us to work with a hypothesis that has already been proven –namely, that a supra-physiologic GK activity results in higher islet proliferation, viability and function. Based on these novel observations, we hypothesize that interventions aimed at increasing GK activity in normal islets will enhance β-cell replication and function. In vitro, such interventions may result in better transplantation outcomes using lower amounts of islets.

Likewise, careful analysis and characterization of these highly efficient islets will offer us a tremendous amount of information about the way human islets react and adapt physiologically and genetically to specific metabolic situations, adaptation that can impinge the equilibrium between insulin, glucagon and somatostatin secretion. In other words we will be able to obtain new and very interesting insights in human islet physiology.

The project will be approached from different and unique perspectives to allow a more complete gain of critical information. To this end, a multi-discipline research team at the University of Copenhagen, involving, the Department of Biomedical Sciences, the section of Metabolic Genetics of The Novo Nordisk Foundation Center for Basic Metabolic Research and the Danish Stem Cell Institute has been assembled.