211-LB: The Islet Tester Mouse, a Stable and Reproducible In Vivo Model to Study Human Islet Function

The current gold standard for assessing the function of human islet in vivo, is to engraft islets under the kidney capsule of hyperglycemic, immunodeficient mice. Current models, such as Streptozotocin (STZ) treatment or NSG-Akita mice, are limited due to instable hyperglycemia and/or morbidity of the mouse strain. The glycemia in STZ treated mice is variable and can even result in death or spontaneous recovery of normoglycemia, making it difficult to discern small differences in human islet function. The NSG-Akita mouse is difficult to breed and maintain, and thus has reduced practicality. To address these limitations, we developed a stable, highly reproducible immunodeficient Islet Tester mouse via CRISPR-Cas9 mediated gene editing of glucokinase (GCK) directly in NSG zygotes. Islet Tester mice are heterozygous for the Arg345->stop variant and present with stable hyperglycemia (∼250mg/dl) , without the severe age-dependent morbidity of the NSG-Akita mice. This mouse will allow us to study human islet biology over time and under different physiological conditions and could provide a useful preclinical platform to investigate drugs targeting islet cells.