HUMANIZED MOUSE MODEL TO STUDY CYSTIC FIBROSIS-RELATED DIABETES

Abstract

Up to 50% of people with cystic fibrosis (CF) develop CF-related diabetes (CFRD), accelerating lung function decline and mortality, particularly among women. Our study validates the B6-Tg(CFTR508del)Cwr (hCF) mouse, expressing the human ΔF508del CFTR gene, to study CFRD. Glucose handling was assessed by oral (OGTT) and intraperitoneal glucose tolerance tests (IPGTT); insulin and glucagon levels were evaluated via ELISAs; and islet structure was analyzed by immunofluorescence. Following IPGTT, hCF mice showed glucose intolerance with higher glucose area under the curve than WT mice; OGTT showed progressive glucose intolerance. hCF mice exhibited low fasting insulin, impaired insulin secretion, and reduced islet insulin signal intensity. Glucagon levels were generally similar across experimental groups; however, pancreatic glucagon levels were elevated in hCF males. hCF pancreata contained fewer and smaller islets than WT pancreata. These results demonstrate features of CFRD within the hCF mouse model: glucose intolerance, insulin insufficiency, and impaired islet architecture.