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Researchers Ferret Out a New Model for Cystic Fibrosis-related Diabetes

The recently developed ferret model of cystic fibrosis (CF) is providing key insights into the development of an important consequence of the disease in humans—CF-related diabetes (CFRD), which is associated with worsening lung function, dangerous weight loss, and increased mortality. Improved antibiotics and other therapeutics have dramatically increased life expectancy for people with CF, roughly quadrupling it over the last 3 decades. As this has happened, complications like CFRD—which affects almost half of CF patients over the age of 30—are of increasing concern to people with CF and those helping them manage their disease. Although the physiological reasons why CF often leads to CFRD are unknown, researchers have found it to be quite different from other major forms of diabetes. Unlike type 1 diabetes, there is no autoimmune attack on the insulin-producing β cells of the pancreas in CFRD. Insulin resistance—a central feature of type 2 diabetes—is often observed to some degree in CFRD, but while obesity is a risk factor for type 2 diabetes, underweight is a much more likely concern in CFRD. 

Mouse and pig models of CF have helped clarify what goes wrong in some of the many organ systems affected by the disease. But the utility of these models has been limited by differences between the animals and humans in the way CF affects certain organs and tissues. Of particular note, CF results in enormous damage to the pancreases of pigs even before birth, while CF mice rarely (if ever) develop CFRD. In contrast, CF ferrets have pancreatic problems that more closely mimic human CF, so researchers used that animal model to help uncover the underlying causes of CFRD. They discovered that CF ferrets had early and gradually worsening regulation of glucose levels, not unlike what is often observed in people who have CF. The researchers found that the CF ferrets have smaller clusters (“islets”) of β cells at birth, and fewer islets at death, than do control animals without CF. Intriguingly, they also discovered that laboratory cultures of islets from newborn CF ferrets did not respond appropriately to changes in glucose levels: compared to islets from ferrets without the disease, the CF ferret’s β cells secreted less insulin at high glucose levels, and also secreted more insulin at low glucose levels. The net effect observed in living CF ferrets was relatively even insulin levels that do not fluctuate normally in response to rising or falling blood glucose levels. These observations show that even at birth, insulin secretion by the pancreas is abnormal in animals with CF. Taken together, the results suggest that despite the insulin resistance often observed in CFRD, the disease quite likely stems from defects in β cell function, and that while some of these β cell problems are present from birth, they are exacerbated by progressive damage to the pancreas. Further study of the ferret model of CF may help researchers find improved ways to prevent or treat CFRD in people with CF. 

Olivier AK, Yi Y, Sun X, et al. Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets. J Clin Invest 122: 3755-3768, 2012.