Cystic fibrosis disrupts pancreas two ways in CF-related diabetes

A new University of Iowa study suggests there are two root causes of a type of diabetes associated with cystic fibrosis (CF). The findings, which already have sparked a clinical trial, may guide development of new treatments or even help prevent diabetes in patients with CF.

Almost half of patients with CF will develop diabetes by age 30 and almost one quarter will develop it in their teens. In addition to the health problems caused by high blood sugar, diabetes also worsens lung disease and increases the risk of dying for people with CF. However, the underlying cause of CF-related diabetes is not well understood, and differs from the causes of type 1 or type 2 diabetes.

Using a new animal model of CF, the study found two abnormalities that affect the pancreas, the organ that produces insulin, which controls blood sugar levels. The study shows that CF progressively damages the pancreas, disrupting insulin production. More surprisingly, the study also found that CF disrupts the pancreas' insulin production even before the physical damage occurs. The results were published Sept. 17 in the Journal of Clinical Investigation.

Ferrets used to study CF-related diabetes

The UI team studied ferrets with CF that were recently developed in the lab of John Engelhardt, Ph.D., professor and head of anatomy and cell biology at the UI Carver College of Medicine.

"We turned to ferrets because studies in humans and mice have been unable to determine the underlying cause of many CF complications, including diabetes," Engelhardt says. "We found that ferrets with CF, just like humans, spontaneously develop diabetes leaving them unable to prevent high blood sugar levels following a meal."

In humans, CF damages the pancreas, which reduces insulin production. The researchers, including lead authors Alicia Olivier, Ph.D., UI assistant professor of pathology, and Yaling Yi and Xingshen Sun, Ph.D., from Engelhardt's lab, found that CF ferrets developed diabetes at 1-2 months of age, the same age the ferrets experienced severe damage to the pancreas.

"This finding fits well with the long-held view that CF-related diabetes stems from physical damage to the pancreas, which limits the amount of insulin the pancreas can produce," says study co-leader Andrew Norris, M.D., Ph.D., associate professor of pediatrics and biochemistry.

Engelhardt and Norris also are members of the Fraternal Order of Eagles Diabetes Research Center at UI.

CF disrupts insulin production from birth

However, studies in newborn CF ferrets led to an interesting twist in the team's findings. The pancreas in newborn ferrets is essentially healthy, so the team expected normal insulin levels and normal blood sugar regulation. Instead, newborn CF ferrets were unable to control spikes in blood sugar. The study showed that this was because the pancreas in these animals did not secrete the appropriate amount of insulin in response to a spike in blood sugar.