Cystic fibrosis related diabetes (CFRD) is one of the most significant co-morbidities in Cystic Fibrosis (CF), affecting almost half of patients over 30 years of age. CFRD is associated with a high morbidity and mortality. Insulin secretory defects are inherent to CF, with diminished and/or delayed insulin responses to oral glucose demonstrated in CF patients both with and without diabetes. Because the islet mass is generally retained in CF, therapies to restore insulin secretion will significantly reduce the incidence of CFRD and thus morbidity and mortality. However, there are no such therapies, because the mechanisms underlying kinetically altered insulin secretion in CF are not known. Oxidative stress and fatty acid perturbations have well-established roles in the pathophysiology of lung disease in CF and type 2 diabetes mellitus, but have not been studied in CFRD. Cystic fibrosis transmembrane conductance regulator (CFTR)-knockout pig and ferret models developed at the University of Iowa have multi-organ disease similar to humans with CF. However, the evolution to CFRD and its severity are different between the two models. At birth, both models have abnormal insulin secretion, but the concomitant exocrine pancreatic disease is mild in CF ferrets and advanced in CF pigs. Pancreatic disease advances rapidly in CF ferrets after birth and they develop progressive hyperglycemia, whereas the pancreatic disease progression is slower in CF pigs and they do not develop hyperglycemia as adults. At birth, CF pigs and ferrets have an imbalance of polyunsaturated fatty acids (PUFA) similar to patients with CF and have markers of pancreatic oxidative stress. Given their varying degrees of exocrine pancreatic disease at birth, divergent evolution to CFRD, fatty acid alterations similar to CF humans and pancreatic oxidative stress, CF ferret and porcine models provide unique and complementary opportunities to investigate the pathogenesis of insulin secretion defects in CF. We hypothesize that the oxidative stress and CF-related PUFA imbalance are key mechanisms that underlie the impaired insulin secretion in CF. We will test this hypothesis in both CF pig and ferret models with the following specific aims: (1) Determine the effect of reactive oxygen species (ROS) and oxidative stress on insulin secretion in vivo by the CF pancreas;(2) Determine the effect of CF-related PUFA imbalance on insulin secretion in vivo by the CF pancreas;(3) Determine the effect of fatty acid alterations and ROS on insulin secretion by isolated islets.
The first aim wil determine the relationship between increased levels of ROS, oxidative stress, and antioxidant capacity in CF pig and ferret pancreas along with correlating the severity of redox changes with insulin secretion.
The second aim will determine whether correcting CF-related PUFA imbalance will restore the !-cell function in CF pancreas.
The third aim will ! examine the extent to which the fatty acid alterations and oxidative stress are intrinsic mechanisms of impaired insulin secretion in CF islets. The objective of this application is to identify oxidative stress and CF-related PUFA imbalance as key pathways in the pathogenesis of CFRD.

Public Health Relevance

Cystic fibrosis related diabetes (CFRD) is the most common comorbidity in Cystic Fibrosis (CF) and it is associated with increased mortality and rapid decline in lung function. The objective of this proposal is to examine the role of oxidative stress and CF-related polyunsaturated fatty acid (PUFA) imbalance in the pathogenesis of CFRD. The long-term goal is to develop improved therapies to prevent the insulin secretory defects in CF and the progression to CFRD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK097820-02
Application #
8543730
Study Section
Special Emphasis Panel (ZDK1-GRB-1 (O2))
Program Officer
Mckeon, Catherine T
Project Start
2012-09-15
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$364,288
Indirect Cost
$123,038
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Uc, Aliye; Andersen, Dana K; Bellin, Melena D et al. (2016) Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 45:1365-1375
Yi, Yaling; Sun, Xingshen; Gibson-Corley, Katherine et al. (2016) A Transient Metabolic Recovery from Early Life Glucose Intolerance in Cystic Fibrosis Ferrets Occurs During Pancreatic Remodeling. Endocrinology 157:1852-65
Yi, Yaling; Norris, Andrew W; Wang, Kai et al. (2016) Abnormal Glucose Tolerance in Infants and Young Children with Cystic Fibrosis. Am J Respir Crit Care Med 194:974-980
Hegyi, Péter; Wilschanski, Michael; Muallem, Shmuel et al. (2016) CFTR: A New Horizon in the Pathomechanism and Treatment of Pancreatitis. Rev Physiol Biochem Pharmacol 170:37-66
Ting, Jie; Wilson, Leslie; Schwarzenberg, Sarah Jane et al. (2016) Direct Costs of Acute Recurrent and Chronic Pancreatitis in Children in the INSPPIRE Registry. J Pediatr Gastroenterol Nutr 62:443-9
Stump, Madeliene; Guo, Deng-Fu; Lu, Ko-Ting et al. (2016) Nervous System Expression of PPARγ and Mutant PPARγ Has Profound Effects on Metabolic Regulation and Brain Development. Endocrinology 157:4266-4275
Pohl, John; Morinville, Veronique; Husain, Sohail Z et al. (2016) Toxic-Metabolic Risk Factors Are Uncommon in Pediatric Chronic Pancreatitis. J Pediatr Gastroenterol Nutr 62:e66-7
Husain, Sohail Z; Morinville, Veronique; Pohl, John et al. (2016) Toxic-metabolic Risk Factors in Pediatric Pancreatitis: Recommendations for Diagnosis, Management, and Future Research. J Pediatr Gastroenterol Nutr 62:609-17
Sawatzke, A B; Norris, A W; Spyropoulos, F et al. (2015) PET/CT imaging reveals unrivaled placental avidity for glucose compared to other tissues. Placenta 36:115-20
Uc, Aliye; Olivier, Alicia K; Griffin, Michelle A et al. (2015) Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass. Clin Sci (Lond) 128:131-42

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