Fatty Acid Defects &Oxidative Stress Modulate Islet Function in Cystic Fibrosis


Principal Investigator: Aliye Uc
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2012-09-15 - 2017-08-31
more information: NIH RePORT

Top Publications

  1. pmc Quantifying insulin sensitivity and entero-insular responsiveness to hyper- and hypoglycemia in ferrets
    Hongshu Sui
    Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America Department of Histology and Embryology, Taishan Medical University, Taian Shandong, China
    PLoS ONE 9:e90519. 2014

Detail Information


  1. pmc Quantifying insulin sensitivity and entero-insular responsiveness to hyper- and hypoglycemia in ferrets
    Hongshu Sui
    Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America Department of Histology and Embryology, Taishan Medical University, Taian Shandong, China
    PLoS ONE 9:e90519. 2014
    ..The incretins GLP-1 and GIP were affected minimally by hyperglycemic and hypoglycemic clamp. These techniques will prove useful in better defining the pathophysiology in ferrets with cystic fibrosis related diabetes. ..

Research Grants30

  1. Early Pathogenesis of Cystic Fibrosis Related Diabetes
    Andrew W Norris; Fiscal Year: 2013
    ..Although the application focuses on early disease pathophysiology, it also has great potential for identifying blood biomarkers for early diagnosis of patients at risk for CFRD. ..
  2. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  3. PPG - Gene Therapy for Cystic Fibrosis Lung Disease
    Paul B McCray; Fiscal Year: 2013
    ..The discoveries from this PPG will accelerate the development of gene-based medicine for patients who suffer from this devastating disease...
  4. Investigation of CFTR on sinus and craniofacial development in a CF porcine model
    Eugene H Chang; Fiscal Year: 2013
    ..The CF pig will allow us to target gene therapy in the sinus. This work will serve as a foundation for future treatment and prevention of sinus disease in humans, and may improve lung function and the health of CF patients. ..
  5. Antioxidative role of GPX1 in transgenic mice.
    XINGEN LEI; Fiscal Year: 2013
    ..Our finding will help address the serious concern over the pro-diabetic risk of Se supplements, and will lead to a powerful innovation to treat type 2 diabetes and metabolic syndrome. ..
  6. Developmental Exposure Alcohol Research Center
    Linda Patia Spear; Fiscal Year: 2013
    ..Thus, the DEARC will serve as a nexus of alcohol research in Central New York and as a beacon for national activities. ..
  7. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..
  9. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  10. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  12. Center for Gene Therapy of Cystic Firbosis
    John F Engelhardt; Fiscal Year: 2013
    ..These efforts have led to numerous basic and applied research findings that have enhanced the utility of gene therapies to both study and treat genetic diseases. ..
    David Ginsburg; Fiscal Year: 2013
    ..This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment. ..
  14. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  15. rAAV-directed gene therapy to the lung in cystic fibrosis ferret models
    John F Engelhardt; Fiscal Year: 2013
    ..This proposal will significantly enhance the field's ability to effectively develop therapeutic strategies for treatment of the CF lung, not only using rAAV vectors, but also other pharmacologic and gene-based therapies. ..
  16. Pathobiology of Cystic Fibrosis-Related Diabetes in a Ferret Model
    Zoe Stewart; Fiscal Year: 2013
    ..These results are expected to have a significant positive impact on the field of CF research. ..
  17. Spinal Cord Injury, Plasticity and Transplant Mediated Repair
    John D Houle; Fiscal Year: 2013
    ..This Program Project has direct relevance to the design and implementation of future treatment programs for acute and delayed intervention after SCI. ..
    Marc R Montminy; Fiscal Year: 2013
    ..Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage diseases, including mood and metabolic disorders ..
    William B Guggino; Fiscal Year: 2013
    ..Project IV will focus on the Biology of AAV. Finally, there are three cores, an Expression, a Vector Core, and an Administration Core. ..
  20. Metabolic Stress-Induced Fatty Acid Nitration and Cardiovascular Function
    Marsha P Cole; Fiscal Year: 2013
    ..This work is of substantial clinical relevance as it will also provide insight as to the potential efficacy of OA-NO2 formed as an adaptive cell signaling mediator in hyperglycemic-induced myocardial injury. ..
  21. Pathogenesis and Treatment of Liver Disease in Transaldolase Deficiency
    Andras Perl; Fiscal Year: 2013
    ..These studies should generate fundamental new information on the cause and treatment of potentially fatal diseases of the liver. ..
    Timothy A Springer; Fiscal Year: 2013
    ..Administrative (Springer) and Protein Expression (Lu) Cores enhance efficiency of the PPG. (End of Abstract) ..