Pilot 5: Role of Islet Amyloid and Il-1β Signaling in β-cell Loss in Cystic Fibrosis-Related Diabetes

P.I.: Rebecca Hull, PhD
Research Associate Professor of Medicine
Metabolism, Endocrinology and Nutrition

Srinath Sanda, MD
Assistant Professor, Pediatrics
University of California at San Francisco

This proposal seeks to determine the role of ILβ in the pathogenesis of cystic fibrosis related diabetes (CFRD). CFRD is a unique form of diabetes and new treatments are needed to improve the morbidity and mortality of cystic fibrosis patients. Therefore the goals of this grant proposal are directly relevant to the mission of the National Institute of Diabetes, Digestive, and Kidney Diseases. The grant proposal consists of 2 broad aims. First we will compare the degree of amyloid deposition between autopsy pancreas sections from CFRD patients, CF patients without diabetes and age-matched controls. Subjects with type 2 diabetes, and appropriately-matched subjects without type 2 diabetes will serve as positive and negative controls for the measurements of interest. We anticipate that CFRD patients will show extensive deposition of islet amyloid, together with decreased β-cell area, reduced insulin expression, and increased β-cell apoptosis. Second we will analyze the same samples for evidence that the IL-1β pathway is active. In particular we will stain for IL-1β, IL-1Ra, NF-κB, MyD88, and CCL2. Aim 2: Do pancreatic sections from patients with CFRD show evidence of IL-1β activation? We will also determine whether correlations exist between these markers of the IL-1β pathway and measured obtained in Aim1, namely islet amyloid deposition, β-cell area and measures of β-cell apoptosis and replication. We anticipate that IL-1β activation will be a major feature of the islet in CFRD, suggesting that this pathway may play a role in the pathogenesis of islet dysfunction in this patient population.