Cystic fibrosis-related diabetes (CFRD) is commonly thought to be a consequence of insulin deficiency combined with insulin resistance. However, this explanation is not satisfactory because clinical studies in CFRD show inadequate insulin secretion but little evidence for insulin resistance. Furthermore, the commonly accepted pathogenesis for the insulin deficiency, namely that the pancreatitis of cystic fibrosis (CF) and subsequent pancreatic atrophy and fibrosis lead to islet destruction, is not likely a sufficient explanation. Since the cystic fibrosis transmembrane conductance regulator (CFTR) is expressed and functional in mouse and human pancreatic islet cells, we propose that CFTR mutations directly impair islet cell function and health. In this proposal, we will test the hypotheses that CFTR plays an important regulatory role in insulin and glucagon secretion and that mutations in CFTR lead to ? cell dysfunction, inadequate ? cell adaptation to islet """"""""stressors"""""""" (pancreatitis, inflammation, hyperglycemia), and reduced ? cell mass, thus greatly increasing the risk for diabetes mellitus. We propose an integrated, multiple component pathogenesis involving abnormal CFTR ion channel activity and abnormal CFTR protein trafficking and cell biology, leading to secretory dysfunction, ? cell ER stress, and ? cell death. Our multidisciplinary team with expertise in electrophysiology, human islet biology, and CF will conduct in vitro and in vivo studies using unique mouse models and human islets to test these hypotheses and to discover information important for understanding the pathogenesis of human CFRD. We will pursue three aims: 1) Define the role of CFTR in regulating insulin and glucagon secretion and ? cell function and health by studying islets lacking CFTR;2)Determine the impact of selected CF mutations on insulin and glucagon secretion and ? cell function and health;and 3) Determine the impact of selected CF mutations on ? cell function, health, and adaptation in response to """"""""islet stressors"""""""" such as pancreatitis, hyperglycemia, and insulin resistance.
Cystic fibrosis (CF) is the most common hereditary disease in Caucasians. Most of the patients are diagnosed at 2-3 years of age and treatment is focused on improving survival and quality of life and recommended to take place at a cystic fibrosis clinic where the lung, bowel and nutritional problems can be properly managed. Over the last three decades, improvement in treatment has increased life span to 40-50 years of age and cystic fibrosis-related diabetes (CFRD) has become the most common complication. A better understanding of the cellular and molecular mechanisms that result in CFRD will be fundamental for the improvement of diagnosis and treatment of this severe CF complication.
|Saunders, Diane C; Brissova, Marcela; Phillips, Neil et al. (2018) Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic ? Cells for In Vitro and In Vivo Analysis. Cell Metab :|
|Brissova, Marcela; Haliyur, Rachana; Saunders, Diane et al. (2018) ? Cell Function and Gene Expression Are Compromised in Type 1 Diabetes. Cell Rep 22:2667-2676|
|Hart, Nathaniel J; Aramandla, Radhika; Poffenberger, Gregory et al. (2018) Cystic fibrosis-related diabetes is caused by islet loss and inflammation. JCI Insight 3:|
|Bogdani, Marika; Blackman, Scott M; Ridaura, Cecilia et al. (2017) Structural abnormalities in islets from very young children with cystic fibrosis may contribute to cystic fibrosis-related diabetes. Sci Rep 7:17231|
|Dean, E Danielle; Li, Mingyu; Prasad, Nripesh et al. (2017) Interrupted Glucagon Signaling Reveals Hepatic ? Cell Axis and Role for L-Glutamine in ? Cell Proliferation. Cell Metab 25:1362-1373.e5|
|Dai, Chunhua; Hang, Yan; Shostak, Alena et al. (2017) Age-dependent human ? cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. J Clin Invest 127:3835-3844|
|Westacott, Matthew J; Farnsworth, Nikki L; St Clair, Joshua R et al. (2017) Age-Dependent Decline in the Coordinated [Ca2+] and Insulin Secretory Dynamics in Human Pancreatic Islets. Diabetes 66:2436-2445|
|Aamodt, Kristie I; Powers, Alvin C (2017) Signals in the pancreatic islet microenvironment influence ?-cell proliferation. Diabetes Obes Metab 19 Suppl 1:124-136|
|Kursan, Shams; McMillen, Timothy S; Beesetty, Pavani et al. (2017) The neuronal K+Cl- co-transporter 2 (Slc12a5) modulates insulin secretion. Sci Rep 7:1732|
|Dai, Chunhua; Kayton, Nora S; Shostak, Alena et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest 126:1857-70|
Showing the most recent 10 out of 16 publications