Human islets expressing HNF1A variant have defective beta cell transcriptional regulatory networks
UMass Chan Affiliations
Department of Medicine, Diabetes Center of ExcellenceDocument Type
Journal ArticlePublication Date
2019-01-02Keywords
DiabetesEndocrinology
Insulin
Islet cells
Endocrine System Diseases
Endocrinology
Endocrinology, Diabetes, and Metabolism
Hormones, Hormone Substitutes, and Hormone Antagonists
Nutritional and Metabolic Diseases
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Show full item recordAbstract
Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained beta cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1alpha (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.Source
J Clin Invest. 2019 Jan 2;129(1):246-251. doi: 10.1172/JCI121994. Epub 2018 Dec 3. Link to article on publisher's site
DOI
10.1172/JCI121994Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40903PubMed ID
30507613Notes
Full author list omitted for brevity. For the full list of authors, see article.
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Copyright © 2019, American Society for Clinical Investigation. Publisher PDF posted as allowed by publisher's policy posted at https://www.jci.org/kiosks/terms.ae974a485f413a2113503eed53cd6c53
10.1172/JCI121994