Human islets expressing HNF1A variant have defective beta cell transcriptional regulatory networks
UMass Chan AffiliationsDepartment of Medicine, Diabetes Center of Excellence
Document TypeJournal Article
Endocrine System Diseases
Endocrinology, Diabetes, and Metabolism
Hormones, Hormone Substitutes, and Hormone Antagonists
Nutritional and Metabolic Diseases
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AbstractUsing 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.
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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/40903
Full author list omitted for brevity. For the full list of authors, see article.
RightsCopyright © 2019, American Society for Clinical Investigation. Publisher PDF posted as allowed by publisher's policy posted at https://www.jci.org/kiosks/terms.