Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 129, Issue 1, Pages 246-251Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI121994
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [RRID:SCR_014393, UC4 DK104211, DK108120, DK112232]
- JDRF
- Leona M. and Harry B. Helmsley Charitable Trust
- Department of Veterans Affairs [BX000666]
- American Cancer Society [RSG-17-063-01]
- V-Foundation [V2016-015]
- [DK106755]
- [DK72473]
- [DK89572]
- [DK97829]
- [DK94199]
- [DK50203]
- [DK90570]
- [T32GM007347]
- [F30DK112630]
- [DK20593]
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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-1 alpha (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.
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