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J Clin Invest. 2019 Jan 2;129(1):246-251. doi: 10.1172/JCI121994. Epub 2018 Dec 3.

Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.

Author information

1
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
2
Departments of Medicine and Pediatrics-Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois, USA.
3
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
4
Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
5
Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
6
Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
7
Departments of Pharmacology and Biochemistry, Vanderbilt University, Nashville, Tennessee, USA.
8
Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA.

Abstract

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 β 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-1α (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.

KEYWORDS:

Diabetes; Endocrinology; Insulin; Islet cells

PMID:
30507613
PMCID:
PMC6307934
[Available on 2019-04-02]
DOI:
10.1172/JCI121994
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