Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks
Rachana Haliyur, … , Marcela Brissova, Alvin C. Powers
Rachana Haliyur, … , Marcela Brissova, Alvin C. Powers
Published January 2, 2019; First published December 3, 2018
Citation Information: J Clin Invest. 2019;129(1):246-251. https://doi.org/10.1172/JCI121994.
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Categories: Concise Communication Endocrinology

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

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.

Authors

Rachana Haliyur, Xin Tong, May Sanyoura, Shristi Shrestha, Jill Lindner, Diane C. Saunders, Radhika Aramandla, Greg Poffenberger, Sambra D. Redick, Rita Bottino, Nripesh Prasad, Shawn E. Levy, Raymond D. Blind, David M. Harlan, Louis H. Philipson, Roland W. Stein, Marcela Brissova, Alvin C. Powers

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Figure 4

Model of HNF1A dysfunction in human β cells.

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Model of HNF1A dysfunction in human β cells. From these results, we prop...
From these results, we propose that dysfunction of HNF1A leads to decreased expression of direct targets, which encompass both enzymatic and gene regulatory products, producing broad changes in transcriptional regulation, glucose metabolism, and hormone secretion. These processes ultimately lead to β cell dysfunction and result in clinical manifestation of insulin-insufficient diabetes.