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 1

Histological and functional analysis of HNF1A+/T260M pancreas and islets.

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Histological and functional analysis of HNF1A+/T260M pancreas and islets...
(A) Example of expression of insulin (INS), glucagon (GCG), and somatostatin (SOM) in donor’s native pancreatic tissue compared with control. Scale bar: 50 μm. (B) β and α cell mass (grams) in HNF1A+/T260M pancreas compared with controls (n = 7 donors; ages 10–55 years). Each data point represents the average mass across the combined pancreatic head, body, and tail regions. (C) Insulin secretion in islets isolated from the HNF1A+/T260M pancreas compared with controls (n = 6 donors; ages 8–55 years) and normalized to overall islet cell volume (expressed as islet equivalents, IEQs). Islets were teated with 5.6 mM glucose (G 5.6); 16.7 mM glucose (G 16.7); 16.7 mM glucose plus 100 μM isobutylmethylxanthine (G 16.7 + IBMX 100); 1.7 mM glucose plus 1 μM epinephrine (G 1.7 + Epi 1); or 20 mM potassium chloride (KCl 20) at the indicated times. Insets show average insulin response of controls and HNF1A+/T260M donor to 30-minute stimulation with 16.7 mM glucose. (D) Integrated insulin secretion was calculated as the area under the curve (AUC) for the indicated secretagogue (shaded to correspond to color-matched regions of perifusion trace in panel C). Results of control samples are expressed as mean ± SEM.