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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Aug 26, 2015; 6(3): 95-109
Published online Aug 26, 2015. doi: 10.4331/wjbc.v6.i3.95
Role of ZAC1 in transient neonatal diabetes mellitus and glucose metabolism
Anke Hoffmann, Dietmar Spengler
Anke Hoffmann, Dietmar Spengler, Max Planck Institute of Psychiatry, Translational Research, 80804 Munich, Germany
Author contributions: Hoffmann A and Spengler D jointly contributed to this work.
Supported by Max Planck Institute of Psychiatry.
Conflict-of-interest statement: The authors declare no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dietmar Spengler, MD, Max Planck Institute of Psychiatry, Translational Research, Kraepelinstrasse 2-10, 80804 Munich, Germany. spengler@psych.mpg.de
Telephone: +49-89-30622587 Fax: +49-89-30622605
Received: April 20, 2015
Peer-review started: April 24, 2015
First decision: June 3, 2015
Revised: June 19, 2015
Accepted: July 11, 2015
Article in press: July 14, 2015
Published online: August 26, 2015
Processing time: 127 Days and 17.1 Hours
Abstract

Transient neonatal diabetes mellitus 1 (TNDM1) is a rare genetic disorder representing with severe neonatal hyperglycaemia followed by remission within one and a half year and adolescent relapse with type 2 diabetes in half of the patients. Genetic defects in TNDM1 comprise uniparental isodisomy of chromosome 6, duplication of the minimal TNDM1 locus at 6q24, or relaxation of genomically imprinted ZAC1/HYMAI. Whereas the function of HYMAI, a non-coding mRNA, is still unidentified, biochemical and molecular studies show that zinc finger protein 1 regulating apoptosis and cell cycle arrest (ZAC1) behaves as a factor with versatile transcriptional functions dependent on binding to specific GC-rich DNA motives and interconnected regulation of recruited coactivator activities. Genome-wide expression profiling enabled the isolation of a number of Zac1 target genes known to regulate different aspects of β-cell function and peripheral insulin sensitivity. Among these, upregulation of Pparγ and Tcf4 impairs insulin-secretion and β-cell proliferation. Similarly, Zac1-mediated upregulation of Socs3 may attenuate β-cell proliferation and survival by inhibition of growth factor signalling. Additionally, Zac1 directly represses Pac1 and Rasgrf1 with roles in insulin secretion and β-cell proliferation. Collectively, concerted dysregulation of these target genes could contribute to the onset and course of TNDM1. Interestingly, Zac1 overexpression in β-cells spares the effects of stimulatory G-protein signaling on insulin secretion and raises the prospect for tailored treatments in relapsed TNDM1 patients. Overall, these results suggest that progress on the molecular and cellular foundations of monogenetic forms of diabetes can advance personalized therapy in addition to deepening the understanding of insulin and glucose metabolism in general.

Keywords: Diabetes mellitus; ZAC1; Transient neonatal diabetes mellitus 1; Genomic imprinting; Insulin; Glucose; Target genes; Tailored therapy

Core tip: Accidents of nature leading to rare genetic diseases can provide important insights into the molecular and cellular foundations of related common diseases. Various genetic anomalies at chromosome 6q24 manifest with life-threatening transient neonatal diabetes mellitus (TNDM1). All of these genetic defects share overexpress-ion of the maternally imprinted transcriptional regulator ZAC1. Genome-wide expression profiling identified a number of downstream target genes sharing a critical role in insulin secretion, β-cell proliferation, and survival. Importantly, Zac1 overexpression in β-cells spares the effects of G-protein signaling on insulin secretion opening the prospect for tailored therapy in TNDM1 patients.