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Free keywords:
Diabetes mellitus, ZAC1, Transient neonatal diabetes mellitus 1, Genomic imprinting, Insulin, Glucose, Target genes, Tailored therapy
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 beta-cell function and peripheral insulin sensitivity. Among
these, upregulation of Ppargamma and Tcf4 impairs insulin-secretion and
beta-cell proliferation. Similarly, Zac1-mediated upregulation of Socs3
may attenuate beta-cell proliferation and survival by inhibition of
growth factor signalling. Additionally, Zac1 directly represses Pac1 and
Rasgrf1 with roles in insulin secretion and beta-cell proliferation.
Collectively, concerted dysregulation of these target genes could
contribute to the onset and course of TNDM1. Interestingly, Zac1
overexpression in beta-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.
