Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM

Abstract

Transient neonatal diabetes mellitus (TNDM) is a rare inherited diabetic syndrome apparent in the first weeks of life and again during early adulthood. The relative contributions of reduced islet β cell number and impaired β cell function to the observed hypoinsulinemia are unclear. The inheritance pattern of this imprinted disorder implicates overexpression of one or both genes within the TNDM locus: ZAC, which encodes a proapoptotic zinc finger protein, and HYMAI, which encodes an untranslated mRNA. To investigate the consequences for pancreatic function, we have developed a high-copy transgenic mouse line, TNDM29, carrying the human TNDM locus. TNDM29 neonates display hyperglycemia, and older adults, impaired glucose tolerance. Neonatal hyperglycemia occurs only on paternal transmission, analogous to paternal dependence of TNDM in humans. Embryonic pancreata of TNDM29 mice showed reductions in expression of endocrine differentiation factors and numbers of insulin-staining structures. By contrast, β cell mass was normal or elevated at all postnatal stages, whereas pancreatic insulin content in neonates and peak serum insulin levels after glucose infusion in adults were reduced. Expression of human ZAC and HYMAI in these transgenic mice thus recapitulates key features of TNDM and implicates impaired development of the endocrine pancreas and β cell function in disease pathogenesis.

Further refinement of the critical minimal genetic region for the imprinting disorder 6q24 transient neonatal diabetes

“…This region is very similar in size and gene content to that used to recapitulate the key features of TND in transgenic mice [10]. It is also noteworthy that all the duplications identified include both the imprinted and upstream promoters of PLAGL1.…”

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

“…In the majority of TNDM patients with a normal karyotype, there was a loss of methylation (LOM) within this highly homologous region, which suggested that epigenetic or genetic mutations of this region probably result in TNDM, possibly by affecting expression of ZAC1/LOT1 in the pancreas and/or the pituitary (Arima et al, 2001). Recently, a high-copy transgenic mouse line carrying the human TNDM locus has been developed, which displayed hyperglycemia in neonates and impaired glucose tolerance in older adults (Ma et al, 2004). Expression of human ZAC1/LOT1 and HYMAI in these transgenic mice recapitulated key features of TNDM, implicating impaired development of the endocrine pancreas and beta cell function in pathogenesis of the disease (Ma et al, 2004).…”

“…Recently, a high-copy transgenic mouse line carrying the human TNDM locus has been developed, which displayed hyperglycemia in neonates and impaired glucose tolerance in older adults (Ma et al, 2004). Expression of human ZAC1/LOT1 and HYMAI in these transgenic mice recapitulated key features of TNDM, implicating impaired development of the endocrine pancreas and beta cell function in pathogenesis of the disease (Ma et al, 2004). Taken together, three genetic mechanisms have been shown to result in TNDM, paternal uniparental isodisomy of chromosome 6, paternally inherited duplication of 6q24, and a methylation defect at a CpG island overlapping exon 1 of ZAC1 (PLAGL1/LOT1)/HYMAI .…”

Zac1 is expressed in progenitor/stem cells of the neuroectoderm and mesoderm during embryogenesis: Differential phenotype of the Zac1‐expressing cells during development

“…Nevertheless, their biological role in neural development and in mature brain remains uncertain. Furthermore, Zac1 and hZAC are highly expressed in somites and limbs during early embryonic stages (Piras et al, 2000;Valente and Auladell, 2001;Tsuda et al, 2004), as well as in cartilage primordium sites (Valente and Auladell, 2001;Tsuda et al, 2004) and skeletal muscle Ma et al, 2004). In adult tissues, hZAC (human homolog of Zac1 mouse gene) and Zac1 are expressed to a low extent in skeletal muscle and bone marrow (Varrault et al, 1998;Piras et al, 2000).…”