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PMID: 15286800 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 114 ·No. 3 ·2004-08-00 ·Pages 339-48

Ma D, Shield JP, Dean W, Leclerc I, Knauf C, Burcelin R Ré, Rutter GA, Kelsey G

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 beta cell number and impaired beta 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, beta 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 beta cell function in disease pathogenesis.

MeSH Terms
Aging Animals Animals, Newborn Blood Glucose/metabolism Diabetes Mellitus, Type 2/genetics,metabolism,physiopathology Disease Models, Animal Genomic Imprinting Homeostasis Humans Hyperglycemia/genetics Immunohistochemistry In Situ Hybridization Insulin/blood,metabolism Islets of Langerhans/physiopathology Mice Mice, Transgenic Pancreas/embryology,pathology,physiopathology Reverse Transcriptase Polymerase Chain Reaction Tissue Distribution Transcription, Genetic
Chemicals
Blood Glucose Insulin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Ma Dan
Developmental Genetics Programme, The Babraham Institute, Cambridge, United Kingdom.
Shield Julian P H
Dean Wendy
Leclerc Isabelle
Knauf Claude
Burcelin R R éMy
Rutter Guy A
Kelsey Gavin
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI19876
Published
2004-08-00
Pages
339-48
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC484972
Subset
IM
Corrections
CommentIn
PMID: 15286795
External Links
PubMed source DOI: 10.1172/JCI19876 PMC Full Text View journal details
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