Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM
Dan Ma, … , Guy A. Rutter, Gavin Kelsey
Dan Ma, … , Guy A. Rutter, Gavin Kelsey
Published August 1, 2004
Citation Information: J Clin Invest. 2004;114(3):339-348. https://doi.org/10.1172/JCI19876.
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Article Metabolism

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.

Authors

Dan Ma, Julian P.H. Shield, Wendy Dean, Isabelle Leclerc, Claude Knauf, Rémy Burcelin, Guy A. Rutter, Gavin Kelsey

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Glucose and insulin tolerance in TNDM29 mice. Glucose tolerance tests (A...
Glucose and insulin tolerance in TNDM29 mice. Glucose tolerance tests (A–C): glucose concentration determined in whole blood at the indicated times following intraperitoneal injection of glucose in neonate (A), juvenile (B), and adult (C) TNDM29 and wild-type mice. Serum insulin concentrations (D–F) at the indicated time points of the glucose tolerance test in neonates (D), juveniles (E), and adults (F). Insulin tolerance tests (G–I): glucose concentration determined in whole blood at the indicated times following intraperitoneal injection of insulin in neonates (G), juvenile (H), and adult (I) TNDM29 and wild-type mice. Euglycemic hyperinsulinemic clamp studies in TNDM29 and wild-type mice (J): whole-body glucose turnover rate (TO), whole-body glycolysis rate (Glycol) and whole-body glycogen synthesis (GlnSynth) during the test are shown. All results are expressed as mean ± SEM (n = 12–20, in more than 3 separate experiments, except for the clamp studies, where n = 5–6). *P < 0.05, **P < 0.01 transgenic versus control group by unpaired, two-tailed Student’s t test and Mann Whitney U test, as appropriate.