HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db06-0658v1 56/5/1268    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Herbach, N. Articles by Wanke, R. Search for Related Content PubMed PubMed Citation Articles by Herbach, N. Articles by Wanke, R. Social Bookmarking                What's this?

Dominant-Negative Effects of a Novel Mutated Ins2 Allele Causes Early-Onset Diabetes and Severe ß-Cell Loss in Munich Ins2^C95S Mutant Mice

¹ Institute of Veterinary Pathology, University of Munich, Munich, Germany
² Institute of Molecular Animal Breeding/Gene Center, University of Munich, Munich, Germany
³ Institute of Experimental Genetics, GSF-National Research Center for Environment and Health, Neuherberg, Germany
⁴ Department of Genetic Medicine and Development, CMU, Geneva, Switzerland

Address correspondence and reprint requests to Nadja Herbach, Institute of Veterinary Pathology, Veterinaerstr. 13, 80539 Munich, Germany. E-mail: herbach{at}patho.vetmed.uni-muenchen.de

Abbreviations: ENU, N-ethyl-N-nitrosourea; HOMA, homeostasis model assessment; OGTT, oral glucose tolerance test; PP, pancreatic polypeptide

The novel diabetic mouse model Munich Ins2^C95S was discovered within the Munich N-ethyl-N-nitrosourea mouse mutagenesis screen. These mice exhibit a TA transversion in the insulin 2 (Ins2) gene at nucleotide position 1903 in exon 3, which leads to the amino acid exchange C95S and loss of the A6-A11 intrachain disulfide bond. From 1 month of age onwards, blood glucose levels of heterozygous Munich Ins2^C95S mutant mice were significantly increased compared with controls. The fasted and postprandial serum insulin levels of the heterozygous mutants were indistinguishable from those of wild-type littermates. However, serum insulin levels after glucose challenge, pancreatic insulin content, and homeostasis model assessment (HOMA) ß-cell indices of heterozygous mutants were significantly lower than those of wild-type littermates. The initial blood glucose decrease during an insulin tolerance test was lower and HOMA insulin resistance indices were significantly higher in mutant mice, indicating the development of insulin resistance in mutant mice. The total islet volume, the volume density of ß-cells in the islets, and the total ß-cell volume of heterozygous male mutants was significantly reduced compared with wild-type mice. Electron microscopy of the ß-cells of male mutants showed virtually no secretory insulin granules, the endoplasmic reticulum was severely enlarged, and mitochondria appeared swollen. Thus, Munich Ins2^C95S mutant mice are considered a valuable model to study the mechanisms of ß-cell dysfunction and death during the development of diabetes.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. L. Edghill, S. E. Flanagan, A.-M. Patch, C. Boustred, A. Parrish, B. Shields, M. H. Shepherd, K. Hussain, R. R. Kapoor, M. Malecki, et al. Insulin Mutation Screening in 1,044 Patients With Diabetes: Mutations in the INS Gene Are a Common Cause of Neonatal Diabetes but a Rare Cause of Diabetes Diagnosed in Childhood or Adulthood Diabetes, April 1, 2008; 57(4): 1034 - 1042. [Abstract] [Full Text] [PDF]

				M. Liu, I. Hodish, C. J. Rhodes, and P. Arvan Proinsulin maturation, misfolding, and proteotoxicity PNAS, October 2, 2007; 104(40): 15841 - 15846. [Abstract] [Full Text] [PDF]

				J. Stoy, E. L. Edghill, S. E. Flanagan, H. Ye, V. P. Paz, A. Pluzhnikov, J. E. Below, M. G. Hayes, N. J. Cox, G. M. Lipkind, et al. Insulin gene mutations as a cause of permanent neonatal diabetes PNAS, September 18, 2007; 104(38): 15040 - 15044. [Abstract] [Full Text] [PDF]