Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity

Jürgen K. Naggert, Lloyd D. Fricker, Oleg Varlamov, Patsy M. Nishina, Yves Rouille, Donald F. Steiner, Raymond J. Carroll, Beverly J. Paigen, Edward H. Leiter

Research output: Contribution to journalArticle

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Abstract

Mice homozygous for the fat mutation develop obesity and hyperglycaemia that can be suppressed by treatment with exogenous insulin. The fat mutation maps to mouse chromosome 8, very close to the gene for carboxypeptidase E (Cpe), which encodes an enzyme (CPE) that processes prohormone intermediates such as proinsulin. We now demonstrate a defect in proinsulin processing associated with the virtual absence of CPE activity in extracts of fat/fat pancreatic islets and pituitaries. A single Ser202Pro mutation distinguishes the mutant Cpe allele, and abolishes enzymatic activity in vitro. Thus, the fat mutation represents the first demonstration of an obesity-diabetes syndrome elicited by a genetic defect in a prohormone processing pathway.

Original languageEnglish (US)
Pages (from-to)135-142
Number of pages8
JournalNature Genetics
Volume10
Issue number2
DOIs
StatePublished - Jun 1995

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Carboxypeptidase H
Fats
Mutation
Enzymes
Proinsulin
Obesity
Chromosomes, Human, Pair 8
Islets of Langerhans
Hyperglycemia
Alleles
Hyperproinsulinemia
Insulin
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. / Naggert, Jürgen K.; Fricker, Lloyd D.; Varlamov, Oleg; Nishina, Patsy M.; Rouille, Yves; Steiner, Donald F.; Carroll, Raymond J.; Paigen, Beverly J.; Leiter, Edward H.

In: Nature Genetics, Vol. 10, No. 2, 06.1995, p. 135-142.

Research output: Contribution to journalArticle

Naggert, JK, Fricker, LD, Varlamov, O, Nishina, PM, Rouille, Y, Steiner, DF, Carroll, RJ, Paigen, BJ & Leiter, EH 1995, 'Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity', Nature Genetics, vol. 10, no. 2, pp. 135-142. https://doi.org/10.1038/ng0695-135
Naggert, Jürgen K. ; Fricker, Lloyd D. ; Varlamov, Oleg ; Nishina, Patsy M. ; Rouille, Yves ; Steiner, Donald F. ; Carroll, Raymond J. ; Paigen, Beverly J. ; Leiter, Edward H. / Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. In: Nature Genetics. 1995 ; Vol. 10, No. 2. pp. 135-142.
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