RGD Reference Report - Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats. - Rat Genome Database

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Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats.

Authors: Fakhrai-Rad, H  Nikoshkov, A  Kamel, A  Fernstrom, M  Zierath, JR  Norgren, S  Luthman, H  Galli, J 
Citation: Fakhrai-Rad H, etal., Hum Mol Genet 2000 Sep 1;9(14):2149-58.
RGD ID: 737717
Pubmed: PMID:10958757   (View Abstract at PubMed)

Genetic analysis of the diabetic GK rat has revealed several diabetes susceptibility loci. Congenic strains have been established for the major diabetes locus, Niddm1, by transfer of GK alleles onto the genome of the normoglycemic F344 rat. Niddm1 was dissected into two subloci, physically separated in the congenic strains Niddm1b and Niddm1i, each with at least one disease susceptibility gene. Here we have mapped Niddm1b to 1 cM by genetic and pathophysiological characterization of new congenic substrains for the locus. The gene encoding insulin-degrading enzyme (IDE:) was located to this 1 cM region, and the two amino acid substitutions (H18R and A890V) identified in the GK allele reduced insulin-degrading activity by 31% in transfected cells. However, when the H18R and A890V variants were studied separately, no effects were observed, demonstrating a synergistic effect of the two variants on insulin degradation. No effect on insulin degradation was observed in cell lysates, indicating that the effect is coupled to receptor-mediated internalization of insulin. Congenic rats with the IDE: GK allele displayed post-prandial hyperglycemia, reduced lipogenesis in fat cells, blunted insulin-stimulated glucose transmembrane uptake and reduced insulin degradation in isolated muscle. Analysis of additional rat strains demonstrated that the dysfunctional IDE: allele was unique to GK. These data point to an important role for IDE: in the diabetic phenotype in GK.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
IDEHumantype 2 diabetes mellitus  ISOIde (Rattus norvegicus)DNA:missense mutations more ...RGD 
IdeRattype 2 diabetes mellitus  IAGP DNA:missense mutations more ...RGD 
IdeMousetype 2 diabetes mellitus  ISOIde (Rattus norvegicus)DNA:missense mutations more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F344.GK-(D1Mit7-D1Mgh25)/SweRatdecreased adipocyte glucose uptake inducedIAGPinsulincompared to F344/NCrl ratsRGD 
F344.GK-(D1Mit7-D1Mgh25)/SweRatimpaired glucose tolerance inducedIAGPglucose solutioncompared to F344/NCrlRGD 
F344.GK-(D1Mit7-D1Mgh25)/SweRatincreased circulating insulin level  IAGP compared to F344/NCrl ratsRGD 
Objects Annotated

Genes (Rattus norvegicus)
Ide  (insulin degrading enzyme)

Genes (Mus musculus)
Ide  (insulin degrading enzyme)

Genes (Homo sapiens)
IDE  (insulin degrading enzyme)

Additional Information