Genetic modifiers of Lepr(fa) associated with variability in insulin production and susceptibility to NIDDM

Wendy K. Chung, Min Zheng, Melvin Chua, Erin Kershaw, Loraine Power-Kehoe, Michael Tsuji, X. Sharon Wu-Peng, Julie Williams, Streamson C. Chua, Rudolph L. Leibel

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

In an attempt to identify the genetic basis for susceptibility to non- insulin-dependent diabetes mellitus within the context of obesity, we generated 401 genetically obese Lepr(fa)/Lepr(fa) F2 WKY13M intercross rats that demonstrated wide variation in multiple phenotypic measures related to diabetes, including plasma glucose concentration, percentage of glycosylated hemoglobin, plasma insulin concentration, and pancreatic islet morphology. Using selective genotyping genome scanning approaches, we have identified three quantitative trait loci (QTLs) on Chr. 1 (LOD 7.1 for pancreatic morphology), Chr. 12 (LOD 5.1 for body mass index and LOD 3.4 for plasma glucose concentration), and Chr. 16 (P < 0.001 for genotype effect on plasma glucose concentration). The obese F2 progeny demonstrated sexual dimorphism for these traits, with increased diabetes susceptibility in the males appearing at approximately 6 weeks of age, as sexual maturation occurred. For each of the QTLs, the linked phenotypes demonstrated sexual dimorphism (more severe affection in males). The QTL on Chr. 1 maps to a region vicinal to that previously linked to adiposity in studies of diabetes susceptibility in the nonobese Goto-Kakizaki rat, which is genetically closely related to the Wistar counterstrain we employed. Several candidate genes, including tubby (tub), multigenic obesity 1 (Mob1), adult obesity and diabetes (Ad), and insulin-like growth factor-2 (Igf2), map to murine regions homologous to the QTL region identified on rat Chr. 1.

Original languageEnglish (US)
Pages (from-to)332-344
Number of pages13
JournalGenomics
Volume41
Issue number3
DOIs
Publication statusPublished - May 1 1997
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Genetics

Cite this

Chung, W. K., Zheng, M., Chua, M., Kershaw, E., Power-Kehoe, L., Tsuji, M., ... Leibel, R. L. (1997). Genetic modifiers of Lepr(fa) associated with variability in insulin production and susceptibility to NIDDM. Genomics, 41(3), 332-344. https://doi.org/10.1006/geno.1997.4672