TY - JOUR
T1 - Genetic modifiers of Lepr(fa) associated with variability in insulin production and susceptibility to NIDDM
AU - Chung, Wendy K.
AU - Zheng, Min
AU - Chua, Melvin
AU - Kershaw, Erin
AU - Power-Kehoe, Loraine
AU - Tsuji, Michael
AU - Wu-Peng, X. Sharon
AU - Williams, Julie
AU - Chua, Streamson C.
AU - Leibel, Rudolph L.
N1 - Funding Information:
We gratefully acknowledge the assistance provided by Renata Ten-enbaum and L. Arthur Camp®eld in the radioimmunoassay for plasma insulin concentration and the glucose oxidase assay for plasma glucose concentration, by Yim Dam and Xavier Pi-Sunyer in the radioimmunoassay for pancreatic insulin and glucagon concentrations, by Sarita Whitehead in manuscript preparation, and by Michele Blum, Florence Chu, Johan Helmer, Charles LeDuc, Alexis Leibel, Mark Lindrud, David Markel, Ellen Murphy, Ephraim Tsalik, and Michael Wajnrajch in collection of relevant tissues. This work was supported by NIH Grants DK52431, DK47473, DK26687, and DK07569.
PY - 1997/5/1
Y1 - 1997/5/1
N2 - 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.
AB - 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.
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U2 - 10.1006/geno.1997.4672
DO - 10.1006/geno.1997.4672
M3 - Article
C2 - 9169130
AN - SCOPUS:0031128599
SN - 0888-7543
VL - 41
SP - 332
EP - 344
JO - Genomics
JF - Genomics
IS - 3
ER -