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This version published online on March 24, 2004
Endocrinology, doi:10.1210/en.2003-1400
A more recent version of this article appeared on July 1, 2004
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Glucose homeostasis and Tissue Transcript Content of Insulin Signaling Intermediates in Four Inbred Strains of Mice: C57Bl/6, C57BLKS/6, DBA/2 and 129X1

H. Joseph Goren*, Rohit N. Kulkarni, and C. Ronald Kahn*

Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215

* To whom correspondence should be addressed. E-mail: c.ronald.kahn{at}joslin.harvard.edu. * To whom correspondence should be addressed. E-mail: c.ronald.kahn{at}joslin.harvard.edu.

Transgenic mice phenotypes generally depend on the background strains used in their creation. To examine the effects of genetic background on insulin signaling, we analyzed glucose homeostasis in four inbred strains of mice (C57Bl/6(B6), C57BLKS/6(KLS), DBA/2(DBA), and 129X1) and quantitated mRNA content of insulin receptor and its substrates in insulin responsive tissues. At 2 months, the male B6 mouse is the least glucose-tolerant despite exhibiting similar insulin-sensitivity and first-phase insulin secretion as the other strains. The 129X1 male mouse islet contains less insulin and exhibits a higher threshold for glucose-stimulated first-phase insulin secretion than the other strains. Female mice generally manifest better glucose tolerance than males, which is likely due to greater insulin-sensitivity in liver and adipose tissue, a robust first-phase insulin secretion in B6 and KLS females, and improved insulin-sensitivity in muscle in DBA and 129X1 females. At 6 months, although males exhibit improved first-phase insulin secretion, their physiology was relatively unchanged while female B6 and KLS mice became less insulin-sensitive. Gene expression of insulin signaling intermediates in insulin responsive tissues was generally not strain dependent with the cell content of insulin receptor mRNA being highest. Insulin receptor substrate-1 (IRS-1) and IRS-2 mRNA are ubiquitously expressed and IRS-3 and IRS-4 mRNA were detected in significant amounts in fat and brain tissues, respectively. These data indicate strain-, gender- and age-dependent tissue sensitivity to insulin that is generally not associated with transcript content of insulin receptor or its substrates and should be taken into consideration during phenotypic characterization of transgenic mice.
Key words: insulin/IGF-1 signaling • knockouts • mouse physiology • insulin receptor • glucose homeostasis • leptin • insulin receptor substrates • real-time PCR




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