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Genetics

Deconstructing and Reconstructing Obesity-Induced Diabetes (Diabesity) in Mice

  1. Peter C. Reifsnyder and
  2. Edward H. Leiter
  1. From the Jackson Laboratory, Bar Harbor, Maine
    Diabetes 2002 Mar; 51(3): 825-832. https://doi.org/10.2337/diabetes.51.3.825
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    Abstract

    Obesity-driven type 2 diabetes (diabesity) involves complex genetic and environmental interactions to trigger disease. Here, we combine variable numbers of known quantitative trait loci (QTL) for obesity and diabetes contributed by New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/Lt) strains in the form of 10 interval-directed recombinant congenic strains (RCS), with NON/Lt as the background strain, to dissect the genetic interactions involved. All 10 RCS gain significantly more weight than the NON parental strain, but none are as obese as the parental, diabetes-prone NZO. Diabetes development in these RCS at F12 ranges between 0 and 100%, depending on genetic constitution. RCS-2, -1, and -10 represent a step-wise increase in numbers of specific diabetogenic QTL, resulting in a step-wise increase in diabetes incidence. RCS-10 recreates the 100% incidence seen in (NZOxNON)F1 males, but with less weight gain. Similarly, RCS-6, -7, -8, and -9 represent diabetes-prone strains with different combinations of diabetogenic QTL. RCS-3, -4, and -5 represent obese strains that do not transit to diabetes. Because these obesity and diabetes syndromes reflect different collections of QTL, rather than null mutations in the leptin or leptin receptor genes, they are extremely relevant as models for the polygenic obesity/diabesity syndromes in humans.

    Footnotes

    • Address correspondence and reprint requests to Edward H. Leiter, the Jackson Laboratory, Bar Harbor, ME 04609-1500. E-mail: ehl{at}jax.org.

      Received for publication 16 August 2001 and accepted in revised form 19 November 2001.

      ALT, alanine aminotransferase; BUN, blood urea nitrogen; Chr, chromosome; NIH, National Institutes of Health; PAS, periodic acid-Schiff; PG, plasma glucose; PI, plasma insulin; PL, plasma leptin; QTL, quantitative trait loci; RCS, recombinant congenic strains.

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    Deconstructing and Reconstructing Obesity-Induced Diabetes (Diabesity) in Mice
    Peter C. Reifsnyder, Edward H. Leiter
    Diabetes Mar 2002, 51 (3) 825-832; DOI: 10.2337/diabetes.51.3.825

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    Deconstructing and Reconstructing Obesity-Induced Diabetes (Diabesity) in Mice
    Peter C. Reifsnyder, Edward H. Leiter
    Diabetes Mar 2002, 51 (3) 825-832; DOI: 10.2337/diabetes.51.3.825
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