Deconstructing and reconstructing obesity-induced diabetes (diabesity) in mice.

Document Type

Article

Publication Date

2002

Keywords

Carrier-Proteins, Diabetes-Mellitus-Non-Insulin-Dependent, Female, Genetic-Predisposition-to-Disease, Human, Islets-of-Langerhans, Leptin, Liver, Male, Mice, Mice-Obese, Mutation, Obesity, Obesity-in-Diabetes, Phenotype, Quantitative-Trait, SUPPORT-U-S-GOVT-P-H-S, Weight-Gain

First Page

825

Last Page

832

JAX Source

Diabetes 2002 Mar; 51(3):825-32.

Grant

CA34196/CA/NCI, DK56853/DK/NIDDK, RR08911/RR/NCRR

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.

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