Inherited obesity-diabetes syndromes in the mouse.
Several different single-gene mutations are known to cause varying degrees of diabetes and obesity in mice. The severity of the diabetes produced depends on both the mutation itself and the interaction of the mutant gene with the inbred background. Establishing the nature of these gene-background interactions should aid us in our understanding of similar interactions that occur in human diabetes. The documentation of several different genes that produce similar, if not identical, diabetes-obesity syndromes suggests that lesions in many pathways can cause diabetes. An understanding of these defects in mice should help us to understand similar defects involved in the human disease. The developmental stages in each mutant are similar. The early symptoms include hyperphagia, hyperinsulinemia, and hypertrophy and hyperplasia of the beta cells of the islets of Langerhans. Hyperglycemia, obesity, and severe diabetes are secondary features that result from insulin resistance and the failure to sustain the secretion of massive amounts of insulin. All models appear to be able to utilize their food in a more efficient manner than normal. Even when restricted to 50% of that amount of food eaten by a normal mouse, mutants are able to maintain their weight and still remain obese. On fasting, the stored fat is utilized more efficiently. One cause of this efficiency in obese and diabetes mice is the ability to convert acetone (the end product of fatty-acid metabolism) to lactate which, in turn, can be converted to glucose, which can sustain continued lipolysis. The occurrence of increased efficiency in obesity and diabetes mutants lends credence to the thrifty-genotype hypothesis regarding the maintenance of the deleterious diabetes genes in human populations.
D000483:Alleles; D000818:Animals; D001835:Body Weight; D003920:Diabetes Mellitus / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1; D004195:Disease Models, Animal; D005808:Genes, Recessive; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008820:Mice, Obese; D009154:Mutation; D009765:Obesity