Estrone treatment dissociates primary versus secondary consequences of "diabetes" (db) gene expression in mice.
Feeding 0.001% estrone in a diet to C57BL/KsJ mice homozygous for the recessive obesity gene "diabetes" (db) permitted dissociation of the primary consequences of obesity gene expression from the secondary consequences of diabetes effected through interaction between the db gene and other diabetogenic genes in the inbred background. Estrone-treated db/db mice were similar to untreated mutants in exhibiting hyperphagia and marked obesity. However, estrone-treated mutants did not develop the hyperinsulinemia, hyperglycemia, and islet atrophy characteristic of untreated db/db mice. Thus, expression of the primary defect could be studied in the absence of the myriad secondary sequelae elicited by chronic hyperinsulinemia and hyperglycemia. Reduced numbers of hepatocyte plasma membrane insulin receptors (50% of normal) persisted in the estrone-treated mice in the absence of hyperinsulinemia, indicating that this deficiency was a consequence of the primary genetic defect and not merely a downregulation phenomenon secondary to hyperinsulinemia. Comparison of insulin secretion from comparably sized +/+ islets versus islets from estrone-treated db/db mice showed no intrinsic defects in beta-cell sensitivity to glucose. In conclusion, db-induced obesity can be dissociated from hyperinsulinemia, hyperglycemia, beta-cell dysfunction, and hyperphagia but is associated with a generalized membrane defect reflected in part by the persistent deficiency of plasma membrane insulin receptors.
D000818:Animals; D003920:Diabetes Mellitus / Q000209:etiology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D004435:Eating; D004970:Estrone / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009765:Obesity; D011972:Receptor, Insulin / Q000378:metabolism
D007328:Insulin; D004970:Estrone; D011972:Receptor, Insulin