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Estrone treatment dissociates primary versus secondary consequences of "diabetes" (db) gene expression in mice
Abstract:
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.
Insights
Estrone treatment in obese mice (db/db) dissociated obesity from diabetes, revealing a primary genetic defect. This defect involves reduced insulin receptors, independent of high insulin levels.
Area of Science:
- Genetics
- Metabolic Disorders
- Endocrinology
Background:
- The
- diabetes
- (db) gene in mice causes obesity and secondary diabetes.
- Obesity often leads to hyperinsulinemia and hyperglycemia, complicating the study of primary genetic defects.
- Estrone administration can modulate gene expression and metabolic pathways.
Purpose of the Study:
- To investigate the primary genetic defect causing obesity in db/db mice.
- To dissociate the consequences of obesity from secondary diabetic complications.
- To determine if insulin receptor deficiency is a primary defect or secondary to hyperinsulinemia.
Main Methods:
- Feeding 0.001% estrone to C57BL/KsJ db/db mice.
- Comparing metabolic parameters (obesity, hyperphagia, insulin, glucose levels) between treated and untreated db/db mice.
- Assessing hepatocyte plasma membrane insulin receptor numbers.
- Evaluating insulin secretion from isolated islets.
Main Results:
- Estrone-treated db/db mice remained obese and hyperphagic but did not develop hyperinsulinemia or hyperglycemia.
- Reduced insulin receptor numbers (50% of normal) persisted in estrone-treated mice, indicating a primary defect.
- No intrinsic defects in beta-cell sensitivity to glucose were observed in estrone-treated db/db mice.
Conclusions:
- Obesity caused by the db gene can be separated from secondary diabetic conditions like hyperinsulinemia and hyperglycemia.
- A generalized membrane defect, including reduced insulin receptors, is a primary consequence of the db gene.
- This study provides a model to study the primary genetic defect of obesity without confounding secondary metabolic sequelae.