Diabetes (db/db) mutation-induced female reproductive tract hypercytolipidemia: estrogenic restoration of utero-ovarian indices.
The diabetes (db/db) mutation (leptin-receptor defect) induces a hyperglycemic-hyperinsulinemic endometabolic environment that promotes hypercytolipidemic, utero-ovarian involution in C57BL/KsJ mice, resulting in reproductive sterility and eventual organoatrophy. The effectiveness of low-dose, 17-B-estradiol therapy (E2-HRx), initiated prior to the genetic expression of the overt diabetes-obesity syndrome (DOS) on preventing female reproductive tract involution was evaluated by analysis of cytochemical, endocrine and tissue lipo-metabolic indices relative to oil (O)-vehicle treated (HRx) control (+/?) and (db/db) groups. All HRx treatments started at 4 weeks of age (i.e., pre-overt DOS stage) and continued through 16 weeks of age (i.e., chronic DOS expression) when tissue parameters were evaluated. The DOS promoted a dramatic increase in phenotypic obesity, hyperglycemia and hyperinsulinemia in (db/db) groups, relative to (+/?) indices, throughout the experimental period. In contrast, utero-ovarian weights were dramatically reduced in (db/db) groups relative to (+/?). Chronic low-dose E2-HRx moderated these DOS-induced trends in (db/db) groups, maintaining lowered body weights and normoglycemic parameters while stimulating utero-ovarian weight indices. In addition, E2-HRx prevented the dramatic hypercytolipidemic condition which promotes utero-ovarian involution in (db/db) mice as evidenced by the maintenance of normal reproductive cytoarchitecture. The concurrent moderation of tissue lipase activity and stimulated glucose uptake rates by (db/db) utero-ovarian compartments, under persistent hyperinsulinemic influences, indicated that E2-HRx effectively reduced both the structural and endometabolic consequences of the DOS from promoting (db/db)-associated reproductive organoatrophy. These results indicate that the pathophysiological alterations induced by the (db/db) mutation may be ameliorated through low-dose steroidal therapy, the efficacy of which is suspected to occur via membrane metabolic cascade induction mechanisms or by direct nuclear transcription modulation in reproductive target cells. The subsequent re-establishment of insulin-coupled glucose utilization and suppressed caloric shunting towards lipogenesis promotes the normalization of utero-ovarian structural and metabolic homeostasis in C57BL/KsJ-db/db mutants.
Garris
David R
DR
Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri-Kansas City, 5007 Rockhill Road, Kansas City, MO 64110, USA. garrisd@umkc.edu
Garris
Bryan L
BL
D000818:Animals; D001284:Atrophy / Q000517:prevention & control; D001835:Body Weight; D003920:Diabetes Mellitus / Q000235:genetics*; D004958:Estradiol / Q000097:blood / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006651:Histocytochemistry; D006943:Hyperglycemia / Q000473:pathology; D006946:Hyperinsulinism / Q000473:pathology; D006949:Hyperlipidemias / Q000473:pathology*; D007328:Insulin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009765:Obesity / Q000473:pathology; D010053:Ovary / Q000473:pathology* / Q000648:ultrastructure; D011863:Radioimmunoassay; D014599:Uterus / Q000473:pathology* / Q000648:ultrastructure
D007328:Insulin; D004958:Estradiol