Hypercytolipidemia promotes diabetes (db/db) mutation-associated utero-ovarian involution: counter-regulatory influences of progesterone

Abstract

Background: The diabetes (db/db) mutation induces a hyperglycemic–hyperinsulinemic endometabolic environment that promotes hypercytolipidemic, utero-ovarian involution in C57BL/KsJ mice, resulting in reproductive sterility and eventual organoatrophy. Objective: Evaluation of the effectiveness of progesterone therapy (P-HRx), initiated prior to the genetic expression of the overt diabetes–obesity syndrome (DOS), on moderating the severity of female reproductive tract involution promoted by db/db mutation expression was evaluated by analysis of cytoarchitectural, endocrine and tissue lipo-metabolic indices relative to oil (O)-vehicle-treated (HRx) control (+/?) and db/db groups. Experimental design: All HRx treatments were started at 4 weeks of age (pre-overt DOS stage) and continued through 16 weeks of age (chronic DOS expression) when tissue and cellular endometabolic parameters were evaluated. Results: The DOS induced a dramatic increase in phenotypic obesity, hyperglycemia and hyperinsulinemia in db/db groups, relative to +/?, throughout the experimental period. In contrast, utero-ovarian weights were dramatically reduced in db/db groups relative to +/? indices. Chronic P-HRx effectively reversed these DOS-induced trends in db/db groups, maintaining moderated body and tissue weights, as well as re-establishing normal insulin indices, under a persistent hyperglycemic condition. In addition, P-HRx moderated the dramatic hypercytolipidemic condition which promotes utero-ovarian involution in db/db mice as evidenced by the reduction in observed tissue cytolipidemia. The concurrent normalization of tissue lipase and enhancement of glucose utilization indices by db/db utero-ovarian compartments, under moderated insulin recognition parameters, indicated that P-HRx effectively suppressed the severity of both the structural and endometabolic consequences of the DOS in db/db groups, without restraining hyperglycemic conditions. Conclusion: These results indicate that the pathophysiological alterations induced by the db/db mutation may be modulated through low-dose steroidal therapy, the efficacy of which is suspected to occur by the augmentation of normal insulin-coupled, post-receptor directed glucose utilization via the stimulation of oxidative metabolic pathways capable of maintaining normal utero-ovarian structural continuity and metabolic homeostasis.