Diabetes (db/db) Mutation-Induced Ovarian Involution: Progressive Hypercytolipidemia

Abstract

Ovarian atrophy and reproductive tract incompetence are recognized consequences of the progressive expression of the overt, diabetes-obesity syndrome (DOS) in C57BL/KsJ (db/db) mutant mice. The present studies evaluated the progressive changes in ovarian cytoarchitecture, endocrine expression, and reproductive tract cytolipidemic parameters that promote reproductive failure and ovarian involution during the pre-onset, initial, progressive, and chronic expression stages of the DOS. Paired littermate control (normal: +/?) and diabetic (mutant: db/db) C57BL/KsJ females were selected for analysis of ovarian parameters at 2 weeks (pre-onset expression of DOS), 4 weeks (initial DOS expression), 8 weeks (progressive DOS: hyper-glycemic/lipidemic), and 16 weeks (overt/chronic DOS expression) of age. All 4- to 16-week-old (db/db) groups were obese, hyperglycemic, and hyperinsulinemic as compared with age-matched (+/?) controls. Prior to phenotypic expression of the DOS (2 week groups), ovarian interstitial cytolipidemia characterized the perifollicular and cortical regions of db/db tissue samples relative to +/? indices, while comparable body weight, blood glucose, as well as serum insulin and ovarian steroid hormone concentrations characterized both the +/? and db/db groups. Overt DOS expression in the 4-week-old db/db groups was characterized by body obesity, systemic hyperglycemia-hyperinsulinemia, and extensive hypercytolipidemia of ovarian folliculothecal compartments, as well as enhanced tissue lipase activities. By 8 weeks of age, progressive hypercytolipidemia characterized interstitial, thecal, and follicular granulosa cell layers of db/db tissue samples concurrent with suppressed ovarian steroid hormone production, enhanced lipid sequestration, and exacerbation of systemic hyper-glycemia/insulinemia. By 16 weeks of age, the chronic-DOS was characterized by extensive ovarian follicular involution, cortical perivascular hyperlipidemic infiltration, thecal cell atrophy, and follicular granulosa lipid imbibition. These data indicate that db/db mutation-induced ovarian structural and functional involution is a direct reflection of the cellular metabolic shift towards lipogenesis, indicated by the progressive cytoarchitectural transformation into adipocyte-like entities. The cytological indications of cellular metabolic compromise, which precede the phenotypic expression of the DOS indices, suggests that correction of these abnormal shifts in ovarian endocrine and cellular metabolism may restore, delay, or prevent the further compromise of ovarian function by db/db mutation expression.

Evaluation of Ovarian Reserve Based on Hormonal Parameters, Ovarian Volume, and Antral Follicle Count in Women with Type 2 Diabetes Mellitus

“…A progressive hyperglycemic-hyperinsulinemic condition in animal models of the diabetes-obesity syndrome was found to be associated with suppression of cyclic ovarian follicular recruitment patterns, anovulation, acyclicity, depressed ovarian steroid hormone synthesis and release, hypovascularization and tissue ischemia, enhanced follicular atresia, and premature tissue atrophy and involution (33,34). It was suggested that the extent of cellular involution observed in obesity and hyperglycemia could be related to glucotoxicity and the presence of a progressive cytolipotoxic effect.…”

Decreased ovarian function is associated with obesity in very long-term female survivors of childhood cancer

“…Furthermore, the fact that stringent glycemic control in diabetic patients improves menstrual cycles and fertility rates underlines the hypothesis that prolonged hyperglycemia and chronic complications of diabetes negatively affect ovarian reserve (37). Animal models have shown that ovulation was suppressed in hyperglycemic-hyperinsulinemic conditions, due to hypovascularization, follicular atresia, and eventually involution of ovaries, caused by glucotoxicity and the cytolipotoxic effect of obesity (38). It should, however, be stressed that due to the cross-sectional design of the current study, cause and effect could not be distinguished.…”

Alterations of the ovarian histomorphometry at pre‐puberty in rat offspring from diabetic mothers

“…Ovarian atrophy and reproductive tract incompetence are recognized consequences of the progressive expression of the overt, diabetes-obesity syndrome (DOS) in diabetic mutant mice. In both humans and experimental models, utero-ovarian structural, functional, and metabolic parameters are altered in response to the progressive hyperglycemic-hyperinsulinemic systemic conditions that characterize noninsulin dependent (Type II) [10]. Diabetes can result in ovarian atrophy, suggesting that ovarian involution in these mutants is directly related to an impaired follicular ability to properly metabolize the elevated intracellular glucose concentrations that develop in the diabetic mice [13].…”

“…Garris and Garris demonstrated that enhanced lipid deposition and cellular metabolic indices promote a very nonhomeostatic, hyperlipogenic metabolic environment within all ovarian compartments of a diabetic mutant rat. The progressive deposition of enhanced interstitial and follicular lipid pools compromises the functional and structural characteristics of all ovarian cellular and tissue compartments, ultimately inducing a hypercytolipidemia, which contributes to premature tissue involution and ovarian failure [10]. Ishikawa et al [25] reported there were definite histopathological alterations such as mitochondrial abnormalities, dense bodies and lamellar structures at the nerve terminal innervating the dilator muscle.…”

“…The most convincing evidence comes from the commonly observed association of premature ovarian failure with some autoimmune disorders in diabetes mellitus [9]. Data suggests that diabetes mutation-induced ovarian structural and functional involution is a direct reflection of the cellular metabolic shift towards lipogenesis [10]. The diabetes mutation (leptin-receptor defect) induces a hyperglycaemic-hyperinsulinaemic endometabolic environment that promotes hypercytolipidaemic, utero-ovarian involution in mice, resulting in reproductive sterility and eventual organoatrophy [11].…”