Ultrastructural and metabolic changes associated with reproductive tract atrophy and adiposity in diabetic female mice

Abstract

The effect of progressive, diabetes-associated adiposity on reproductive tract structure and function was examined in 4- to 16-week-old C57BL/KsJ, control (+/?) and diabetic (db/db) mice. Uterine and ovarian tissues were analyzed by transmission electron microscopy for ultrastructural changes associated with increased intracellular lipid accumulation. In addition, the same tissues were analyzed for changes in activity of tissue lipoprotein lipase, an enzyme that hydrolyzes lipoprotein-associated triacylglycerols and supports the cellular uptake and storage of free fatty acids. Between 8 and 16 weeks of age, intracellular lipid deposits increased dramatically in the ovarian granulosa, thecal and stromal cell populations, as well as in the uterine epithelium, of diabetic mice compared to controls. By 16 weeks of age, the lipid deposits essentially occupied the entire cytoplasmic area of both the ovarian and uterine cell types in diabetics. The basal lamina underlying the uterine epithelium was expanded in the diabetics relative to controls, and the hyperglycemic condition induced an observable increase in endometrial intercellular space that was occupied by a hyaline type of ground substance of unknown composition and origin. In association with these structural changes, both ovarian and uterine lipase activities were greatly increased in the db/db mice compared with controls. These data suggest that the structural adiposity and functional decline in reproductive tract condition of the db/db mutants are related to the enhanced cellular lipid deposition observed in this species. These changes in structural and metabolic parameters are related to the reproductive incompetence characteristic of this murine model.

Heat shock protein production and immunity and altered fetal development in diabetic pregnant rats

“…Diabetes mellitus comprises a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both (American Diabetes Association 2011). Impaired reproductive performance is a well-known result of the diabetic syndrome in many mammalian species, including humans (Chieri et al 1969;Kirchick et al 1978;Vomachka and Johnson 1982;Garris et al 1986). Placental dysfunction contributes to an increased frequency of fetal complications in diabetic pregnancies (Daskalakis et al 2008).…”

Diabetes-Induced, Progressive Endometrial Involution Characterization of Periluminal Epithelial Lipoatrophy

“…he expression of the diabetes-obesity syndrome in C57BL/KsJ (db/db) mice is accompanied by a progressive cellular atrophy and functional compromise of the female reproductive tract (1)(2)(3). Characterized by ovarian follicular atresia (4), inhibition of follicular recruitment (4), depressed ovarian steroid hormone production (1,3,5), refractory responsiveness to gonadotropin stimulation (6), and failure of corpus luteum formation (4,7,8), the maturation of the reproductive tract is developmentally and structurally impaired as compared with littermate controls (ϩ/?).…”

“…Characterized by ovarian follicular atresia (4), inhibition of follicular recruitment (4), depressed ovarian steroid hormone production (1,3,5), refractory responsiveness to gonadotropin stimulation (6), and failure of corpus luteum formation (4,7,8), the maturation of the reproductive tract is developmentally and structurally impaired as compared with littermate controls (ϩ/?). Uterine structural parameters influenced by the expression of the db/db mutation include a marked depression in uterine epithelial cellular integrity (1,7), depressed responsivity to ovarian steroid hormone therapy (7,9,10), suppressed mitotic indexes (3), and premature tissue involution (2), accompanied by an enhanced cytoplasmic lipid inclusion volume (4). In addition, the progressive exacerbation of the hyperglycemic condition with age is accompanied by a parallel accentuation of these cytological alterations, especially within the endometrial epithelial layer (5).…”

“…Pronounced basal pole lipid accumulations, enhanced folding of epithelial basal membranes, dispersion and volume reduction of the cytoplasmic organelles, as well as the progressive thickening and separation of the basal membrane from adjacent endometrial stroma support, has been recognized to occur after overt expression of the db/db mutation (1,4,7). These findings have suggested that the deleterious influences of the diabetes-obesity syndrome on reproductive tract competency are evidenced by a progression of cellular cytoplasmic changes linked to the expression of abnormal endocrine parameters and the hyperglycemic-hyperlipidemic conditions in this species (1,4,5).…”

Estabelecimento de um modelo de gestação complicada por diabetes tipo 1 em camundongos: avaliação do seu impacto sobre o ambiente uterino no início da gestação.

“…(Hoggard et al, 1998). Fêmeas de camundongo da linhagem db/db, com mutações no receptor da leptina, são inférteis devido a diversas alterações morfofuncionais no sistema reprodutor e a interrupção do ciclo estral (Garris et al, 1986;Garris, Garris, 2004 A diminuição do número de sítios de implantação foi descrita por outros grupos em ratas diabéticas (De Hertogh et al, 1989;Wentzel et al, 1995). Em fêmeas de camundongo, entretanto, alguns estudos descrevem tanto a diminuição ) como a ausência de alterações no número de sítios de implantação (Torchinsky et al, 1997;Fein et al, 2002;Burke et al, 2007;Dong et al, 2008 (Chieri et al, 1969;Diamond et al, 1989;Moley et al, 1991;Pampfer et al, 1994;Revisão em: Jungheim, Moley, 2008).…”