Maternal Diabetes Adversely Affects Preovulatory Oocyte Maturation, Development, and Granulosa Cell Apoptosis

Abstract

Abstract Maternal diabetes adversely affects preimplantation embryo development and pregnancy outcomes. The objective of this study was to determine whether diabetes has an impact at an earlier stage of development, the preovulatory oocyte. Models of both acute and chronic insulin-dependent diabetes were used. Acute hyperglycemia was induced by a single streptozotocin injection. Akita mice, which harbor an autosomal dominant mutation causing them to be chronically hypoinsulinemic and hyperglycemic, were used. In both models, preovulatory oocytes were markedly smaller when compared with control animals. A significantly greater number of control oocytes had progressed to meiotic maturation before diabetic oocytes. Both models were found to have smaller, less developed ovarian follicles with a greater number of apoptotic foci by histological evaluation as well as by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining. Immunohistochemistry displayed a greater amount of TNF-related apoptosis-inducing ligand (TRAIL) and KILLER, a key murine ligand and receptor involved in the extrinsic pathway, expressed in cumulus cells from hyperglycemic mice compared with controls, suggesting that this apoptotic pathway may be up-regulated under diabetic stress. Elevated KILLER expression was also confirmed through Western blotting. Connexin-43 expression was found to be lower by immunohistochemistry and Western blot analysis in the diabetic samples. Both models of maternal hyperglycemia and hypoinsulinemia may have a detrimental effect on oocyte maturation and development as detailed by the smaller sizes of oocytes and developing ovarian follicles, the lowered percentage reaching germinal vesicle breakdown, and the greater amount of apoptosis. In addition, there may be dysfunctional or decreased communication in diabetic oocytes, as demonstrated by lower expression of connexin-43.