Table 2. The physiological and biochemical consequences of targeted disruption or overexpression of components of insulin signalling pathways in other (non-ovarian) cells.
Note: knockout of insulin is lethal 2 days after birth [202] and knockout of the IR is lethal 1 week after birth [199].
| Component | Tissue/cell type | Effect on fertility | Ovarian consequences | Reference |
|---|---|---|---|---|
| IR | Brain neurons | Impaired fertility (50%) | Fewer antral follicles and corpora lutea due to reduced release of LH | [210] |
| IRS-1 | All | 70% pregnancy rate | Mildly defective reproductive function | [211] |
| IRS-2 | All | Infertile | Reduced LH levels and gonadotropin number, show reduced gonadotropin-stimulated ovulation and markedly reduced numbers of ovarian follicles and corpora lutea | [212] |
| IRS-2 | All | Infertile | Reduced follicle size, increased numbers of atretic follicles, as well as impaired oocyte growth and antral cavity development, granulosa cell proliferation defective | [213] |
| IRS-2 | CNS and hypothalamus | Fertile | Minimal defects in pituitary and ovarian hormone concentrations, ovarian anatomy and function | [213] |
| IRS-3 | All | Fertile | No effects on fertility or embryonic viability | [214] |
| IRS-4 | All | 50% pregnancy rate | Null females are less nurturing of their pups | [215] |
| FOXO3a | All | A marked age-dependent decline in reproductive fitness and were sterile by 15 weeks of age | Global follicular activation, oocyte death, early depletion of functional follicles and secondary infertility | [216] |
| SHB (3Src homology 2 domain-containing adapter protein B) | All | Fertile. Shb−/− embryos cannot be created on a C57Bl/6 background but only on a mixed genetic background. Heterozygotes (Shb+/−) are viable | Defective meiosis I and early embryo development | [217] |
| p110δ (pik3cd) | All | Sub-fertile | Defects in ovarian follicle maturation | [218] |
| Akt1 | All | Reduced fertility | Abnormal oestrous cycles, POF, no compensation was observed by Akt2 or Akt3 | [219] |
| Akt2 | All | Reduced fertility in aged mice | Aged mice have testosterone concentrations and ovarian cysts with increased numbers of thecal-interstitial cells | [220] |
| Akt2 | All | Normal fertility for young mice | ||
| GSK3 isoforms | Fertile | GSK3α or GSK3β did not induce a lethal phenotype. Individual loss of oocyte but no effect on fertility | [221] | |
| IGFBP1 | Overexpression in liver | Reduced fertility | Impaired fertilization or implantation, interrupted or prolonged pregnancies with fetal and neonatal death | [222] |