Objective To explore the action mechanism of metformin in improving insulin resistance of rats with polycystic ovary syndrome (PCOS) by interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway.
Methods A total of 50 SD rats were injected subcutaneously with dehydroepiandrosterone into the back of the neck to establish a PCOS model, and were randomly divided into model group, metformin group, STAT3 inhibitor group, IL-6 activator group, and metformin+IL-6 activator group, with 10 rats per group. Another 10 SD rats (subcutaneously injected with oil 2 mL/kg on the back of the neck) were selected as sham operation group. The levels of blood glucose, testosterone (androgen), insulin level of rats in each group were measured, and the insulin resistance index was calculated; hematoxylin and eosin staining (HE) was performed to observe the ovarian morphology; immunohistochemical method was performed to measure the positive expression of IL-6; real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) method was performed to measure the level of microRNA-21 (miR-21); western blot was performed to measure the expressions of IL-6, STAT3, phosphorylated-STAT3 (p-STAT3) and downstream insulin receptor substrate-2 (IRS-2), signal transduction pathway inhibitor protein 3 (SOCS-3), peroxisome proliferator activation receptor γ (PPARγ) proteins.
Results Compared with the sham operation group, the insulin resistance index(40.88±3.74) versus (15.23±1.00) and androgen secretion level(1.73±0.19) ng/mL versus(1.10±0.10) ng/mL in the model group were increased, the follicles cystic changes, the disappearance of the oocyte radiation crown, the decrease of the corpus luteum and the granulosa cells and other pathological damages in the ovarian tissue were serious, the IL-6/STAT3 pathway was in an active state, leading to inflammation, insulin resistance, androgen secretion-related proteins and genes mediated increased (P<0.05). Compared with the model group, IL-6/STAT3 pathway activation in both metformin group and STAT3 inhibitor group were inhibited, and insulin resistance index(20.39±2.41), (20.89±2.54) versus (40.88±3.74) and androgen secretion level(1.29±0.11) ng/mL, (1.29±0.11) ng/mL versus (1.73±0.19) ng/mL(P<0.05). Compared with the metformin group, insulin resistance index(39.87±3.88) versus (20.39±2.41), androgen secretion level(1.70±0.18) versus (1.29±0.11)ng/mL in the metformin+IL-6 activator group increased, and the recovery of ovarian pathological injury was slow, the differences were statistically significant (P<0.05).
Conclusion Metformin can inhibit IL-6/STAT3 activation to improve insulin resistance, androgen secretion and ovarian morphology changes of PCOS rats.
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