エストロゲン・プロゲステロンによるインスリン抵抗性(シンポジウム2:周産期「妊娠とインスリン抵抗性」,第64回日本産科婦人科学会・学術講演会)

NDLデジタルコレクション 参考文献6件
  • 和田,努
    富山大学大学院医学薬学研究部病態制御薬理学

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  • Insulin Resistance Induced by Estrogen and Progesterone

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Maternal insulin resistance is essential for efficient provision of nutrients to the fetus. However, excess development of insulin resistance in pregnancy is associated with the onset of gestational diabetes. Although precise molecular mechanisms of maternal insulin resistance are unknown, some of hormones or cytokines derived from placenta are thought to be implicated in its development. Therefore, we investigated the effect of estrogen (E2) and progesterone (P4) on the insulin signaling and their actions in 3T3-L1 adipocytes. Treatment the cells with high concentrations of E2 (10^<-5>M; postulated concentration in late pregnancy) suppressed insulin signaling at the step of IRS1. The E2 promoted accumulation of estrogen receptor α(ERα) at the plasma membrane, and stimulated phosphorylated of IRS1 at Ser^<307> through membrane-located ERα and JNK, resulting in the inhibition of insulin-induced tyrosine-phosphorylation of IRS1 and downstream signals leading to glucose uptake. In contrast, low concentrations of E2 (10^<-8>M; physiological concentration) enhanced insulin-induced tyrosine-phosphorylation of IRS1 and glucose uptake. In the case of P4, low doses of progesterone did not affect insulin signaling and glucose uptake. However, higher concentrations of P4 inhibited insulin signaling at multiple steps. Progesterone at 10^<-4>M reduced the amount of IRS1 and suppressed downstream signals. Subsequently, insulin-induced translocation of GLUT4 to the plasma membrane and glucose uptake were decreased. Surprisingly, P4 suppressed glucose uptake elicited by adenovirus-mediated expression of constitutive-active mutant of PI3-kinase and Akt, indicating that P4 suppressed insulin signaling independent to the reduction of IRS1 protein. Interestingly, insulin-induced tyrosine phosphorylation of Cbl and activation of TC10 were inhibited by P4. In summary, we clarified the molecular mechanisms of insulin resistance induc ed by female sex hormones, E2 or P4. In particular, the concentration-dependent biphasic action of E2 on the insulin signaling is of clinical importance. Present findings would contribute to the further understanding of pathophysiology in maternal insulin resistance and GDM.

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