Progesterone inhibits glucose uptake by affecting diverse steps of insulin signaling in 3T3-L1 adipocytes

Tsutomu Wada, Satoko Hori, Maine Sugiyama, Eriko Fujisawa, Tetsuro Nakano, Hiroshi Tsuneki, Kiyofumi Nagira, Shigeru Saito, Toshiyasu Sasaoka

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Maternal insulin resistance is essential for efficient provision of glucose to the fetus. Although elevation of placental hormones is known to relate to the development of insulin resistance, the precise underlying mechanism of maternal insulin resistance is unknown. Therefore, we examined the molecular mechanisms of progesterone causing insulin resistance in 3T3-L1 adipocytes. Progesterone at 10-4 M, but not 10-5 M, reduced the amount of IRS-1. As a result, insulin-induced phosphorylation of IRS-1, the association of IRS-1 with p85α, and subsequent phosphorylation of Akt1 and -2 was decreased moderately by 10-4 M progesterone. Subsequently, insulin-induced translocation of GLUT4 to the plasma membrane evaluated by immunostaining on the plasma membrane sheet by confocal laser microscope was also decreased by 10-4 M progesterone. In contrast, 2-[ 3H]deoxyglucose (2DG) uptake was markedly inhibited by both 10 -5 and 10-4 M progesterone in a dose-dependent manner. Surprisingly, 2DG uptake elicited by adenovirus-mediated expression of constitutive-active mutant of PI 3-kinase (myr-p110) and Akt (myr-Akt) was suppressed by progesterone. Interestingly, insulin-induced tyrosine phosphorylation of Cbl and activation of TC10 were inhibited by progesterone at 10-5 M. These results indicate that progesterone is implicated in insulin resistance during pregnancy by inhibiting the PI 3-kinase pathway at the step of 1) IRS-1 expression and 2) distal to Akt and 3) by suppressing the PI 3-kinase-independent pathway of TC10 activation by affecting Cbl phosphorylation.

Original languageEnglish
Pages (from-to)E881-E888
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume298
Issue number4
DOIs
Publication statusPublished - 2010 Apr 1
Externally publishedYes

Keywords

  • Gestational diabetes
  • Insulin resistance
  • TC10

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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