Progesterone inhibits glucose uptake by affecting diverse steps of insulin signaling in 3T3-L1 adipocytes.
Level 5 - mechanism / opinion, no new human data
In vitro laboratory bench research in cultured cell lines
PubMed 20071559 · doi:10.1152/ajpendo.00649.2009
What was done
Researchers investigated the molecular mechanisms by which progesterone causes insulin resistance in cultured mouse 3T3-L1 adipocytes. Cells were treated with progesterone at 10(-5) M and 10(-4) M and evaluated for insulin receptor substrate-1 (IRS-1) abundance, insulin-induced IRS-1 phosphorylation, IRS-1 association with p85alpha, and Akt1/Akt2 phosphorylation. GLUT4 translocation to the plasma membrane was assessed via confocal laser microscopy immunostaining, and glucose uptake was measured using 2-[(3)H]deoxyglucose (2DG). They also tested 2DG uptake in cells transduced with constitutively active PI 3-kinase or Akt mutants, as well as insulin-induced Cbl tyrosine phosphorylation and TC10 activation.
What was found
Progesterone at 10(-4) M, but not 10(-5) M, reduced IRS-1 protein levels and moderately decreased insulin-induced IRS-1 phosphorylation, IRS-1-p85alpha association, Akt1/2 phosphorylation, and GLUT4 plasma membrane translocation. In contrast, 2DG uptake was inhibited by both 10(-5) M and 10(-4) M progesterone in a dose-dependent manner. Progesterone also suppressed 2DG uptake stimulated by constitutively active PI 3-kinase (myr-p110) and Akt (myr-Akt). Progesterone at 10(-5) M inhibited insulin-induced Cbl tyrosine phosphorylation and TC10 activation. Specific numerical values and effect sizes were not reported in the abstract.
Why it matters
This study delineates specific cellular pathways through which progesterone impairs adipocyte glucose uptake, identifying inhibition at the level of IRS-1 expression, distal to Akt, and via the PI 3-kinase-independent Cbl/TC10 pathway. This provides mechanistic insight into gestational insulin resistance.
Limits
The study was conducted entirely in an immortalized mouse cell line (3T3-L1 adipocytes) in vitro using high pharmacological concentrations of progesterone (10(-5) to 10(-4) M). In vivo confirmation, human tissue validation, exact sample sizes (replicates), and quantitative values were not reported in the abstract.
Cited by
- supports Progesterone antagonizes insulin action by impairing insulin-mediated glucose uptake and reducing GLUT4 receptor translocation, as well as altering hepatic glucose handling.