Progesterone impairs cell respiration and suppresses a compensatory increase in glucose transport in isolated rat skeletal muscle: a non-genomic mechanism contributing to metabolic adaptation to late pregnancy?
OBJECTIVE
The aim of the study was to gain better insight into the mechanisms responsible for impaired glucose metabolism during late pregnancy. We explored the direct effects of progesterone on glucose metabolism of skeletal muscle.


METHODS
Specimens of skeletal muscle from untreated rats were incubated with progesterone and rates of substrate fluxes through the various pathways of glucose metabolism were analysed.


RESULTS
Progesterone dose-dependently reduced the rates of glucose and pyruvate oxidation (insulin-stimulated rates after 5 h of exposure to 1 and 10 mumol/l progesterone: glucose oxidation, -6 +/- 4%, NS, and -39 +/- 4%, p < 0.001; pyruvate oxidation, -28 +/- 2% and -55 +/- 4%, p < 0.001 each) and increased lactate release (+28 +/- 4% and +58 +/- 9%, p < 0.005 each), which indicated inhibition of mitochondrial respiratory function. Impairment of cell respiration, e.g. by the specific inhibitor rotenone, is known to trigger a compensatory increase in glucose transport, but this response was blunted in the case of progesterone (change of glucose transport in response to 10 mumol/l progesterone vs 60 nmol/l rotenone, both causing a reduction in glucose oxidation by -39%: progesterone, +14 +/- 8% vs rotenone, +84 +/- 23%, p < 0.03). Further experiments dealt with the underlying mechanisms and revealed a rapid mode of action (50 mumol/l progesterone, reduction in insulin-stimulated glucose oxidation after 30 min: -29 +/- 7%, p < 0.01) not affected by blockers of gene expression or the nuclear progesterone receptor.


CONCLUSIONS
Progesterone inhibits cell respiration and at the same time suppresses a compensatory increase in glucose transport, causing cellular carbohydrate deficiency in isolated rat skeletal muscle. This effect is mediated by a direct, rapid and non-genomic mechanism and could contribute to pregnancy-associated changes in glucose homeostasis.
Gras
F
F
Department of Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Brunmair
B
B
Quarré
L
L
Szöcs
Z
Z
Waldhäusl
W
W
Fürnsinn
C
C
D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D016678:Genome / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009924:Organ Culture Techniques; D011247:Pregnancy; D011263:Pregnancy Trimester, Third / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology; D013997:Time Factors
D007328:Insulin; D008565:Membrane Proteins; C486424:Pgrmc1 protein, rat; D011500:Protein Synthesis Inhibitors; D011980:Receptors, Progesterone; D013256:Steroids; D011374:Progesterone; D005947:Glucose