INSULIN AND VANADATE ACTION ON HEME BIOSYNTHESIS GENES TRANSCRIPTION IN DIABETIC MICE

Oliveri Leda, Vazquez Elba, Batlle Alcira, Gerez Esther

 

CIPYP-CONICET and University of Buenos Aires

 

 

Treatment of porphyria acute attacks with carbohydrates diminishes the production and excretion of heme precursors such as 5´aminolevulinate acid (ALA). In spite of its therapeutic use, the molecular and biochemical basis of the known glucose effect are yet to be dilucidated.

Diabetes-induced alterations on the transcription of heme biosynthesis genes were examined in male CF1 mice. Animals were diabetized with a single dose of streptozotocin (STZ, 170 mg/Kg ip) and Northern blot analysis were performed at different times after treatment. Animals with serum glucose levels higher than 300 mg/ml were considered diabetic and were treated with vanadate (0.2 mg/ml in drinking water) during 16 days (STZ+V group), or insulin (30 U/100g, sc) during 9 days (STZ+I group) or only STZ  (STZ group). Ferrochelatase (FQ) and ALA Synthetase (ALA-S) mRNA levels increased 100% 32 days after STZ injection. Insulin and vanadate treatment restored ALA-S RNAm to basal levels. However, FQ mRNA induction in diabetic animals was not modified by insulin treatment although vanadate administration was able to restore basal levels. No changes were detected in ALA dehydratase (ALA-D), Uroporphyrinogen Decarboxylase URO-D) and Heme Oxygenase (HO-1) mRNA. The increase in ALA-S mRNA was due to higher transcription levels as the mRNA stability was not altered in diabetic animals compared to controls (ALA-S mRNA half life = 25 min).

Employing an experimental model of diabetes we have demonstrated that insulin regulates the in vivo transcription of ALA-S. By using an insulin-mimetic agent we have corroborated that insulin is involved in the downmodulation of this gene transcription.