Insulin and vanadate action on heme biosynthesis genes transcription in diabetic mice

OLIVERI, LEDA; BATLLE, ALCIRA; GEREZ, ESTHER

Mar del Plata

Congreso; Sociedad Argentina de Investigación Clínica; 2008

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, both agents were unable to decrease FQ mRNA induction in diabetic animals. 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.