Heme biosynthesis markers of porphyria in a model of diabetic mice

OLIVERI, LEDA; VARELA, LAURA; ROSSI, JUAN PABLO; BATLLE, ALCIRA; GEREZ, ESTHER

Estocolmo, Suecia

Congreso; PORPHYRINS AND PORPHYRIAS 2009; 2009

The Swedish Society of Medicine

Diabetes decreased significantly cellular hemeproteins, possibly as a consequence of a biochemical hindrance of the hepatic enzymes involved in heme biosynthesis. Besides, treatment of porphyria acute attacks with glucose 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 so-called »glucose effect« and the relationship between carbohydrate metabolism and heme biosynthesis are yet to be elucidated. To examine the rapport of these phenomena, we studied the diabetes-induced alterations of heme biosynthesis in male CF1 mice. Animals were treated with a single dose of streptozotocin (STZ, 170 mg/ Kg ip) or vehicle (Normal group). Animals with serum glucose levels higher than 300 mg/ml 16 day after STZ-treatment were considered diabetic. This group was treated with insulin (30 U/100g, sc) during 16 days (STZ+I group) or vehicle (STZ group). Northern and Western blot analyses were performed after treatment to assess mRNA and protein levels of ALA synthase (ALA-S) and ALA dehydratase (ALA-D). Results show that after 32 days of STZ injection, STZ group increased 100% the levels of ALA-S mRNA, while protein levels were increased tenfold compared with Normal group. Insulin treatment restored both mRNA and ALA-S protein to basal values after 16 days. STZ inhibited 50% ALA-D activity. However, no changes were detected either in the mRNA or the protein content of this enzyme. Insulin treatment of diabetic animals restored ALA-D activity to control levels. ALA and PBG urinary content were increased in the STZ group (ALA excretion in STZ group: 10mg/24hs, Normal group: 2.18 mg/24hs; PBG excretion in STZ group: 6mg/24hs, Normal group: 1.56mg/24hs). These results indicate that there is a clear relationship between carbohydrate metabolism and heme biosynthesis whereby insulin would play a key role. We have shown that changes in insulin levels have dramatic effects on classical markers of an acute porphyria, such as ALA-S and ALA-D activities and urinary content of ALA and PBG. Our findings suggest that the glucose effect may be mediated by an increase of insulin which in turns would diminished ALA-S activity and subsequently reduced precursors accumulation.