Hexokinase and phosphofructokinase as possible targets of insulin‐independent cardioprotective action of metformin

Diabetes mellitus (DM) is characterized by hyperglycemia and its associated complications, including cardiomyopathy. Metformin, in addition to reducing glycemia, can cause cardioprotective effect in diabetic patients. Inhibition of hexokinase (HK) and phosphofructokinase (PFK), rate‐limiting glycolytic enzymes, may contribute to diabetic cardiomyopathy. Thus, our aim was to determine whether metformin modulates heart HK and PFK from streptozotocin‐induced diabetic mice. HK and PFK activities are reduced in diabetic mice, an effect abrogated upon treatment with metformin injected intraperitoneally for three days, once a day. Mitochondrial bound HK and cytoskeleton bound PFK activities are increased in diabetic hearts treated with metformin as compared to non‐treated diabetic. Metformin treatment reverses the reduced PFK levels, analyzed by Western blot, in diabetic mice. Diabetes induction and/or metformin treatment do not alter either HK or PFK mRNA levels, detected by RT‐PCR, as well as threonine and tyrosine phosphorylation levels of PFK. However, diabetes induction raises serine phosphorylation level of PFK, an effect reverted by metformin treatment. Also, diabetic hearts treated with metformin uptake more glucose than those not treated. Thus, cardiac protection by metformin could involve the activation of glycolysis through the regulation of HK and PFK. Support by: FAPERJ, CNPq, CAPES.