Like
catching two fish with one worm, treating two problems with
a single drug is efficient, but exceedingly difficult. In
particular, for new diabetes medications, in which one drug
aims to tackle two major complications of diabetes the
excess of both lipids and glucose in the blood the
therapeutic benefits, while great, frequently are
accompanied by dangerous toxic effects to the heart. Why and
how these drugs, known as dual PPARα/γ agonists cause heart
dysfunction in diabetes patients has been unclear.
Researcher show for the first time that dual PPARα/γ
diabetes drugs have a profound toxic effect on the
generation and function of mitochondria, the tiny energy
factories that power cells. Researcher found that the
combined activation of PPARα and PPARγ receptors by a single
agonist drug, tesaglitazar, blocked the activity of proteins
involved in mitochondrial biogenesis and energy production,
including a protein known as SIRT1. The popular diabetes
drugs known as thiazolidinediones (TZDs), which include
pioglitazone and rosiglitazone (the latter marketed as
Avandia), bind to PPARγ receptors. Because these drugs given
alone have been questioned for cardiac toxicity, the idea
emerged for dual PPARα/γ activation by a single drug the one
piece of bait that in theory successfully lures the two fish
the combined lipid- and glucose-lowering effects of PPARα/γ
coactivation. The researchers then repeated their
experiment, this time treating diabetic mice with
tesaglitazar in combination with resveratrol, which serves
as an activator of SIRT1. Mice treated with the combination
of the two drugs had reduced heart toxicity, relative to
tesaglitazar-only therapy, and their heart cells exhibited
normal mitochondrial function. |