The role of
thiazolidinediones (currently
rosiglitazone and
pioglitazone) in the treatment of
Type 2 diabetes is firmly established. The mechanism of action involves binding to the
peroxisome proliferator-activated receptor-gamma, a
transcription factor that regulates the expression of specific genes especially in fat cells but also other cell types such as endothelial cells, macrophages and monocytes, vascular smooth muscle cells and colonic epithelium.
Thiazolidinediones have been shown to interfere with expression and release of mediators of
insulin resistance originating in adipose tissue (e.g., increased
free fatty acids, decreased
adiponectin) in a way that results in net improvement of
insulin sensitivity (i.e., in muscle and liver). A direct or indirect effect on
AMP-dependent
protein kinase may also be involved. Prevention of
lipid accumulation in tissues critical to glycaemia such as visceral adipocytes, liver, muscle and beta-cells at the expense of
lipids accumulating at the less harmful subcutaneous site may be central to their net metabolic effect. The sustained beneficial effect of
troglitazone on beta-cell function in women with previous
gestational diabetes in addition to the
insulin-sensitising properties point to an important role of this class of drugs in the prevention of
Type 2 diabetes. Original safety concerns based on animal and in vitro studies (e.g., fatty bone marrow transformation,
colonic cancer, adipogenic transdifferentiation of blood cells) remain theoretical issues but become less pressing practically with prolonged uneventful clinical use. Hepatotoxicity for
troglitazone and fluid retention, which can aggravate pre-existing
heart failure, are the most important side effects. In summary, with the
thiazolidinediones, a novel concept for the treatment of
insulin resistance and possibly preservation of beta-cell function is available that could become effective in the prevention of
Type 2 diabetes. Moreover, their anti-inflammatory properties also make them interesting in the prevention and treatment of
atherosclerosis and possibly other inflammatory conditions (e.g.,
inflammatory bowel disease). Long-term data will be necessary for a final risk-benefit assessment of these substances.