Insulin pleiotropic effects

Smith, R. et al. (1997). Insulin internalization and other signalling pathways in the pleiotropic effects of insulin. Int. Rev. 

Among patients with hyperinsulinemia, the benefit of gemfibrozil therapy increased as the severity of insulin resistance rose (145). Of considerable importance is the fact that VA-HIT was the first trial to show a reduction in cardiovascular and cerebrovascular events with an antilipedmic medication independent of changes in serum LDL. Most of the benefit of fibrate therapy in this trial was attributed to HDL elevation and the pleiotropic effects of gemfibrozil (145). 

Thyroid hormone, like insulin, continues to present a puzzle in terms of its mechanism of action. Since thyroid hormones increase the activity of a number of enzymes, as well as protein synthesis in general, an effect on protein synthesis either at the level of transcription or translation has been sought (Rail, 1978). Nuclear binding of T4 has been demonstrated, apparently to nonhistone proteins. It appears that it is free T4 which binds to the nucleus and not the T4 already bound to the cytoplasmic receptor. In fact, it appears that cytoplasmic receptors compete for T4 bound to nuclear sites. Nonetheless, there is strong inferential evidence for a role of T4 on transcription of mRNA (Rall,1978), but this does not represent the only means of explaining the pleiotropic effects of the hormone (Sterling, 1979). 

Fig. 1. Mechanism of the pleiotropic actions of the thiazolidinediones. Working via the PPAR-y receptor system in adipose tissue, the thiazolidinediones interrupt the pathogenic signaling between the expanded visceral adipose mass in obesity, which leads to improved insulin sensitivity in skeletal muscle and hver, enhanced pancreatic P-cell insulin secretion, and improved vascular endothelial function. The processes affected by the thiazolidinediones include redistribution of adipose stores, reduced circulating levels of FFA, diminished levels and tissue effects of cytokines (TNF-a), and increased circulating levels of the insulin-sensitizing, anti-atherogenic plasma protein adiponectin, which also arises from adipose tissue. The thiazohdinediones have also been shown to have direct effects in muscle and endothelial cells, which is likely to also contribute to some of their pharmacologic activity.

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