How do insulin sensitizers work

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Carey, J. In the case of the addition of metformin to a TZD or vice versa, because of their different sites of action liver with metformin and muscle with the TZD , it will result in a decrease in the hemoglobal Hb A1c that will be greater than that achieved by monotherapy with a larger dose of either drug. Perhaps of more importance is that, at lower doses, the side-effects of metformin anorexia, nausea, and diarrhea and TZDs weight gain, edema, and dilutional anemia are much less.

Both metformin and TZDs lower cardiac events. This is important with type 2 diabetes, which has been described as a cardiac condition characterized by hyperglycemia and is a cardiac risk equivalent i. Furthermore, the smaller HDL3 particle in addition to being less cardioprotective, is also more easily broken down by the liver, accounting for the low total HDL seen with insulin resistance.

Therefore, insulin sensitizers used in combination can, even at lower doses by their effects on the lipid profile, provide a further lowering in cardiac risk and are complementary to the statins which most type 2 diabetic patients will be or should be utilizing.

Endothelial dysfunction is improved by both TZDs and metformin. When the endothelium is healthy, nitric oxide is produced, vasodilatation occurs, and the endothelium is resistant to both clot formation and penetration by monocytes to start the process of atherogenesis. When insulin resistance is present, superoxides are produced, nitric oxide activity is effectively quenched, and endothelial dysfunction occurs with vasoconstriction, clotting, and atheroma formation.

Because of its association with endothelial dysfunction in the Paris Protective and the Quebec Heart Studies, the presence of insulin resistance has been shown to be an independent risk factor for cardiac events and increases the risk of a cardiac event in the non-diabetic insulin-resistant subject by over five times. With lowering of insulin resistance, vasodilatation occurs accompanied by a small but significant decrease in blood pressure.

Furthermore, with less endothelial damage, there are reductions in the levels of both Von Willebrand factor and homocystein. Albuminuria is an easily assessed manifestation of endothelial dysfunction since the glomerulus is an arteriole, and with the decrease in permeability of that arteriole, which occurs with insulin sensitization and improved endothelial function, albuminuria decreases beyond that which would be expected from lowering of the glucose alone.

Elevation of PAI 1 is associated with a decrease in the conversion of plasminogen to plasmin, a slowing of fibrinogen and clot breakdown and higher serum fibrinogen levels and increased thromboembolic events.

However, of more importance is that with high PAI 1 levels in the vessel wall, the ensuing low plasmin levels are associated with decreased removal of collagen from the atheromatous plaque, which is needed to facilitate the entry of vascular smooth muscle cells into the plaque so that the plaque can be stabilized. Therefore, insulin resistance due to high PAI 1 levels is associated not only with an increased frequency of thromboembolism, but with unstable atheromatous plaques and increased cardiovascular events.

By reducing insulin resistance, both metformin and TZDs have been shown to lower PAI 1 levels, which can be further lowered by improved glycemic control and this combination should lead to less cardiac events. The presence of a high serum C-reactive protein level is associated with both insulin resistance and unstable atheromatous plaques.

An autopsy study of coronary arteries showed that C-reactive protein was only present in the segments of the artery that had atherosclerotic lesions and was present even at the very earliest stages of atherogenesis.

A specific receptor for C-reactive protein CRP resides on the monocyte, and activation of this receptor promotes migration of the monocytes into the arterial wall with activation of complement. Therefore, C-reactive protein is not only a marker of inflammation within a plaque but also plays a very active role in the formation of the atheromatous plaque.

TZDs are generally well tolerated and Actos is easy to take because it may be taken only once a day at any time that is convenient.

In a similar fashion to Glucophage, Glyset, and Precose, TZDs do not stimulate the pancreas; therefore, hypoglycemia is not a problem and there is better longterm effectiveness by resting the pancreas compared with the SFUs see previous discussion on the ADOPT here or in chapter 7 of my book.

TZDs have also been shown to improve abnormal cholesterol and triglyceride levels and blood pressure. TZDs have additional effects that may help keep the heart and cardiovascular system healthy such as reducing inflammation and the tendency of the blood to be too thick , thus reducing the risk of blood clots. The benefits and shortfalls of TZDs are listed below:. The TZDs in general are safe and well-tolerated medications.

Avandia rosiglitazone is not being used because of the false scare that it may cause heart disease discussed above. The most common side effects of the TZDs are fluid retention, commonly presenting as edema or swelling of your ankles, and weight gain. For some, the ankle edema is very mild and the benefits of improved glucose control far outweigh this side effect.

However, some individuals may have significant swelling and the medication must be discontinued the swelling goes away after stopping or reducing the medication. Like all medications, there have been other side effects associated with Actos, such as bone fractures especially in postmenopausal women with osteoporosis and bladder cancer.

It is very important to discuss this with your HCP if pioglitazone is being considered. It really comes down to the risk-benefit ratio, and the decision to use Actos or Avandia or any drug for that matter should be individualized. The typical weight gain that is observed with Actos in clinical studies is about 5 to 10 pounds; however, there are many variables that may affect potential weight gain.

Once again, in my opinion, this is a small price to pay for improving blood glucose control and in turn, reducing the complications of diabetes.

It is important to know that because of the way the insulin sensitizers work mechanism of action , it may take several weeks for you to observe any improvement in your blood glucose level.