Glitazones and Weight Gain

Many people who take a glitazone drug -- pioglitazone (Actos) or rosiglitazone (Avandia), also known as TZDs (thiazolidinediones) -- find that the drug works well to lower their blood glucose (BG) levels, but it also seems to make them gain weight.

Some doctors will say that the weight gain is simply fluid retention, which is a known side effect of the TZDs. That did happen to me when I was in a short clinical study of Avandia. I put on about 6 pounds during the study, but I lost them without effort when I went off the drug at the end of the study.

But the TZDs are also supposed to trigger the differentiation of precursor cells into new fat cells. The new, small fat cells aren't stuffed with fat like some of the older, large fat cells, and they're more responsive to insulin. Hence they take up more glucose, and this keeps the BG levels down.

Several recent studies have shed more light on the weight gain that occurs with the TZDs.

One study, published in the Journal of Biological Chemistry, showed that in obese mice, at least, rosiglitazone increased the expression of the VLDL receptor gene in fat cells. VLDL is the type of cholesterol particle that carries fats from the liver to the various organs that use it.

With more VLDL receptors on the fat cells, more VLDL would get bound to the fat cells, which would take up more fat. And the mice did, in fact, get fatter than the control mice, although their insulin resistance decreased.

They also showed that in certain mutant mice that couldn't bind VLDL, the effect on insulin resistance was preserved, but the mice didn't gain any weight, meaning it would be possible in theory to separate the effects on BG levels from weight gain.

Another study, in the journal Clinical Endocrinology and Metabolism, showed that pioglitazone treatment enlarges subcutaneous fat cells in insulin-resistant patients.

This is rather ironic, because obesity-related insulin resistance is associated with large fat cells, and TZD therapy is supposed to result in the birth of smaller fat cells. But in this study, although insulin resistance decreased, the size of the fat cells increased with the TZD treatment.

The TZDs work by stimulating a nuclear transcription factor called PPAR gamma. A third article described a study in humans in which they separated patients into TZD responders and TZD nonresponders. Previous studies had suggested that about 30% of patients do not respond to the TZDs.

They found that in insulin sensitive people, those without insulin resistance, feeding resulted in the expression of many genes involved with glucose metabolism. This response was blunted in people with insulin resistance.

In the insulin resistant people who responded to a TZD, the drug caused an increase in the genes that were stimulated in the insulin sensitive people. In the insulin resistant nonresponders, the expression of the same genes was not changed.

But they also noted that fat cell gene expression in muscle increased after TZD treatment, especially in those people who responded to the drug, suggesting that the decrease in insulin resistance in the drug responders was caused by more fat cells in the muscle tissue.

Hence they suggested that the fat infiltration often seen in the muscles of insulin resistant persons may not, in fact, be causing the insulin resistance. Rather, they suggest, the fat cells are absorbing extra calories from overeating and are attempting to reduce the insulin resistance.

All these studies -- and I'm sure there are many more -- are consistent in suggesting that the TZDs do work by increasing the amount of fat in the body, both subcutaneous fat and fat in muscle tissue, and perhaps elsewhere as well.

They are consistent in suggesting that the TZDs work by stimulating this increased amount of fat while at the same time reducing insulin resistance. If you're taking one of these drugs and you gain weight, don't let your doctor tell you that you're not watching your portion sizes. The drug is probably causing the weight gain.

However, the one study suggested that these two effects could be separated, although no one knows how yet.

The last study also notes the difference between drug responders and nonresponders. The TZDs don't work for everyone.

Most drugs can have both good and bad effects. For example, it turns out that the fat cell precursor cells that the TZDs stimulate to differentiate into baby fat cells are the same ones that can be turned into bone-forming cells. When you produce more fat cells, you produce fewer bone-producing cells. Hence the TZDs can contribute to bone loss, or osteoporosis.

As with all drugs, we need to weigh the pros and cons of the TZDs in light of our own particular situation. First, do they work to reduce BG levels when we take them? Or are we nonresponders? No point in risking side effects if the drug isn't working for us.

Second, are we unhappy with the amount of weight gain that results from the drugs?

Third, are we at high risk for osteoporosis so even a small loss of bone-producing cells might have terrible consequences?

Diabetes is complicated, and there are no simple answers. But the more we understand about how these drugs work, the better the decisions we can make about which drug or drugs work best for our own particular physiology.