Tuesday, August 2, 2011

Is DPP-4 an Adipokine?

DPP-4, or dipeptidyl peptidase 4, is an enzyme that breaks down certain proteins, including GLP-1, or glucagon-like peptide.

GLP-1 has positive effects on insulin secretion, and the drug exenatide (Byetta) works by mimicking natural GLP-1. Because GLP-1 can help people with diabetes, it was thought that drugs that inhibit DPP-4, which would keep GLP-1 in the circulation longer, would also help people with diabetes.

Several DPP-4 inhibitors, the "gliptins" have been developed and include Januvia (sitagliptin) and Trajenta (linagliptin). They do reduce A1c levels somewhat, although they don't appear to be as effective as the GLP1-mimetics.

And one problem with such drugs is that DPP-4 affects many different proteins, and the inhibitors seem to reduce the effectiveness of the immune system, which could be deleterious.

DPP-4 exists as a membrane-bound protein and also free in solution. Both forms break down GLP-1.

But now European researchers report that DPP-4 is an adipokine that impairs insulin sensitivity.

An adipokine is a cytokine secreted by adipose tissue. A cytokine is similar to a hormone; it is a signalling molecule. Many of these substances have been discovered only recently and not everyone agrees about which should be called hormones and which cytokines. The important thing is that they're secreted by one type of cell and can affect others.

The European researchers found that the levels of DPP-4 were higher in persons with more fat cells, and in those with larger fat cells. Also, the production of DPP-4 in obese persons was fivefold higher in visceral adipose tissue (the tissue around organs that is associated with metabolic syndrome) than it was in subcutaneous fat. There were no regional differences in lean subjects.

After weight loss, the release of DPP-4 reverted to levels similar to those of lean subjects.

If DPP-4 is an adipokine that impairs insulin sensitivity, then it makes sense that the DPP-4 inhibitors would improve insulin sensitivity and lower BG levels. It's not clear at this time which of the DPP-4 effects would be more important.

But this could be the link between obesity and insulin resistance, or it could simply be one of many links between the two conditions. Perhaps this report will stimulate more research in this area.


  1. Fascinating. Thanks for the clear, succinct treatment of something I wouldn't otherwise have a prayer of understanding!

  2. Thanks, Karenn. Glad it was helpful.

  3. Are you saying that fat around the waist is more harmful than anywhere else?

  4. LuYoung, Yes it is. Fat elsewhere might even be protective.

  5. Hi, Gretchen. WRT to abdominal adiposity, there was this contrary evidence:

    The study, published online in the Lancet on March 11, 2011, was conducted by the international group known as the Emerging Risk Factors Collaboration.

    "It has been thought that central adiposity (apple shape) is associated with a greater risk of cardiovascular disease than other types of obesity, but we have shown in our study that any one of three measures of obesity are equally associated with heart disease. So being an apple is no worse than being a pear. Both are bad."


  6. Thanks, Lerner. The study you cite is a meta-analysis, and they're always suspect.

    Statistics is not my strong suit, but I know you can manipulate statistics, so in order to evaluate any paper like this you have to go over it with a fine-tooth comb. Even if you do, they often don't supply enough raw data that you can evaluate it properly.

    They'll often pull out the conclusion they like and emphasize it in the discussion, and this is what all the popular press summaries focus on.

    Example: a BMJ study (doi:10.1136/bmj.d4169) said in the the Abstract: "We cannot exclude a 9% reduction or a 19% increase in all-cause mortality. . ." What does that mean?

    It means these are the extremes of the 95% confidence interval, and it's statistically possible that either one of the extremes is the true result.

    But in the Conclusions of the article, they cite only the 19% increase, ignoring the possible 9% decrease, thus indicating their bias. So one wonders what else was presented in a biased way.

    My conclusion is usually that the result is of interest but not definitive. There are too many variables in population characteristics, end points, etc. And knowing average risk doesn't necessarily tell you what your risk is.

    In some of their graphs, they show only data controlled for by sex. We know that men tend to be apples and women tend to be pears. Hence controlling for sex would also be controlling for shape and would reduce the effect of shape.

    We know that visceral fat is different physiologically from subcutaneous fat. And visceral fat contributes to the apple shape. We know that Asian Indians with skinny arms and legs and large stomachs have high rates of CVD.

    Perhaps we need a better measure of visceral fat, but I wouldn't use this one meta-analysis to negate all the previous evidence.

  7. Hi Gretchen! Is it true that as a general rule, a man that is pear-shaped is unhealthy? I am concerned about this issue.

    Of course, it is much better to lose weight, but it is not easy. I agree that there is strong link. Yes, a better measure will surely help data gathering.

  8. The problem with your question is defining "unhealthy." We know that being obese is, on average, associated with more medical problems, but there are obese people who are quite healthy and thin people who are quite unhealthy, when we define health as absence of diagnosed disease.

    If by "unhealthy" you mean a slightly greater chance of developing a health problem like diabetes, then having more visceral fat would increase your chances of that, but it wouldn't guarantee it.

    Yes, it's difficult to lose weight, but when I was younger and prediabetic, I noticed that whenever I went on a diet, the stomach fat seemed to come off first. So that might be an inspiration to stick with the program.