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.