A DPP-IV Head Scratcher

A manuscript in press is suggesting that the mechanism of DPP-IV inhibitors, like Merck’s blockbuster Januvia, may eliminate a potentially beneficial natural effect, especially in obese people.

The DPP-IV’s are designed to prevent the enzyme dipeptidyl peptidase-4 from degrading GLP-1, a hormone that stimulates insulin secretion. Specifically, they stop it from clipping two amino acids from GLP-1 and converting it to a metabolite, GLP-1(9-36).

Researchers have long believed that the GLP-1 metabolite is inactive, but this may not be the case. “This idea that 9-36 is not a discarded product is not generally accepted,” explains Joel Habener of Massachusetts General Hospital, who discovered GLP-1 nearly 30 years ago. The notion that the metabolite performed some function was first aired by Habener's colleague Dariush Elahi (now at Johns Hopkins) at an oral presentation at the American Diabetes Association Scientific Sessions in 2006. (Abstract 363-OR, for those of you with the book.)

Elahi led a research team that infused subjects already in a fasting state with a steady flow of glucose, then gauged the changes in that steady state glucose metabolism after administration of GLP-1 metabolite. They found that GLP-1 metabolite lowered plasma glucose concentration in obese subjects, and concluded that it was insulinomimetic—GLP-1 metabolite acted like insulin to lower glucose levels in the liver.

That’s of interest because the main source of fasting hyperglycemia in type 2 diabetics is uncontrolled hepatic glucose output, Habener explains, and fasting hyperglycemia, along with post-prandial surges of blood sugar, are the major contributors to elevated HbA1C. (That the effect of the GLP-1 metabolite was more pronounced in obese, insulin-resistant subjects – it was up to 50% greater than in lean subjects in the experiment -- is also significant because obesity is an obvious risk factor for the development of type 2 diabetes. So you especially don’t want to remove it from them.)

At the time of the ADA meeting, a paper describing these properties of GLP-1 metabolite was already under review at The New England Journal of Medicine. But NEJM rejected it. Subsequently, so did Diabetes, the Journal of Clinical Endocrinology & Metabolism, and the American Journal of Physiology.

The general consensus, both at the ADA and among journal editors, was that the findings went so much against current thinking that the researchers needed to show the mechanism. “It was not part of the current understanding,” Habener explains, “which is that the 9-36 is an undesirable degradation product, an inert metabolite, and that it’s good to prevent it at the expense of increasing the insulinotropic hormone [referring to GLP-1].” The paper was finally accepted by Obesity, but after that journal changed editor and publisher at the end of 2007, publication of the first three monthly issues of 2008 log-jammed. (The paper is now slated for the April issue.)

It’s yet to be determined how profound an insulin-like effect the GLP-1 metabolite has on the liver. But the Obesity paper does get into a possible rationale for the effect of GLP-1 metabolite and its ramifications (a discussion Habener won’t put on the record prior to publication).

The next step for Elahi, Habener, and colleagues will be to give subjects GLP-1 under the same fasting conditions, either with or without a DPP-IV inhibitor (one group would therefore make GLP-1 metabolite and the other group would not), to see the extent to which inhibiting the production of GLP-1 metabolite in this way affects them. “If we give concomitant administration of DPP-IV inhibitor to block the formation of 9-36, we should attenuate the good effect [of GLP-1] in reducing hepatic glucose production,” Habener predicts. To be sure, it'll be interesting to see the extent of that attenuation.

The blocking of GLP-1 metabolite production might help explain why DPP-IV’s are not more potent: Januvia, for example, is less effective as monotherapy than the older and much cheaper drug metformin, although without some of the side effects. GLP-1 analogs, such as Amylin/Lilly’s Byetta, are not degraded by DPP-IV and so do not generate GLP-1 metabolite. Thus, like the DPP-IV’s, they fail to deliver that second potential insulinomimetic punch—an argument in favor of assessing whether GLP-1 metabolite could offer a new therapeutic strategy for diabetes.

As of last week, Obesity appeared to finally be back on track. According to the journal, the April issue should be out March 31. So stay tuned.

Update: As of March 27, lead author Elahi had yet to see the proofs of the Obesity paper, suggesting it's unlikely to be in the April issue.

Update: the Elahi-Habener paper is now on-line (April 17 AOP) at the Obesity journal website. Title is: GLP-1 (9–36) Amide, Cleavage Product of GLP-1 (7–36) Amide, Is a Glucoregulatory Peptide.