Drug_Discovery_Incretins

In drug discovery, researchers use plus-size mice to try to slim them down with investigational medicine. Image credit: Wikimedia Commons

Incretins are hormones that the body uses to stimulate insulin release when nutrients are ingested. The two that are the most well-studied are:

  • glucagon-like peptide-1 (GLP-1), which suppresses appetite and leads to fat loss.
  • glucose-dependent insulinotropic polypeptide (GIP) which improves body weight.

Not surprisingly, these hormones have attracted considerable interest in the drug discovery field as weapons against obesity and diabetes.

GLP-1 and GIP are agonists, and as such they work by binding to their respective receptors and stimulating them to action. Coadministration of GLP-1 and GIP is indeed especially helpful in controlling insulin levels, but a medicine with two components comes with complications in development. As detailed in a recent paper [1], researchers set out to advance a hybrid drug that by itself can function like both GLP-1 and GIP at the same time.

GLP-1 and GIP are both peptides and thus are composed of amino acid building blocks. The researchers Finn et al., endeavoured to do some “mixing and matching” for their drug discovery, taking some of the amino acids from GLP-1 and some from GIP to create a new peptide that represents a blend of both. In mice, this new peptide interacted with the receptors for GLP-1 and GIP, leading to a decrease in body weight, food intake, fat mass, and blood glucose levels.

In drug discovery research, peptides are known to have a tough time staying intact in the bloodstream for long. To allow for less-frequent dosing, the researchers attached a protective lipid group to the co-agonist. Injections at twice a week resulted in a number of favourable changes in mice, including reduced body weight, fat mass, and even cholesterol levels.

After turning to cynomolgus monkeys and continuing to see promising results, the researchers were ready for human subjects. Diabetic patients treated with the pegylated co-agonist had improved glucose levels. Upsetting gastrointestinal problems, a side effect of GLP-1 receptor agonists, were minimal.

As those acquainted with drug discovery will know, more work remains to be done. Larger studies will be necessary to fully determine these new incretins’ safety and efficacy, and high drug development costs may one day rear its expensive head. But the intriguing results suggest that these “double-dealing” incretins are worth watching as a possible treatment for some of the modern world’s ails.

Reference

[1] Finan, B. et al. 2013. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5:209ra151