Targeting a microRNA could improve diabetes treatment with GLP-1 drugs

Diabetes paraphernalia
Blocking miR-204 kills two birds with one stone: it improves insulin production and increases GLP-1 receptor expression, which could improve GLP-1 drugs used to treat diabetes.

People with Type 2 diabetes who don’t respond to basal insulin may get relief from GLP-1 agonists—but these drugs can cause side effects. New research from the University of Alabama has uncovered a beta-cell pathway that could be harnessed to improve the efficacy of these drugs and reduce unwanted effects.

The researchers already knew that high levels of the microRNA miR-204 block insulin production in pancreatic beta cells, according to a statement. Their new study, published in Diabetes, suggested that miR-204 also regulates the receptor for the hormone GLP-1, or glucagon-like peptide-1.

GLP-1 drugs like AstraZeneca's Byetta (exenatide) work by activating receptors that increase insulin production and lower blood sugar levels. However, the required doses of these drugs can lead to side effects, such as nausea and diarrhea.

The team, led by Anath Shalev, M.D., looked at miR-204 expression in rat beta cells, as well as in mouse and human pancreatic islets. High levels of miR-204 reduced GLP-1 receptor expression, they found, while deleting it had the opposite effect. And mice whose miR-204 had been knocked out had better responses to GLP-1 drugs.

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Suppressing miR-204 to ramp up GLP-1 expression not only leads to increased insulin secretion, but also provides more targets for GLP-1 agonists so a lower dose may be used to achieve the same effects. And because miR-204 is abundant in beta cells—but not in the rest of the pancreas, or in gastrointestinal cells—it can be targeted to selectively raise GLP-1 expression.

"Since miR-204 is expressed primarily in pancreatic beta cells, manipulating its levels allows for preferential upregulation of GLP1R in the beta cell, where it helps secrete insulin, rather than in the gastrointestinal system, where it can cause nausea and impaired gastric emptying, or in the pancreas, where it can increase the risk for pancreatitis," Shalev said in the statement.

Exploiting the link between miR-204 and GLP-1 could improve the performance of a number of drugs, including Sanofi’s Adlyxin (lixisenatide), Novo Nordisk’s Victoza (liraglutide) and AstraZeneca’s Byetta (exenatide).

Scientists developed GLP-1 agonists because the hormone itself breaks down too quickly to effectively treat diabetes. But an Australian team discovered a stable version of GLP-1 in a curious place—the venom of the platypus and the echidna. While the researchers are unsure how this finding will translate into human treatments, they do suggest using a longer-lasting version of GLP-1 may be feasible.