A single overactive enzyme worsens the two core defects of diabetes—impaired insulin sensitivity and overproduction of glucose—suggesting that a drug targeting the enzyme could help correct both at once, according to mouse studies done by researchers at Columbia University Medical Center. The findings were published Nov. 21 in the online edition of Cell Metabolism.
A drug that inhibits the enzyme, MK2, eventually could be added to metformin—the current first-line treatment for type 2 diabetes—to achieve better control over insulin and glucose levels than is possible with either drug alone, said the researchers.
“MK2’s compatibility with metformin makes it a very exciting potential drug target,” said Ira Tabas, MD, PhD, Richard J. Stock Professor and Vice Chair of Research in the Department of Medicine and professor of anatomy & cell biology, who led the study with Lale Ozcan, PhD, associate research scientist.
“The one clear leader among drugs currently available for type 2 diabetes is metformin, which does a pretty good job of attacking both problems. But because metformin is often not enough, we need drugs that can be added to metformin—or used in patients who cannot tolerate metformin,” Tabas said. “If you take an obese, diabetic mouse and give it metformin, you get a partial improvement. If you give it an MK2-inhibitor, you also get a partial improvement. However, if you give both, the benefit is additive, which is consistent with our data that metformin and MK2 work through different biochemical pathways.”
The researchers’ earlier findings, on MK2’s effects on glucose, were published last year in the same journal.
Though both papers report the biochemical details of how MK2 works in mice, Tabas and Ozcan, working with CUMC surgeons Marc Bessler, MD, and Beth Schrope, MD, PhD, also have recent unpublished data suggesting that MK2 is overactive in obese people, including those with pre-diabetes, but not in lean people. The MK2 pathway is active in human liver cells, and, according to a large human genetic study called DIAGRAM, a key component of the pathway that activates MK2 is associated with diabetes, the researchers said.
“As the disease progresses, the insulin-producing cells have to put out more and more insulin to deal with the ever-increasing amounts of glucose in the bloodstream. Eventually, they burn out and the patient must use insulin,” Dr. Tabas said. “If we can protect the pancreas’s beta cells from the stress of dealing with high glucose, we may be able to prevent or delay progression to full diabetes.”
Tabas and Ozcan are planning to test this hypothesis with pre-diabetic mice.
The doctors have created a company to develop compounds able to inhibit MK2. “As with all drug development, it’s a long shot, but we think MK2 is less of a long shot than most," they said.
The research paper is titled, “Activation of Calcium/Calmodulin-Dependent Protein Kinase II in Obesity Mediates Suppression of Hepatic Insulin Signaling.”
Ozcan and Tabas are among the co-founders of Tabomedex Biosciences LLC, which is developing inhibitors of the pathway described above for treatment of type 2 diabetes.