Researchers are one step closer to a new drug that could lower blood glucose levels in patients with insulin resistance, but without the potentially harmful side effects.
As a result, blood glucose levels can become too high, and this may lead to type 2 diabetes. There are medications that can help to prevent the progression to type 2 diabetes in patients with insulin resistance, such as thiazolidinediones.
But unfortunately, these medications can promote weight gain and a number of other health problems.
Dr. Domenico Accili — director of the Columbia University Diabetes Research Center at Columbia University Medical Center in New York City, NY — and colleagues have identified a number of compounds that may be just as effective as current insulin resistance medications on the market, but which do not lead to weight gain.
The researchers recently reported their findings in the journal Cell.
FOXO1 and insulin resistance
The reason why currently available medications for insulin resistance can cause weight gain is because they target and block a protein called FOXO1.
While inhibiting FOXO1 reduces glucose production in the liver — thereby reducing blood glucose levels — it also increases the production of lipids, or fat.
"Thus, treatment of insulin resistance with a broadly acting FOXO1 inhibitor can lead to a host of unwanted side effects, such as weight gain," says Dr. Accili. "Unfortunately, with FOXO1 insulin sensitizers, you get the good with the bad."
Researchers have been searching for ways to block FOXO1 without influencing lipid production but have yet to yield success. Could Dr. Accili and colleagues have broken the chain?
The team began their research with mouse experiments. They aimed to unravel the mechanisms by which FOXO1 regulates glucose production in the liver, and how this differs to the way the protein controls lipid production.
The researchers found that in order to restrict lipid production, FOXO1 teams up with a transcriptional regulatory protein called SIN3A.
"This suggested that if we could find molecules that act on the glucose-production arm of FOXO1 while leaving SIN3A alone," explains Dr. Accili, "we could improve insulin sensitivity and lower blood sugar without increasing fat."
A safer treatment for diabetes?
For the next phase of their study, the researchers screened more than a million small molecules.
The team identified a number of small molecules that were able to inhibit FOXO1 in liver cells and reduce glucose production, but which managed to avoid SIN3A.
"In a clinical setting, this can reduce hepatic glucose production without increasing triglyceride accumulation," the researchers note.
While this current study only offers proof of concept, Dr. Accili and team believe that their findings may pave the way to new treatments for insulin resistance.
"The next step is to optimize these compounds for animal testing and lay the groundwork for clinical trials. We're excited by the possibility of developing a new and safer way to treat diabetes."
Dr. Domenico Accili