New York, NY (October 24, 2017)–A source of type 2 diabetes is a condition called insulin resistance, in which cells stop responding to orders from the hormone that regulates glucose (sugar) storage. Restoring insulin sensitivity can be an effective strategy for treating and preventing diabetes, but the only insulin-sensitizing drugs on the market also stimulate the production of lipids (fats), which can lead to a number of severe side effects.
A new study, led by researchers at Columbia University Medical Center, indicates that it can be possible to improve insulin sensitivity while avoiding these adverse results. The findings were published online in Cell.
Insulin, a hormone made in the pancreas, indicates cells to catch glucose from the blood and use it for energy. When cells become resistant to insulin, glucose accumulates in the blood. Finally, insulin resistance can lead to diabetes.
“Researchers have been on the lookout for ways to overcome insulin resistance without unintentionally triggering fat accumulation,” said study leader Domenico Accili, MD, the Russell Berrie Foundation Professor of Diabetes and manager of the Columbia University Diabetes Research Center at CUMC. “But previous efforts have been unsuccessful.”
One approach that’s been studied will be to inhibit a protein known as FOXO1. Animal studies have shown that if FOXO1 is suppressed, the liver makes less sugar. But like other insulin sensitizers, inhibiting FOXO1 also stimulates the production of lipids. “Thus, treatment of insulin resistance using a widely acting FOXO1 inhibitor can lead to a range of unwanted side effects, such as weight gain,” stated Dr. Accili. “Regrettably, with FOXO1 insulin sensitizers, you get the good with the bad.”
In the current study, the researchers looked for a means to partially inhibit FOXO1 so that sugar levels diminished but lipid levels were untouched. “What we needed to comprehend is how the two FOXO1-mediated mechanisms differ, so that we could identify selective inhibitors,” stated co-author Daniel Lindén, a scientist with AstraZeneca’s Innovative Medicines and Early Development biotech Unit in Gothenburg, Sweden.
In studies performed in mice, Dr. Accili and his colleagues found that FOXO1 works using a protein known as SIN3A to restrict lipid production. “This suggested that if we could find molecules that act on the glucose-production arm of FOXO1 whilst departing SIN3A alone, we could improve insulin sensitivity and lower blood sugar without increasing fat,” said Dr. Accili.
From a display of one million small molecules, the team identified several with the desired effect in liver cells. They moved on to describe three of those molecules in greater detail–possibly paving the way for the evolution of a new class of insulin sensitizers.
“The next step is to optimize these compounds for animal testing and also lay the groundwork for clinical trials,” said Dr. Accili. “We are excited by the possibility of creating a new and safer way to deal with diabetes.”
The study is titled, “Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Managing” Another contributors are Fanny Laglet (CUMC), Rebecca A. Haeusler (CUMC), Elke Ericson (AstraZeneca), Tyrell Norris (AstraZeneca), Anders Johansson (AstraZeneca), Joshua R. Cook (CUMC), Kumiko Aizawa (CUMC), Ling Wang (Mount Sinai School of Medicine, New York, NY), along with Christoph Buettner (Mount Sinai).
The study was supported by grants from the National Institutes of Health (DK57539 and DK63608) and the Fondation Bettencourt Schueller.
Dr. Accili is cofounder of Forkhead Biotherapeutics, LLC, that expects to create FOXO1 inhibitors for the treatment of diabetes. The authors declare no further competing financial interests.
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