Targeting early marker of insulin resistance shows promise in type 2 diabetes.
A recent study revealed a new drug target that involves blocking a cellular glucose sensor in muscle to potentially prevent type 2 diabetes, a disease that affects approximately 8% of Americans.
Skeletal muscles are the primary insulin-responsive tissue in the body. Since insulin resistance is the precursor to type 2 diabetes, a team of researchers decided to make it the primary focus of their study.
An early marker of insulin resistance is the accumulation of fat in muscles, and the decreased import of glucose. In a study published in the Journal of Clinical Investigation, researchers wanted to examine whether these 2 processes were linked.
Researchers screened thousands of molecules for the ability to block fat synthesis, and enhance glucose uptake in muscle cells, in order to find a protein that regulates both.
“Investigating the cellular effects of SBI-477, the best hit molecule from our screen, led us to MondoA,” said researcher Daniel P. Kelly, MD. “Our experiments showed that this protein regulates genes involved in synthesizing fats as well as inhibiting insulin signaling. Until now, it wasn’t clear why people who are insulin resistance accumulate fat in their muscle. These results show that MondoA is one mechanism that ties these phenomena together, serving as a gatekeeper for fuel burning in muscle.”
Researchers were also able to show that SBI-477 can enhance glucose uptake in liver cells, as well. The findings suggest that a MondoA blocker may have this effect on several other tissues.
Furthermore, it mitigated insulin resistance in mice fed a high-fat diet.
“We think that MondoA normally responds to oversupply of glucose by inhibiting transport of glucose into cells and enhancing its conversion to fat, but persistent activation promotes insulin resistance,” Kelly said.
Next, researchers plan to develop better molecules that can inhibit MondoA.
“Directly enhancing glucose uptake by muscle and other tissues is a very different strategy from those of other anti-diabetic drugs in development,” Kelly said. “Since this action would favor energy burning, it may also have beneficial effects on overall metabolism and body weight.”