Researchers discover potential avenue to treating type 2 diabetes at early stages

August 8, 2016, Sanford-Burnham Prebys Medical Discovery Institute
Blood glucose monitoring. Credit: Wikipedia

Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new potential target for drugs to prevent type 2 diabetes. A paper published today in the Journal of Clinical Investigation shows that blocking a cellular glucose sensor in muscle improves insulin responsiveness.

"Our new study shows that a protein called MondoA may serve as a key link between insulin resistance and accumulation of fat in muscle, which occurs in obesity-related ," said Daniel P. Kelly, M.D., professor and director of SBP's Center for Metabolic Origins of Disease. "This study is the first step towards testing MondoA-targeted drugs to prevent type 2 diabetes in pre-clinical studies."

About 8% of Americans have type 2 diabetes, and another 25% of the population is at risk because of obesity. Type 2 diabetes is a lifelong disease that represents an enormous public health burden, accounting for as much as 20% of all healthcare costs in the US. A significant proportion of those costs result from complications of diabetes, including damage to the kidneys, peripheral nerves, and retinas.

The precursor to type 2 diabetes is insulin resistance, in which insulin no longer causes the body's cells to take up the from a meal and use it for energy. This leads to diabetes because glucose continues to circulate in the blood, stimulating the pancreas to make more and more insulin, which eventually becomes so taxing that the insulin-producing cells die.

Kelly's team focused on skeletal muscle because it's the main insulin-responsive tissue in the body. An early marker of insulin resistance is the accumulation of fat in muscle, along with decreased import of glucose, so they examined whether these two processes are linked. To find a protein that regulates both, they screened thousands of molecules for their ability to block fat synthesis and enhance glucose uptake in muscle cells.

"Investigating the cellular effects of SBI-477, the best hit molecule from our screen, led us to MondoA," added Kelly. "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 resistant accumulate fat in their muscle," he explained. "These results show that MondoA is one mechanism that ties these phenomena together, serving as a gatekeeper for fuel burning in muscle."

The researchers went on to demonstrate that SBI-477 also enhances glucose uptake in liver cells, suggesting that a MondoA blocker may have this effect on multiple tissues. Further, it mitigates 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 ," Kelly said.

Kelly and his collaborators next plan to develop better molecules that inhibit MondoA.

"Directly enhancing by and other tissues is a very different strategy from those of other anti-diabetic drugs in development. Since this action would favor energy burning, it may also have beneficial effects on overall metabolism and body weight."

Explore further: Skeletal muscle TRIB3 mediates diet-induced insulin resistance

More information: Byungyong Ahn et al. MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling, Journal of Clinical Investigation (2016). DOI: 10.1172/JCI87382

Related Stories

Skeletal muscle TRIB3 mediates diet-induced insulin resistance

May 18, 2016
(HealthDay)—Skeletal muscle TRIB3 mediates glucose-induced insulin resistance (GIIR) in a mouse model of diabetes, according to a study published online May 10 in Diabetes.

Gastric bypass surgery improves blood sugar handling and insulin sensitivity, study finds

October 5, 2015
Roux-en-Y, the most common type of gastric bypass surgery, can lead to remission of type 2 diabetes along with weight loss. A new study in the American Journal of Physiology—Regulatory, Integrative and Comparative Physiology ...

Researchers identify cause of insulin resistance in type 2 diabetics

March 7, 2016
More than 29 million Americans are currently living with diabetes. The majority have type 2 diabetes, and for them insulin resistance - their body's inability to effectively process sugar - is a part of daily life. Therefore, ...

Junk food causes similar high blood sugar levels as type 2 diabetes

May 10, 2016
A junk food diet can cause as much damage to the kidney as diabetes, according to a study published in Experimental Physiology.

Study characterizes insulin secretion in response to metabolic stress

April 7, 2016
The development of type 2 diabetes is linked to persistent inflammation as a consequence of metabolic stress. Prolonged exposure to the proinflammatory molecule IL-1β is associated with reduced insulin secretion by pancreatic ...

How brown fat fuels up to combat type 2 diabetes and obesity

November 10, 2014
A newly identified signaling pathway that stimulates glucose uptake in brown fat cells might be useful for treating type 2 diabetes and obesity, according to a study in The Journal of Cell Biology.

Recommended for you

Implantable islet cells come with their own oxygen supply

April 25, 2018
Since the 1960s, researchers have been interested in the possibility of treating type 1 diabetes by transplanting islet cells—the pancreatic cells that are responsible for producing insulin when blood glucose concentration ...

Study shows drug effectiveness in reducing glucocorticoid-induced bone loss

April 25, 2018
About one in every 100 people in the world takes glucocorticoids long term to treat immune-mediated diseases. However, glucocorticoids, such as prednisone, have a side effect—they induce the bone loss called osteoporosis, ...

Bariatric surgery successes lead to type 2 diabetes treatment

April 24, 2018
Bariatric surgery has long yielded almost immediate health benefits for patients with type 2 diabetes, and new findings on the reasons for remission may be the key to developing drug alternatives to surgery.

Hacking human 'drug trafficking' network could make diabetes treatments more effective

April 23, 2018
Making tiny changes to existing diabetes treatments can alter how they interact with cells, and potentially make the medicines more effective.

Vitamin D deficiency linked to greater risk of diabetes

April 19, 2018
An epidemiological study conducted by researchers at University of California San Diego School of Medicine and Seoul National University suggests that persons deficient in vitamin D may be at much greater risk of developing ...

One class of drug used to treat type 2 diabetes may not reduce the risk of death when compared with placebo

April 17, 2018
One class of drug used to treat type 2 diabetes may not reduce the risk of death when compared with placebo, suggests new findings.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.