Scientists discover new class of anti-diabetes compounds that reduce liver glucose production

March 27, 2017
TSRI Professor Pat Griffin, co-chair of the TSRI Department of Molecular Medicine. Credit: James McEntee

Scientists may have found a new tool for studying—and maybe even treating—Type 2 diabetes, the form of diabetes considered responsible for close to 95 percent of cases in the United States.

A team of scientists from the Florida campus of The Scripps Research Institute (TSRI), Dana-Farber Cancer Institute, Harvard Medical School and the Yale University School of Medicine, among others, have identified a new class of compounds that reduce production of in the liver. One of these compounds, designed and optimized by TSRI scientists, significantly improves the health of diabetic animal models by reducing in the blood, increasing insulin sensitivity and improving glucose balance.

The study, published recently in the journal Cell, was led by Pere Puigsever of Harvard Medical School and the Dana-Farber Cancer Institute and included Patrick Griffin, co-chair of the TSRI Department of Molecular Medicine, and Theodore Kamenecka, TSRI Associate Professor of Molecular Medicine.

The compound they identified, called SR-18292, modifies a protein known as PGC-1α. This protein plays a pivotal role in energy balance and helps control genes involved in energy metabolism. When cells overexpress PGC-1, during fasting or starvation, for example, glucose production in the liver soars. But when scientists modify PGC-1α function through a process called acetylation, glucose production declines.

"This protein was generally considered non-druggable," said Griffin. "But the team approached the problem through the process of acetylation, which means we can influence the protein's behavior indirectly. SR-18292 increases acetylation of PGC-1, which in turn shuts down glucose production in liver cells."

Suppressing this overproduction makes PGC-1αa target ripe for exploitation in anti-diabetes treatments.

"After the screening process found several potential candidates, the TSRI team designed derivatives of those initial hits," Griffin said. "We selected this compound based on its ability to induce acetylation and the fact that it had good pharmaceutical properties-so we could use it in animal models of Type 2 diabetes."

While it isn't known at this point what protein or enzyme is directly targeted by SR-18292, Griffin explained, this new compound, plus several others we've made, can be used as chemical tools to study the regulation of . The researchers added that these same small molecules could one day be developed as either a single agent to treat diabetes, or used in combination with current anti-diabetic drugs.

The first author of the study, "Small Molecule Screen Identifies Selective PGC-1α Gluconeogenic Inhibitors that Ameliorate Type 2 Diabetes," is Kfir Sharabi of Dana-Farber and Harvard Medical School.

Explore further: Study suggests new drug candidate could treat both type 2 diabetes and bone loss

Related Stories

Study suggests new drug candidate could treat both type 2 diabetes and bone loss

July 27, 2016
In addition to its more obvious ills, type 2 diabetes is a condition closely associated with bone fractures, increasing the risk of fractures twofold. To make matters worse, certain anti-diabetic drugs further increase this ...

New strategy to lower blood sugar may help in diabetes treatment

September 3, 2015
Some treatments for type 2 diabetes make the body more sensitive to insulin, the hormone that lowers blood sugar. But new research at Washington University School of Medicine in St. Louis suggests a different strategy: slowing ...

Size matters when it comes to keeping blood sugar levels in check

February 10, 2017
Keeping blood sugar levels within a safe range is key to managing both type 1 and type 2 diabetes. In a new finding that could lead to fewer complications for diabetes patients, Yale School of Medicine researchers have found ...

Protein linked to aging identified as new target for controlling diabetes

November 5, 2014
Indiana University School of Medicine researchers have identified a small protein with a big role in lowering plasma glucose and increasing insulin sensitivity. Their research appeared online today in Diabetes, the journal ...

Research team identifies link between inflammation and type 2 diabetes

February 5, 2015
A Yale-led research team has identified the molecular mechanism by which insulin normally inhibits production of glucose by the liver and why this process stops working in patients with type 2 diabetes, leading to hyperglycemia.

Insulin resistance reversed by removal of protein

November 3, 2016
By removing the protein galectin-3 (Gal3), a team of investigators led by University of California School of Medicine researchers were able to reverse diabetic insulin resistance and glucose intolerance in mouse models of ...

Recommended for you

Personalized blood sugar goals can save diabetes patients thousands

December 11, 2017
A cost analysis by researchers at the University of Chicago Medicine shows treatment plans that set individualized blood sugar goals for diabetes patients, tailored to their age and health history, can save $13,546 in health ...

Kidney disease increases risk of diabetes, study shows

December 11, 2017
Diabetes is known to increase a person's risk of kidney disease. Now, a new study from Washington University School of Medicine in St. Louis suggests that the converse also is true: Kidney dysfunction increases the risk of ...

Type 2 diabetes is not for life

December 5, 2017
Almost half of the patients with Type 2 diabetes supported by their GPs on a weight loss programme were able to reverse their diabetes in a year, a study has found.

Skipping breakfast disrupts 'clock genes' that regulate body weight

November 30, 2017
Irregular eating habits such as skipping breakfast are often associated with obesity, type 2 diabetes, hypertension and cardiovascular disease, but the precise impact of meal times on the body's internal clock has been less ...

Type 2 diabetes has hepatic origins

November 28, 2017
Affecting as many as 650 million people worldwide, obesity has become one of the most serious global health issues. Among its detrimental effects, it increases the risk of developing metabolic conditions, and primarily type ...

Critical link between obesity and diabetes has been identified

November 28, 2017
UT Southwestern researchers have identified a major mechanism by which obesity causes type 2 diabetes, which is a common complication of being overweight that afflicts more than 30 million Americans and over 400 million ...

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.