MAR 27, 2017 9:55 AM PDT

Scientists Discover New Class of Anti-Diabetes Compounds that Reduce Liver Glucose Production

 

Image Credit: Myriams-Fotos/Pixabay

JUPITER, FL – March 27, 2017 – 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 glucose in the liver. One of these compounds, designed and optimized by TSRI scientists, significantly improves the health of diabetic animal models by reducing glucose levels 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 glucose metabolism. 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. Other authors include Hua Lin of TSRI; Clint D. J. Tavares, John E. Dominy and Amy K. Rines of Dana-Farber and Harvard Medical School; Mark P. Jedrychowski and Steve P. Gygi of Harvard Medical School; Joao Paulo Camporez and Rachel J. Perry of Howard Hughes Medical Institute and Yale University; Jaemin Lee and Umut Ozcan of Boston Children's Hospital, Harvard Medical School; Marc Hickey, Melissa Bennion, Michelle Palmer, Partha P. Nag, Josh A. Bittker and José Perez of the Broad Institute of MIT and Harvard University.

The study was supported by the National Institutes of Health (grants F32 DK102293-01, U54HG005032, R24DK080261, R01DK-409369, 2U2CDK059635, R03DA032468 and R01 DK069966), the American Heart Association (15POST22880002) and the American Diabetes Association (1-16-PDF-111 and 7-12-MN-68).

This article was originally published on Scripps.edu.

About the Author
  • The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists-including two Nobel laureates-work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
You May Also Like
APR 23, 2020
Cardiology
APR 23, 2020
Blood Pressure Spikes in Young Adults Linked to Heart Disease Later on
Researchers have found that young adults in their 20’s and 30’s who experience inconsistent blood pressure m ...
APR 26, 2020
Cell & Molecular Biology
APR 26, 2020
Nose Cells Found to Be Likely SARS-CoV-2 Entry Points
This work may help explain why the virus is so easy to transmit.
APR 30, 2020
Cardiology
APR 30, 2020
Nighttime Blood Pressure Changes Linked to Cerebrovascular Disease and Impaired Cognition
When most people go to sleep, their blood pressure decreases, or dips, compared to daytime values. However, for some, a ...
MAY 03, 2020
Cell & Molecular Biology
MAY 03, 2020
How One Protein is Linked to Three Different Brain Disorders
The accumulation of aberrant, misfolded proteins is a known feature of several different kinds of brain diseases.
MAY 12, 2020
Drug Discovery & Development
MAY 12, 2020
Does Herbal Drink from Madagascar Cure COVID-19?
Andry Rajoelina, the president of Madagascar, an island off the coast of Southern Africa, has made claims that his count ...
MAY 15, 2020
Health & Medicine
MAY 15, 2020
Study Recommends 19 As Minimum Legal Age for Recreational Cannabis
Scientists concluded from a recent study that 19 years of age is the “optimal minimum legal age” for recreat ...
Loading Comments...