Breaking new ground on the diabetes front

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

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JUPITER, Fla.—A scientific team consisting of researchers from the Florida campus of The Scripps Research Institute (TSRI), Dana-Farber Cancer Institute, Harvard Medical School, the Yale University School of Medicine and other institutions has discovered what the researchers thing could be a new tool for studying and also perhaps treating type 2 diabetes. What it boils down to is a new class of compounds that reduce production of glucose in the liver.
One of these compounds, designed and optimized by TSRI scientists, is said to significantly improve 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, a TSRI associate professor of molecular medicine.
The compound has been dubbed SR-18292, and it modifies a protein known as PGC-1α, which 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.”
According to the team, successfully suppressing this overproduction makes PGC-1αa means they and other researcher now have “a 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.”
The team acknowledges that it still doesn’t know yet which specific protein or enzyme is directly targeted by SR-18292, but as 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 possibly be developed as either a single agent to treat diabetes, or used in combination with current antidiabetic drugs.

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