Decanoic Acid May Lead to a New Generation of Diabetes Drugs

Diabetes researchers have outlined a molecular pathway based on the ten-carbon fatty acid decanoic acid (capric acid) that may lead to new treatments for the disease.

Investigators at Van Andel Research Institute (Grand Rapids, MI, USA) have been working with a diabetic mouse model. In the current study, they used this system to examine the relationship between decanoic acid and the protein receptor PPARG (peroxisome proliferator activated receptor-gamma).

PPARG is known to regulate fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells. PPARG knockout mice fail to generate adipose tissue when fed a high fat diet. PPARG has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. Drugs that block PPARG activity have been used in the treatment of dyslipidemia and hyperglycemia. Many insulin sensitizing drugs used in the treatment of diabetes target PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion.

Results published in the October 28, 2011, online edition of the Journal of Biological Chemistry revealed that decanoic acid was a direct ligand of PPARG. Decanoic acid bound to and partially activated PPARG without leading to adipogenesis. Crystal structure studies revealed that decanoic acid occupied a novel binding site on the PPARG molecule. Treatments with decanoic acid and its triglyceride form improved glucose sensitivity and lipid profiles without weight gain in diabetic mice.

“We studied a nuclear receptor (PPARG) that plays a key role in glucose and lipid metabolism and is the molecular target of the thiazolidinedione (TZD) class of antidiabetic drugs, which have been shown to have negative side effects such as weight gain, fluid retention, and increased risk for cardiovascular diseases,” said senior author Dr. H. Eric Xu, director of the center for structural biology and drug discovery at Van Andel Research Institute. “Our results showed that decanoic acid could be used in designing better and safer PPARG – based drugs.”

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Van Andel Research Institute