Researchers discover PKD1 may limit AMPK activity in insulin-resistant settings

Researchers have made an important discovery that may open the door for finding newer and more effective ways to regulate insulin. Specifically, they discovered that the upstream signaling protein kinase PKD1 may limit or inhibit AMP-activated protein kinase (AMPK), which is an energy-sensing enzyme found to be inhibited in patients with insulin resistance—including those who are obese and have diabetes—leading to reduced insulin signaling in the muscle cells. Their results were published earlier this year in The Journal of Biological Chemistry. Thus, finding a way to prevent PKD1 from doing this may help in the treatment of diabetic individuals.

Currently, although AMPK activation is understood, why it is being reduced in those who are obese or diabetic is unknown.

“It’s a pretty technical process,” said Rudy Valentine, assistant professor of kinesiology at Iowa State University, Ames, IA. “There are probably a lot of different molecules that are also involved in this process, but this is definitely one of the mechanisms by which the molecule AMPK is downregulated.”

Valentine and colleagues from Boston University School of Medicine and Harvard Medical School conducted this study and found that PKD1 slows down cells removing glucose from the blood stream and causes a back-up or an increase in blood glucose. They tested two methods to determine whether PKD1 can be prevented from limiting AMPK—medication and gene silencing, and both were effective in restoring the activity of AMPK and insulin signaling.

Using the PKC/D1 activator phorbol 12-myristate 13-acetate (PMA) that acts as a daicylglycerol (DAG) mimetic, they saw both dose- and time-dependent increases in AMPK Ser485/491 phosphorylation, which in turn were associated with an approximately 60% decrease in the activity of AMPKα2. When they tested genetic knockdown of PKD1, they found it also prevented Ser485/491 phosphorylation of AMPK.

Valentin's future plans also involve assessing the role of diet and exercise.

“We want to know if there are lifestyle things people can do such as nutraceuticals and certain foods that can inhibit this enzyme and lead to more activation of AMPK and improve insulin sensitivity,” Valentine concluded.

The study was supported by grants from U.S. Public Health Services, National Institutes of Health, and the JPB Foundation.