Sanford-Burnham researchers identify key protein involved in glucose metabolism

Team’s results suggest CDP138 is a key molecule linking the Akt2 pathway to the regulation of GLUT4 vesicle/plasma membrane fusion, but most importantly, the finding greatly enhances our understanding of glucose metabolism, which contributes to the development of type 2 diabetes

| 2 min read

Amy Swinderman

ORLANDO, Fla.—In a study published Sept. 7 in Cell Metabolism, scientists at theSanford-Burnham Medical ResearchInstitute have unveiled a new blueprint for glucose uptake, the foundation ofwhich involves a protein called CDP138 that is responsible for the properinsertion of the glucose transporter GLUT4 into the cellular membrane.

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Amy Swinderman

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Internal Medicine

ORLANDO, Fla.—In a study published Sept. 7 in Cell Metabolism, scientists at the Sanford-Burnham Medical ResearchInstitute have unveiled a new blueprint for glucose uptake, the foundation ofwhich involves a protein called CDP138 that is responsible for the properinsertion of the glucose transporter GLUT4 into the cellular membrane.

High glucose levels in the bloodstream trigger the pancreasto produce insulin. In turn, muscle and fat cells respond to insulin by movingGLUT4, a glucose transporter, from intracellular storage out to the cellsurface. There, GLUT4 can take up the glucose the cell needs from thebloodstream.

A protein called Akt2 is known to initiate both of thesesteps. The authors of this study investigated how the cell specificallycontrols the fusion of the glucose storage vesicles and the cell's outermembrane by looking for Akt2 substrates.

The team's results suggest that CDP138 is a key moleculelinking the Akt2 pathway to the regulation of GLUT4 vesicle/plasma membranefusion. But most importantly, according to the Sanford-Burnham team, thefinding greatly enhances our understanding of glucose metabolism, which contributesto the development of type 2 diabetes, the most common form of diabetes and acondition that reportedly affects more than 150 million people globally.

"At this stage, we are not sure yet how this will impact ourunderstanding of diabetes, but we have identified one potential mechanismthere, and we hope there is some kind of connection," says Dr. Zhen Y. Jiang,assistant professor in Sanford-Burnham's Diabetes and Obesity Research Center,located in Orlando's Medical City at Lake Nona. "If we are on the right track, thiscould result in a potential drug target for diabetes and human obesity."

The Sanford-Burnham team arrived at this discovery by takinga proteomic research approach. They discovered CDP138 through phosphoproteomicsand RNAi-based functional analyses, and to pinpoint its exact function, they geneticallydampened the protein in live fat cells. They observed that CDP138 is requiredfor optimal insulin-stimulated GLUT4 transport to the cell surface and fusionof GLUT4-containing vesicles with the membrane. In addition, they noted thatCDP138 was also required for glucose transport in live fat cells. Ultimately,the Sanford-Burnham researchers identified the exact part of the CDP138 proteinthat is chemically modified by Akt2 and showed that, without that region,CDP138 was unable to carry out its function.

Other more preliminary experiments showed that miceengineered to be obese had lower CDP138 levels than normal mice. To furtherprobe this possible correlation, the team is generating a mouse model thatlacks CDP138. Over the next year, they will study whether the mice experiencechanges in their glucose metabolism in response to insulin and exercise.

"It will be very interesting to see if we can potentiallymoderate this protein expression or function, which would lead to thedevelopment of a treatment," says Jiang.

Jiang's co-authors included Xiangyang Xie, Zhenwei Gong,Virginie Mansuy-Aubert, Daniel Sehrt, Laurence M. Brill, KhaterehMotamedchaboki and Zhen Y. Jiang from Sanford-Burnham; Qiong L. Zhou andMichael P. Czech from the University of Massachusetts Medical School; Suren A.Tatulian from the University of Central Florida; Florian Gnad, Matthias Mannand Marcus Krüger from the Max-Planck Institute; and Yu Chen from the EuniceKennedy Shriver National Institute of Child Health & Human Development(NICHD) at the National Institutes of Health.

Sanford-Burnham researchers identify key protein involved in glucose metabolism

About the Author

Amy Swinderman

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