Scientists at Joslin Diabetes Center have investigated PKC-beta -- a critical enzyme implicated in the devastating complications of type 1 and type 2 diabetes -- for more than two decades.
Their latest research, to be presented June 11 at the American Diabetes Association's (ADA) 65th Scientific Sessions in San Diego, Calif., confirms the link between hyperglycemia (high blood glucose), overexpression of PKC-beta 2 and kidney disease.
The poster is one of 89 presentations Joslin scientists will deliver at the ADA Scientific Sessions, to be held Friday, June 10, through Tuesday, June 14 at the San Diego Convention Center. Some 13,000 scientists, physicians and health professionals from around the world will attend the conference, to be held at the San Diego Convention Center. (Abstract Number: 849-P)
"The significance of this study is that we found strong evidence linking chronic activation of a specific form of the PKC enzyme -- beta 2 -- to the abnormal kidney changes and oxidative stress seen in diabetes," said George L. King, M.D., the study's lead author, Joslin's Director of Research, Head of the Section on Vascular Cell Biology, and a Professor of Medicine at Harvard Medical School. Other investigators in the study included previous Joslin fellows Yutaka Yasuda, M.D., Ph.D., and Noriko Takahara, M.D., as well as Timothy S. Kern, Ph.D., of Case Western Reserve Medical School, Cleveland, Ohio.
Protein kinase C (PKC) is an enzyme essential to the normal functions of the cell and the body. The PKC family of enzymes, which helps regulate many blood vessel functions, comprises about a dozen different molecular forms, or isoforms, including PKC-alpha, PKC-beta 1, PKC-beta 2 and PKC-delta.
In this study, Dr. King and his colleagues proposed that chronic activation or overexpression of the PKC-beta 2 isoform plays an important role in the progression of diabetic kidney disease. To test this hypothesis, researchers used genetic engineering techniques to develop mice that expressed three times the normal amount of PKC-beta 2 in tiny blood vessels.
"Using transgenic mice, we targeted the specific isoform, PKC-beta 2, to the blood vessels to test our hypothesis," said Dr. King. "By manipulating the gene that makes this isoform, we created mice that overexpressed only PKC-beta 2 which mimics the effects of high glucose levels and diabetes."
Dr. King and his team compared these transgenic "overexpressors" with normal mice -- in both diabetic and nondiabetic mice models -- using conventional screening and diagnostic tests to assess the progression of kidney disease in each model.
In diabetes, hyperglycemia overactivates PKC-beta and gradually damages the microvessels of the kidney. Over time, tiny capillaries known as glomeruli become so porous they can no longer adequately filter waste from the blood, and instead allow large proteins such as albumin to pass into the urine (an early sign of kidney damage).