Calcium-Sensing Enzyme May Be Drug Target for Treating Type II Diabetes

Their goal was to elucidate the underlying molecular mechanisms responsible for glucose production in the liver, which is crucial for glucose homeostasis.

Preliminary results led them to focus their attention on a calcium-sensing enzyme, CaMKII (calcium/calmodulin-dependent protein kinase II). This enzyme appeared to be required for the release of glucose into the blood following binding of glucagon to its receptor.

Glucagon is a hormone secreted by the pancreas that raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when glucose levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. High blood glucose levels stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels at a stable level.

The investigators reported in the April 12, 2012, online edition of the journal Cell Metabolism that CaMKII dispatched a protein called FoxO1 to the cell nucleus, where it activated the genes needed for glucose secretion. Genetic deficiency or inhibition of CaMKII blocked nuclear translocation of FoxO1 by affecting its phosphorylation, which lowered blood glucose levels, while constitutively active CaMKII had the opposite effect.

“What we have found is a way to reduce glucagon’s influence on blood sugar without the side effects of global glucagon repression,” said senior author Dr. Ira Tabas, professor of anatomy and cell biology at Columbia University. “Even when their disease is well controlled, most patients with type II diabetes have excess glucagon action, so blocking CaMKII could potentially be a new way to lower blood sugar and better treat the disease. Until now, it has been difficult to block glucagon’s effect on blood sugar without interfering with glucagon’s other functions, but we think CaMKII is different.”

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