Coordinated control of both insulin secretion and insulin action through calpain-10-mediated regulation of exocytosis?

Calpain-10 was first identified through a genome scan seeking to identify diabetes predisposition genes. Both genetic and functional data has since indicated that calpain-10 has an important role in insulin resistance and intermediate phenotypes, including those associated with adipocytes and skeletal Muscle. Evidence presented in this issue by Brown, Yeaman, and Walker utilizes siRNA technology to specifically knock down calpain-10 expression, and suggests that calpain-10 facilitates GLUT4 translocation through effects on the distal. pathway. Calpain-10 is also an important molecule in the pancreatic I secretory beta-cell, where it has been shown to regulate exocytosis through partial proteolvsis of a member of the secretory granule fusion machinery. In addition, calpain-10 has also been implicated in reorganization of the actin cytoskeleton that accompanies both GLUT4 vesicle translocation and insulin secretion. Taken together, these findings provide fresh hope for the development of novel diabetic treatments, utilizing either pharmacological activators that specifically target calpain-10, or through targeted calpain-10 gene therapy. Therapeutic intervention in this way could simultaneously enhance both insulin secretion and insulin action. (c) 2007 Elsevier Inc. All rights reserved.