An insulin-like modular basis for the evolution of glucose transporters (GLUT) with implications for diabetes.
Glucose transporters (GLUT) are twelve-transmembrane spanning proteins that contain two pores capable of transporting glucose and dehydroascorbate in and out of cells. The mechanism by which transport is effected is unknown. An evolutionarily-based hypothesis for the mechanism of glucose transport is presented here based on reports that insulin has multiple binding sites for glucose. It is proposed that insulin-like peptides were incorporated as modular elements into transmembrane proteins during evolution, resulting in glucose transporting capacity. Homology searching reveals that all GLUT contain multiple copies of insulin-like regions. These regions map onto a model of GLUT in positions that define the glucose transport cores. This observation provides a mechanism for glucose transport involving the diffusion of glucose from one insulin-like glucose-binding region to another. It also suggests a mechanism by which glucose disregulation may occur in both type 1 and type 2 diabetes: insulin rapidly self-glycates under hyperglycemic conditions. Insulin-like regions of GLUT may also self-glycate rapidly, thereby interfering with transport of glucose into cells and disabling GLUT sensing of blood glucose levels. All aspects of the hypothesis are experimentally testable.
Department of Physiology, 2174 Biomedical and Physical Sciences Building, Michigan State University, East Lansing, MI 48824, U.S.A. rootbern@msu.edu
Robert
R
Root-Bernstein