Researchers from the National Institutes of Health have discovered the critical sequence of events by which insulin stimulates the entry of glucose into fat cells.

The study, appearing in the May 9 Journal of Cell Biology, was conducted by researchers from the National Institute of Child Health and Human Development and the National Institute of Diabetes and Digestive and Kidney Diseases.

“This finding provides useful information for understanding disorders in which cells have difficulty using insulin, such as insulin resistance and type 2 diabetes,” said NICHD Director Duane Alexander, M.D.

Glucose, a simple sugar, is a nutrient that cells need to survive, explained the study’s corresponding author, Joshua Zimmerberg, M.D., Ph.D., chief of NICHD’s Laboratory of Cellular and Molecular Biophysics. Glucose is ferried through the cell’s outer covering, or membrane, by a family of molecules known as glucose transporters. In the study, the researchers discovered how glucose transporter 4 (GLUT 4) carried insulin into fat cells.

Previously, scientists had learned that, within the cell, GLUT 4 is contained in the membrane of tiny sacs known as vesicles. Another author of the current study, Samuel Cushman, Ph.D., of NIDDK’s Diabetes Branch, had found in earlier studies that GLUT 4 was transferred from the vesicles within the cell to the cell membrane, when the vesicles combined, or fused with, the membrane. Researchers had been unable to determine, however, where in the cell the vesicles were stored and how insulin stimulated them to fuse with the cell membrane.

In the current study, the NIH researchers observed fat cells taken from mice and learned that the GLUT 4 vesicles are highly active. They discovered that, although a few vesicles are scattered throughout the cell, the majority circulate just under the cell’s surface. The vesicles travel along a railroad track-like network of molecules known as microtubules. When insulin binds to the cell’s outer surface, those vesicles immediately stop moving, tether to the cell’s inner surface, then fuse with the cell membrane. GLUT 4, contained in the vesicles’ membrane, then enters the cell membrane, where it ferries glucose into the cell.

The researchers made their observations using a technique known as total internal reflector florescent microscopy. The technique consists of aiming a laser beam at an angle at the glass cover slip beneath the microscope, explained the last author of the paper, Vadim A. Frolov, Ph.D., of NICHD’s Laboratory of Cellular and Molecular Biophysics and the Russian Academy of Science in Moscow. The light bounces off the cover slip, away from the microscope’s lens. However, residual energy from the light passes through the cover slip, to the cell beneath, illuminating the area just below the cell’s surface while leaving the inside of the cell dark.

“When we started the experiment, we thought that the vesicles would be stationary,” Dr. Zimmerberg said. “The vesicles looked like comets streaking by.”

Dr. Zimmerberg added that studying the chemical steps of the process in which the vesicles fuse with the cell membrane might yield a new drug to treat insulin-related disorders. He added that each step in the process might provide the basis for a treatment: when the vesicles first stop moving, when they tether to the inside of the cell’s membrane, and when they fuse with the membrane.

Next, the researchers plan to observe cells taken from mice having conditions resembling human disorders of insulin metabolism. Eventually, the researchers hope to obtain cell samples from volunteers who have been diagnosed with type 2 diabetes and insulin resistance.

The NICHD is part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is an agency of the U.S. Department of Health and Human Services. The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.