NIH researchers map out process by which cells take in glucose

Researchers at the National Institutes of Health have made important progress in the knowledge of how insulin stimulates fat cells to take in glucose, which could aid in our understanding of diabetes and other insulin-resistant conditions

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BETHESDA, Md.—Researchers at the National Institutes of Health (NIH) have made important progress in the knowledge of how insulin stimulates fat cells to take in glucose. Publishing their findings in the Sept. 8 issue of the journal Cell Metabolism, the researchers say their work shows how regulation of this process is important for cell survival and normal body function—insights that could aid in our understanding of diabetes and other insulin-resistant conditions.

The researchers' work focuses on the process by which glucose transporter proteins called Glucose transporter type 4, or GLUT4, work in normal, insulin-sensitive cells. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell. The protein is expressed only in muscle and fat cells, the major tissues in the body that respond to insulin.

While it is currently known that GLUT4 is fundamental to insulin-regulated glucose metabolism, its dynamic spatial organization in the plasma membrane is unclear, explains Dr. Karin G. Stenkula, a researcher at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and a lead author of the paper.

"What we did not know is all the molecular steps needed for GLUT4 to get translocated from the surface to within the cell," says Stenkula, who helped to conduct the research as part of a postdoctoral fellowship from the Swedish Research Council.

To solve that mystery, Stenkula and her colleagues—reknowned insulin researchers Dr. Samuel Cushman of the NIDDK, and Drs. Joshua Zimmerberg and Vladimir Lizunov of the National Institute of Child Health and Human Development (NICHD)—used high-resolution microscopy to how insulin prompts fat cells to take in glucose in a rat model. To get detailed images of how GLUT4 is transported and moves through the cell membrane, the researchers used high-resolution imaging to observe GLUT4 that had been tagged with a fluorescent dye. They then observed fat cells suspended in a neutral liquid and later soaked the cells in an insulin solution to determine the activity of GLUT4 in the absence of insulin and in its presence.

In the neutral liquid, individual molecules of GLUT4 as well as GLUT4 clusters were distributed across the cell membrane in equal numbers. Inside the cell, GLUT4 was contained in GLUT4 storage vesicles (GSV), which transported GLUT4 to the cell membrane and fused with the membrane.

After fusion, the individual molecules of GLUT4 were the first to enter the cell membrane, moving at a continuous but relatively infrequent rate—a process the researchers terms "fusion with release." But the researchers observed that when exposed to insulin, the rate of total GLUT4 entry into the cell membrane peaked, quadrupling within three minutes. The researchers saw a dramatic rise in fusion with release—60 times more often on cells exposed to insulin than on cells not exposed to insulin.

After exposure to insulin, a complex sequence occurred, with GLUT4 shifting from clusters to individual GLUT4 molecules. Based on the total amount of glucose the cells took in, the researchers deduced that glucose was taken into the cell by individual GLUT4 molecules as well as by clustered GLUT4. The researchers also noted that after four minutes, entry of GLUT4 into the cell membrane started to decrease, dropping to levels observed in the neutral liquid in 10 to 15 minutes.

The researchers made three primary conclusions: one, that clusters are generated by fusion-with-retention of GLUT4 in nascent domains; two, that GLUT4 is internalized at these domains after subsequent recruitment of clathrin; and finally, that insulin induces a burst of GLUT4 exocytosis that mostly bypasses these domains and disperses GLUT4 directly into the plasma membrane.

"Taken together, the data presented in this study suggest that GLUT4 clusters may function as intermediate hubs from the time of GLUT4 exocytosis until their internalization. In the basal state, these domains appear to play the major role in regulating the recycling of GLUT4 between plasma membrane and the intracellular pool of GSV. In the insulin-stimulated state, a rapid increase of plasma-membrane GLUT4 is achieved by an increase in GSV fusion, particularly events with full and immediate release of GLUT4 molecules diffusely into plasma membrane," the researchers concluded.

As Stenkula prepares to move back to Sweden after a three-year fellowship here, she and her colleagues are planning to next examine the activity of glucose transporters in human fat cells. Understanding this process may lead to ideas for stimulating this activity when cells become insulin-resistant, Stenkula says, although she hesitates to speculate on any eventual commercial opportunities that could arise from the researchers' findings. However, many in the research community believe that the NIH team's study holds promise for patients with type 2 diabetes and other insulin-affected conditions polycystic ovarian syndrome, metabolic syndrome and hepatitis C.

"Research is fun, but it's hard to talk about because people tend to focus on the future promise of what you're doing," she says. "For right now, our focus is on understanding the problems associated with insulin resistance."

The study was funded by the Swedish Research Council and the NIDDK and NICHD, intramural research programs of two divisions at the NIH.

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