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Understanding Insulin Sensitivity and Diabetes

A new discovery helps explain how adipose tissue (fat) affects insulin sensitivity and results in type 2 diabetes. The finding may lead to new strategies for treating the disease.

Diabetes is a disorder in the way the body uses glucose, a sugar that serves as fuel for the body. When blood glucose levels rise, the pancreas normally makes the hormone insulin, which signals cells to take sugar from the blood. Fat cells store excess glucose in the form of lipids (fats). In the most common form of diabetes, type 2, cells lose their sensitivity to insulin.

About 80% of people with type 2 diabetes are overweight, but the connection between adipose tissue and insulin sensitivity has been difficult to decipher. A research team led by Drs. Barbara Kahn and Mark Herman of Harvard Medical School and Beth Israel Deaconess Medical Center set out to investigate. Their work was funded primarily by NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). It appeared in the advance online edition of Nature on April 1, 2012.

The team began with 2 types of transgenic mice in which insulin resistance and obesity don't correlate. The mice have alterations in GLUT4, the protein primarily responsible for transporting glucose into muscle and fat cells in response to insulin. AG4OX mice overexpress GLUT4 in adipose tissue. They become obese, yet they're able to control blood glucose levels. AG4KO mice, in contrast, don't produce GLUT4 in adipose tissue. They have a normal body weight but develop insulin resistance and type 2 diabetes.

The researchers compared gene expression in adipose tissue from the 2 types of mice. Genes involved in making lipids were expressed at high levels in AG4OX mice but low levels in AG4KO mice. These genes are known to be controlled by certain master regulator genes, so the team examined expression of these genes. One called ChREBP was found to be 50% higher in AG4OX adipose tissue and 44% lower in AG4KO adipose tissue. This suggests that adipose tissue GLUT4 affects fatty acid synthesis and insulin sensitivity by regulating ChREBP.

But analysis of ChREBP expression in numerous mouse strains and people showed a more complicated releationship. While ChREBP expression usually correlates with GLUT4 levels, it doesn't always. A closer look revealed a new form of the ChREBP gene, ChREBP-β, that begins from a different DNA start site than the previously known one, ChREBP-α, and makes a more active form of the protein.

The researchers found that expression of ChREBP-β isn't induced directly by GLUT4 but by ChREBP-α. This means that increased glucose transport into fat cells activates ChREBP and leads it to produce another, more potent version of itself.

Mice fed a high-fat diet showed reduced adipose ChREBP-β expression, while ChREBP- αlevels remained unchanged. This suggests that ChREBP-β may play a role in insulin resistance. When the researchers examined obese people, they found that expression of ChREBP-β, but not ChREBP-α, in adipose tissue predicts insulin sensitivity.

"Two things were surprising—first, that a lone gene could shift the metabolism of the fat cell so dramatically and then, that turning on this master switch selectively in adipose tissue is beneficial to the whole body," says Kahn.

This research revealed a new molecular player in fat cell insulin sensitivity. ChREBP-β might one day prove to be a good drug target to help treat or prevent type 2 diabetes.

—by Harrison Wein, Ph.D.