Why do some obese people develop diabetes?

July 3, 2014 § Leave a comment

Obese mice in which one is missing heme oxygenase-1 and develops insulin resistance and the other is "healthy obese." Image provided by Harald Esterbauer

Obese mice in which one is missing heme oxygenase-1 and develops insulin resistance and the other is “healthy obese.” Image provided by Harald Esterbauer

More than half a billion people suffer from obesity and diabetes around the world. But a good number of people are obese but not diabetic. To understand what triggers obese people to become diabetic, researchers now show in a paper published in the journal Cell that a protein involved in chronic inflammation is a key factor in determining whether an obese person goes on to develop diabetes. The researchers suggest that inhibiting this protein could be one way to treat diabetes and other metabolic diseases.

Researchers have suspected that metabolic disorders, such as obesity and diabetes, could be the consequence of chronic inflammation and proinflammatory signaling that doesn’t get turned off.  This hypothesis led a team spearheaded led by Harald Esterbauer at the Medical University of Vienna in Austria and J. Andrew Pospisilik at the Max Planck Institute of Immunobiology and Epigenetics in Germany to consider the role of heme oxygenase-1. This protein is an anti-inflammatory molecule that breaks down heme in red blood cells.

But “nobody had tested the role of HO-1 in metabolic disease,” says Esterbauer. The investigators wanted to know if this important anti-inflammatory protein was the reason some obese people developed diabetes as a secondary metabolic disorder while other obese people didn’t. Based on the literature, the investigators were expecting to find that HO-1 was lower in insulin-resistant patients. “Higher HO-1 levels should protect from insulin resistance since it was thought to be anti-inflammatory, based on rather unspecific chemical studies,” says Esterbauer.

With this expectation, Esterbauer and Pospisilik’s team first looked at liver and adipose tissue samples taken from overweight patients who were undergoing bariatric surgery. They were surprised to find the exact opposite: Those with low HO-1 levels rarely developed diabetes; those with high levels often were also diabetic.

To confirm their observations, the investigators turned to mouse models in which they specifically turned off HO-1 in certain cell types. When HO-1 went missing from the immune system’s macrophages, the animals didn’t develop diabetes even though they were obese. When HO-1 was turned off in liver cells and the animals were fed high caloric diets, they had better responses to insulin. Furthermore, the investigators found that cells without HO-1 had higher mitochondrial activity.  The enzyme appears not to have an effect in fat cells, pancreatic beta cells and skeletal muscle “at least in mice,” notes Esterbauer.

So the bottom line is that, contrary to expectations, HO-1 promotes chronic metabolic inflammation, says Esterbauer. He says the next step will be to understand the mechanism of action of HO-1 in the cells in which it has an effect. Based on what they discover about how HO-1 works at the molecular level, Esterbauer says, the investigators hope to find molecules capable of selectively inhibiting the enzyme to halt the development of insulin resistance and diabetes.

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