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Hormone That Regulates Blood Glucose Levels, Links Obesity to Diabetes
posted 02/27/04

Hepatic gluconeogenesis is reduced in mice lacking the adipocyte hormone resistin, Dr. Mitchell A. Lazar and colleagues report. In addition to at least partially explaining the role of obesity in the development of type 2 diabetes, targeting the resistin metabolic pathway may offer a new therapeutic strategy.

If correct, we may want to reduce resistin levels in diabetes. This could perhaps be accomplished "by reducing the amount of resistin that cells produce, binding it to an antibody, or by developing a drug to block the action of resistin on cells."

He noted that resistin levels are increased in people with obesity or type 2 diabetes. However, the normal physiologic function of the hormone is unknown. To elucidate resistin's mechanism of action, Dr. Lazar, at the University of Pennsylvania School of Medicine in Philadelphia, and his associates generated resistin knockout mice, which appeared to be normal in fertility, size and distribution of adipose deposits.

However, when fed normal chow or a high-fat diet, the knockout mice had reduced fasting glucose levels compared to wild-type mice, the researchers report in the February 20th issue of Science. Serum levels of insulin, leptin, adiponectin and triglycerides were unaffected.

Obese animals lacking resistin exhibited significantly better glucose tolerance than wild-type mice, and more glucose was required to maintain normal glucose levels during induced hyperinsulinemia. Thus, "absence of resistin protects against fasting hyperglycemia associated with obesity," the authors conclude.

Administration of resistin to the null mice raised their fasting glucose levels and glucose production to near normal levels.

The authors traced the effect of resistin absence to impaired levels of enzymes involved in hepatic gluconeogenesis, which are down-regulated by activation of adenosine monophosphate-activated protein kinase (AMPK). Their research further confirmed that resistin decreased the active, phosphorylated form of AMPK but not total AMPK, an increase that was abolished by treatment with resistin.

Dr. Lazar noted that, in mice, resistin is produced almost totally by fat cells, whereas in humans, most of the hormone appears to be secreted by macrophages.

"But what is exciting is the tremendous amount of evidence linking obesity and diabetes with inflammation and inflammatory disease," he continued. "And recently, studies have found macrophages actually intermingling with fat cells in obese people and mice."

"The other thing that is fascinating is that in the condition of nutritional excess, fat cells start to make the same inflammatory mediators that macrophages make, and macrophages start storing fat like fat cells."

"This raises the question, is resistin a marker for the inflammatory/metabolic condition, much like C-reactive protein, or is it even causing it?"

Source: Diabetes In Control.com: Science 2004;303:1195-1198.

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