Working with a national team of researchers, a scientist from the Florida campus of The Scripps Research Institute has shown for the first time a link between low levels of a specific hormone and increased risk of metabolic disease in humans.
The study, published online ahead of print in The Journal of Clinical Endocrinology & Metabolism, focuses on the hormone adropin, which was previously identified by Scripps Research Associate Professor Andrew Butler's laboratory during an investigation of obese and insulin-resistant mice. Adropin is believed to play an important role in regulating glucose levels and fatty acid metabolism.
"The results of this clinical study suggest that low levels of adropin may be a factor increasing risk for developing metabolic disorders associated with obesity and insulin resistance, which could then lead to diseases such as type 2 diabetes," said Butler, who led the new study with Peter J. Havel, professor of molecular biosciences and nutrition at the University of California, Davis.
Approximately 47 million adults in the United States have metabolic syndrome, according to the American College of Cardiology. The National Institutes of Health defines metabolic syndrome as a group of risk factors, especially obesity and insulin resistance, that occur together and increase the risk for coronary artery disease, stroke, and type 2 diabetes.
In the new study, which involved 85 women and 45 men, Butler and his colleagues showed that obesity is associated with lower adropin levels. Lower adropin levels were also observed in individuals with a higher "metabolic syndrome risk factor" score, a score determined by measuring triglycerides, LDL cholesterol, HDL, glucose, blood pressure, and waist circumference.
The scientists also observed circulating adropin concentrations increased significantly at three and six months following gastric bypass surgery in morbidly obese patients. Interestingly, adropin levels returned to pre-surgical levels at 12 months after surgery.
Another surprising finding of the new study was that in people of normal weight, women had lower plasma adropin levels than men. In addition, obesity had a bigger negative effect on adropin levels in men. Interestingly, obesity in woman was also not associated with lower plasma adropin levels. The significance of the differences between men and woman is unknown at the moment.
"But the link between low levels of adropin and increased metabolic risk was observed in both sexes," Butler said. "The impact is there, irrespective of gender."
Adropin levels were also found in general to decrease with age -- the decline was highest in those over 30 years of age. As with obesity, the aging effect appeared to be more pronounced in men.
Findings in Humans Mirror Preclinical Work
The new study is an important extension of earlier pre-clinical studies using animal models published in the July edition of Obesity. In that study, Butler and colleagues deleted the gene encoding adropin from mice. The scientists found that, while normal in appearance, adropin-deficient mice have insulin resistance and, when fed diets with a high fat content, develop a more severe impaired glucose tolerance (IGT). These findings suggest reduced insulin production and attenuated response to insulin, which are the defining features of type 2 diabetes. Importantly, mice having only one functional copy of the gene encoding adropin also exhibited increased propensity for developing impaired glucose tolerance with obesity. These findings provided important pre-clinical evidence evidence that low levels of adropin are associated with increased risk of developing type 2 diabetes.
In other studies, Butler's laboratory observed that obese mice exhibit dramatic reductions in circulating adropin levels, and that insulin resistance was reversed after injections with a synthetic form of adropin.
"The data from these studies provide strong evidence suggesting that low levels of adropin may be an indicator of risk for insulin resistance in obesity and, consequently, an increased risk for metabolic diseases, including type 2 diabetes," Butler said. "We see a lot of similarity between animal model data and the new human data -- low adropin levels in humans are associated with a host of metabolic syndrome risk factors normally associated with obesity and insulin resistance."
Taken together, these studies suggest the possibility that therapeutics designed to boost the supply of adropin might be useful in fighting obesity and metabolic disease.
In addition to Butler and Havel, authors of the study, "Low Circulating Adropin Concentrations With Obesity And Aging Correlate With Risk Factors For Metabolic Disease And Increase After Gastric Bypass Surgery In Humans," include Charmaine S. Tam and Eric Ravussin of Louisiana State University, Baton Rouge; Kimber L. Stanhope and Mohamed R. Ali of the University of California, Davis; Bruce M. Wolfe of the Oregon Health Sciences University, Portland; and Majella O'Keeffe and Marie-Pierre St Ongeof Columbia University.
The study was supported by the National Institutes of Health (award numbers HL061352, DK060412, HL075675, HL09133, UL1 RR024156-03, UL1 RR024146, and 1P30 DK072476-06); the American Diabetes Association; The Novo Nordisk Diabetes Innovation Award Program; the University of California, Davis Health Care Systems Award; the Irving Center for Translational Science; and the Pennington Biomedical Research Center's Nutrition Obesity Research Center program.
- Andrew A. Butler, Charmaine S. Tam, Kimber L. Stanhope, Bruce M. Wolfe, Mohamed R. Ali, Majella O’Keeffe, Marie-Pierre St-Onge, Eric Ravussin and Peter J. Havel. Low Circulating Adropin Concentrations with Obesity and Aging Correlate with Risk Factors for Metabolic Disease and Increase after Gastric Bypass Surgery in Humans. Journal of Clinical Endocrinology & Metabolism, 2012; DOI: 10.1210/jc.2012-2194
- K. Ganesh Kumar, Jingying Zhang, Su Gao, Jari Rossi, Owen P. McGuinness, Heather H. Halem, Michael D. Culler, Randall L. Mynatt, Andrew A. Butler. Adropin Deficiency Is Associated With Increased Adiposity and Insulin Resistance. Obesity, 2012; 20 (7): 1394 DOI: 10.1038/oby.2012.31
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