Fat-Storage Gene Identified in Amish, Implicated in Diabetes

May 28, 2014

Scientists in the US have discovered a mutation in a gene that codes for a key enzyme that breaks down fat; individuals carrying this mutation have impaired metabolic function with dyslipidemia, insulin resistance, and a higher risk for type 2 diabetes.

Those carrying this defect do not store more fat in their fat cells, however; rather, "the adipocytes are not able to properly act as a depot, so the fat is going to other tissues." For example, there is increased fat deposition in the liver, senior author Coleen M. Damcott, PhD, from the University of Maryland School of Medicine, Baltimore, told Medscape Medical News. And as well as reducing white fat cell storage and adversely affecting lipid profiles, the defect appears to result in greater inflammation.

Dr. Damcott and colleagues identified the mutation in the gene encoding hormone-sensitive lipase (HSL) in an Amish population in the United States but showed that it is also present, but at a much lower frequency, among non-Amish white subjects. Their work was published online May 21 in the New England Journal of Medicine.

"To our knowledge this is the first mutation identified that appears to have a functional effect on the HSL enzyme," she noted. "Future studies of this gene will allow us to look more closely at the effects of its deficiency on human metabolism to better understand the function of the HSL protein and its impact on fat and glucose metabolism."

Future research "will also examine the potential of using HSL as a drug target for treating type 2 diabetes and related complications," she added.

Eric Topol, MD, from Scripps Research Institute, La Jolla, California, who was not involved in the study, said the findings were interesting and enhance the understanding "of this key pathway of lipolysis in adipocytes." They also highlight "the central role of the protein hormone-sensitive lipase," he noted.

Amish: Genetically Homogeneous Population Good for Gene Studies

The researchers sequenced 12 lipolytic pathway genes in 24 Old Order Amish individuals whose fasting serum triglyceride levels were at the extremes of the distribution range (ie, very high or very low).

They explain that the Old Order Amish are ideal for these studies because they are a genetically homogenous population that can trace their ancestry back 14 generations to a small group who came to Pennsylvania from Europe in the mid-1700s.

A novel deletion in a gene encoding for HSL was identified, and they went on to examine the frequency of this mutation among 2738 further Amish participants.

They also obtained biopsy specimens of abdominal subcutaneous fat tissue from 2 participants who were homozygous for the deletion, 10 who were heterozygous, and 7 who were noncarriers to assess factors such as adipose histologic characteristics, lipolysis, and enzyme activity.

In this study, 5.1% of the Old Order Amish study participants had at least 1 copy of the mutation.

"We found that Amish people with this mutation have defects in fat storage, increased fat in the liver, high triglycerides, low 'good' [HDL] cholesterol, insulin resistance, and increased risk of developing type 2 diabetes," Dr. Damcott noted.

Four people were homozygous and consequently produced no HSL enzyme: the result of this was that all 4 developed type 2 diabetes before the age of 50, she told Medscape Medical News.

The mutation is less common in non-Amish whites of European descent (0.2%). The higher prevalence of the mutation in the Amish is what makes it possible to characterize its full range of effects, the researchers note.

"Discovery of this mutation adds to the growing list of insights gained from genomic studies that can be used to develop new treatments and customize existing treatments for type 2 diabetes and related metabolic disorders," concluded Dr. Damcott, who is also a member of the Program for Personalized and Genomic Medicine at the University of Maryland School of Medicine.

The study is supported by grants from the National Institutes of Health (NIH), the American Heart Association, the University of Maryland Multidisciplinary Clinical Research Career Development Program, the Mid-Atlantic Nutrition and Obesity Research Center, the Baltimore Diabetes Research Center, the American Diabetes Association, the US Department of Agriculture National Institute of Food and Agriculture, the Geriatric Research Education and Clinical Center, and the Baltimore Veterans Affairs Medical Center and by a VA Research Career Scientist Award. Dr. Damcott reports grant support from the NIH during the conduct of the study. Disclosures for the coauthors are listed in the article. Dr. Topol is editor in chief of Medscape.

New Engl J Med. Published online May 21, 2014. Article

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