Obesity And Diabetes May Be A Downside Of Human Evolution

New research in the FASEB Journal suggests that a gene called CMAH has been lost during the course of recent evolution, and may lead to an increased risk of Type 2 diabetes in humans

As if the recent prediction that half of all Americans will have diabetes or pre-diabetes by the year 2020 isn't alarming enough, a new genetic discovery published online in the FASEB Journal provides a disturbing explanation as to why: we took an evolutionary "wrong turn." In the research report, scientists show that human evolution leading to the loss of function in a gene called "CMAH" may make humans more prone to obesity and diabetes than other mammals.

"Diabetes is estimated to affect over 25 million individuals in the U.S., and 285 million people worldwide," said Jane J. Kim, M.D., a researcher involved in the work from the Department of Pediatrics at the University of California, San Diego in La Jolla, CA. "Our study for the first time links human-specific sialic acid changes to insulin and glucose metabolism and therefore opens up a new perspective in understanding the causes of diabetes."

In this study, which is the first to examine the effect of a human-specific CMAH genetic mutation in obesity-related metabolism and diabetes, Kim and colleagues show that the loss of CMAH's function contributes to the failure of the insulin-producing pancreatic beta cells in overweight humans, which is known to be a key factor in the development of type 2 diabetes. This gene encodes for an enzyme present in all mammalian species except for humans and adds a single oxygen atom to sialic acids, which are sugars that coat the cell surface.

To make their discovery, the researchers used two groups of mice. The first group had the same mutant CMAH gene found in humans. These mice demonstrated that the CMAH enzyme was inactive and could not produce a sialic acid type called NeuSGc at the cell surface. The second group had a normal CMAH gene. When exposed to a high fat diet, both sets of mice developed insulin resistance as a result of their obesity. Pancreatic beta cell failure, however, occurred only in the CMAH mutant mice that lacked NeuSGc, resulting in a decreased insulin production, which then further impaired blood glucose level control. This discovery may enhance scientific understanding of why humans may be particularly prone to develop type 2 diabetes. Results may also suggest that conventional animal models may not accurately mirror the human situation.

"The diabetes discovery is an important advance in its own right. It tells us a lot about what goes wrong in diabetes, and where to aim with new treatments," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal, "but its implications for human evolution are even greater. If this enzyme is unique to humans, it must also have given us a survival advantage over earlier species. Now the challenge is to find the function of CMAH in defending us against microbes or environmental stress or both. This evolutionary science explains how we can win some and lose some, to keep our species ahead of the extinction curve."

Details:
Sarah Kavaler, Hidetaka Morinaga, Alice Jih, WuQiang Fan, Maria Hedlund, Ajit Varki, and Jane J. Kim. Pancreatic ß-cell failure in obese mice with human-like CMP-Neu5Ac hydroxylase deficiency. FASEB J. fj.10-175281; doi:10.1096/fj.10-175281.

Evolution Led To Genetic Variation That May Affect Diabetes, Stanford Scientist Says

The root causes of complex diseases such as type-2 diabetes and obesity have been difficult to identify because the diseases are, well, complex. They occur at the dicey biological intersection of genes and environment, and, because they arose in our relatively recent past, it's not easy to simply compare DNA sequences from "then" and "now" to pinpoint likely genetic culprits.

Now researchers at the Stanford University School of Medicine have identified genetic variations in a hormone involved in the secretion of insulin - a molecule that regulates blood sugar levels - that occur more frequently in some human populations than others. People with the "new" variants, which are thought to have first occurred 2,000 to 12,000 years ago, have higher fasting levels of blood glucose than those with the more traditional, or ancestral, form of the gene. High blood glucose levels are associated with the development of diabetes, which occurs when the body is unable to produce or respond properly to insulin.

The finding may help scientists better understand the subtle changes in human metabolism, or "energy balance regulation," that occurred as our species shifted from being primarily hunter-gatherers to a more agriculturally based society. It may also help clinicians identify individuals likely to develop diabetes, and direct the development of new therapies for diabetes and obesity.

"These studies are fascinating because it shows how much the selection process has affected human energy-balance regulation in just a few thousand years and how complex it could be for the future practice of personalized medicine," said Sheau Yu "Teddy" Hsu, PhD, assistant professor of obstetrics and gynecology and senior author of the study.

The research was published online Feb. 7 in Diabetes. It follows a similar paper in the January issue of Genome Research that also explored the recent evolution of energy balance regulation, or how humans choose whether and how to store excess calories, among populations.

In the new paper, Hsu and his colleagues at Chang Gung Memorial Hospital in Taiwan and Texas A&M University first identified 207 genetic regions that have been associated with diabetes or obesity. They then looked to see which of these had increased in prevalence in the time since humans began to move out of Africa about 60,000 years ago. They identified 59 genetic regions of particular interest, and homed in on those that occurred in at least 30 percent of people in the HapMap project - a worldwide survey of genetic differences among populations. (Restricting their search to relatively common variants ensured that their findings would be widely applicable and would provide a more powerful tool to identify any associated phenotype differences.)

The researchers identified five genes with genetic differences that occurred frequently in Asians and/or Europeans, but infrequently in Africans. (These groups were pre-identified as part of the HapMap project, which sampled people of Nigerian, Chinese, Japanese and European ancestry.) Hsu's team selected GIP, one of the five genes, for further study because the GIP protein was known to be involved in stimulating insulin secretion in humans after a meal.

"We thought GIP was the most interesting because the newly selected form occurs in about 50 percent of people from Europe or Asia, but in only about 5 percent of Africans. That indicates this gene is highly adaptable to new environments," said Hsu.

He and his colleagues identified three individual changes in the regulatory region of GIP - that is, the DNA adjacent to the GIP gene that affects when and how it is translated into protein - that reduced the levels of the hormone. What's more, these three also tended to occur with another mutation in the coding region that results in a slightly different form of the protein. This alternate form is degraded more slowly in human blood.

"So now we know there are two different forms of the protein, which allowed one form to be selected in one population, and the other in a different population," said Hsu. "But we still needed to show that these variants led to phenotypic differences in modern humans."

Because previous studies of GIP variants hadn't showed any conclusive differences among their human carriers, Hsu and his colleagues focused their study more narrowly on a population that is not only metabolically challenged, but also critical to evolutionary success: pregnant women. They found that, out of 123 East Asian pregnant women, those who carried two copies of the newly evolved variant had significantly lower levels of GIP circulating in their blood. These women were also at a significantly increased risk to have fasting blood glucose levels that exceeded the recommended threshold of 140 mg/dL (48.3 percent vs. 20.9 percent of those who carry the ancestral variant).

The finding is particularly interesting because it may help clinicians identify pregnant women likely to develop gestational diabetes, according to Hsu. But it also gives a glimpse into our not-so-distant past and the ways our ancestors grappled with environmental change.

"Like other humans at the time, the Eurasian population really had to fight for survival," said Hsu. "Now we're starting to pinpoint how they did that on a molecular level. These gene variants, and the resulting higher blood sugar levels it fostered, may have helped women maintain successful pregnancies in the face of the inevitable famines that occur in an agriculturally based society. Now, in a more food-secure environment, variations in GIP could contribute to the development of diabetes or obesity."

Notes:

In addition to Hsu, James Cai, PhD, a former Stanford postdoctoral scholar in biology, was also involved in the study. He is now an assistant professor at Texas A&M University.

The research was funded by the National Institutes of Health, the Avon Foundation and Chang Gung Memorial Hospital. Stanford's Department of Obstetrics and Gynecology supported the work.

Source:
Krista Conger
Stanford University Medical Center

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