Missing Sugar Molecule Raises Diabetes Risk in Humans

Researchers at the University of California, San Diego School of Medicine and Rady Children's Hospital-San Diego say an evolutionary gene mutation that occurred in humans millions of years ago and our subsequent inability to produce a specific kind of sugar molecule appears to make people more vulnerable to developing Type 2 diabetes especially if they're overweight.

Type 2 diabetes is caused by both genetic and environmental factors, such as a fatty diet and lack of exercise, that result in progressively dysfunctional pancreatic beta cells, elevated blood sugar levels due to insulin resistance and eventual health complications, sometimes fatally so.

Sialic acids are sugar molecules found on the surfaces of all animal cells, where they act as vital contact points for interaction with other cells and with their surrounding environment. Virtually all mammals produce two types: N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc).

Humans are the exception. For reasons lost in the mists of evolution, a mutation in a gene called CMAH occurred 2 to 3 million years ago, inactivating an enzyme in humans that catalyzes production of Neu5Gc by adding a single oxygen atom to Neu5Ac.

Researchers compared two groups of mice: one with a functional CMAH gene, the other with an altered CMAH gene similar to the human mutation. Both groups of mice were fed a high-fat diet. Mice in both groups became obese and developed insulin resistance. However, only mice with the CMAH gene mutation experienced pancreatic beta cell failure.

Corresponding study author, Jane J. Kim is an assistant professor in the UCSD Department of Pediatrics and a member of the Pediatric Diabetes Research Center.  Kim said the findings represent the first documented evidence linking the sugar production to insulin and glucose metabolism problems associated with diabetes. "It opens up a new perspective in understanding the causes of diabetes." "Given the global epidemic of obesity and diabetes, we think that these findings suggest that evolutionary changes may have influenced our metabolism and perhaps increased our risk of the disease."

Kim said the findings help refine understanding of why obese humans appear to be particularly vulnerable to Type 2 diabetes, and also suggest that current animal models used to study diabetes may not accurately mirror the human condition. In clinical terms, she said further research to determine how sialic acid composition affects pancreatic beta cell function may reveal new strategies to preserve the cells, improve insulin production and prevent diabetes.

Published online edition of The FASEB Journal, Feb. 24, 2011