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Jane Kim and Collaborators Discover Evolutionary Footprint of Type 2 Diabetes

Jane Kim

PDRC physician-scientist Jane Kim and colleagues have learned that an evolutionary gene mutation millions of years ago resulted in our subsequent inability to produce a specific kind of "sialic acid" molecule. This change appears to make people more vulnerable to developing type 2 diabetes, especially if they're overweight.

The findings are published in The Faseb Journal, a publication of the Federation of American Societies of Experimental Biology.

According to Dr. Kim, the discovery represents the first documented evidence linking the non-human sialic acid production to insulin and glucose metabolism problems associated with diabetes.

"It opens up a new perspective in understanding the causes of diabetes," said Dr. Kim. "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."

Sialic acids are 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. All mammals studied to date produce two types: N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc).

Humans are an exception. For reasons lost in the mists of evolution, a mutation in a gene called CMAH occurred about 2 to 3 million years ago, inactivating an enzyme in humans that catalyzes production of Neu5Gc by adding a single oxygen atom to Neu5Ac. This earlier discovery, by UC San Diego evolutionary biologist Ajit Varki, M.D. and colleagues, led the way to creation of mice with a human-like defect in the CMAH gene.

Dr. Kim's group compared mice with a functional CMAH gene to mice with the human-like mutation in CMAH. 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.

Dr. 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.

Co-authors of the study are Sarah Kavaler and Alice Jih, UCSD Department of Pediatrics; Hidetaka Morinaga and WuQuiang Fan, UCSD Department of Medicine; Maria Hedlund and Ajit Varki, UCSD departments of Medicine, and Cellular and Molecular Medicine the UCSD Glycobiology Research and Training Center (GRTC), and the Center for Academic research and Training in Anthropogeny (CARTA).

"It is exciting to see real-life significance of our discovery of the human CMAH mutation," said Dr. Varki, who is Co-Director of the GRTC and CARTA. "This shows yet again that research in fundamental processes of biology and evolution can yield unexpected dividends for understanding human disease."​