Explanations of how diabetes develops and progresses often invoke the yin and yang of disease: genes and environment. In other words, you may be born with a genetic disposition to diabetes that is then triggered by an environmental event or behavior. As it turns out, though, these factors aren’t always so separate. Scientists are finding that the environment can affect and even permanently modify genes themselves. How and why this happens is the subject of an emerging field of research called epigenetics. And the evidence suggests that diabetes may both cause epigenetic changes and be caused by them.

On Top of Genes
The human genome, our complete set of genes, is like an instruction booklet for all the workings of the body. Genes are written in an alphabet of just four chemicals (abbreviated as A, C, G, and T) and are inscribed in DNA, a very long molecule that is the physical embodiment of genes. At the heart of almost every cell are 46 chromosomes, each an intricately wound spool of DNA.

Although the genes in every cell “read” about the same, their message can clearly be different. For example, heart cells look and act nothing like brain cells, yet they carry the same genes. The key is that genes can vary in how active they are in any particular cell, and that, in turn, profoundly affects a cell’s behavior. These variations in gene activity can depend, in part, on epigenetics.

The prefix epi- means “on top of” or “in addition to”; epigenetics is the modification of the surface and message of a gene without altering the underlying DNA sequence. It’s something like making a proofreading mark on a document. One example of an epigenetic change is known as methylation, the attachment of a methyl group (a carbon atom linked to three hydrogens) to a gene. Methylation reduces the impact of a gene in a cell, essentially crossing the gene out, in a phenomenon referred to as “gene silencing.”

For people with diabetes, high or low blood glucose may trigger epigenetic changes. Some research suggests that these changes to genes may spur the development of diabetic complications, such as kidney damage and heart disease. Even a brief exposure to high blood glucose may cause an epigenetic change that persists. This is called hyperglycemic memory, and it may explain why some people with diabetes get complications in spite of having good blood glucose control on average.

The development of both type 1 and type 2 diabetes is known to be influenced by the environment. Researchers are looking into what types of environmental factors, from nutrients and toxins to behavior and lifestyle, can trigger epigenetic changes that raise or lower diabetes risk.

Family Ties
Heredity is a hot topic in epigenetics. Researchers are pretty sure that environment can cause changes in genes in the here and now, but it’s less clear what kinds of epigenetic changes can be passed along to the next generation. Scientists use the term “inheritance” to refer to the transfer of genes, with or without epigenetic changes, to later generations through reproduction or to cells during replication (when one cell divides into two). “Most people in the field say that [methylation] is the only true epigenetic modification because it can be inherited,” says Rebecca Simmons, MD, associate professor of pediatrics at the University of Pennsylvania. “When a cell divides, the methylation on DNA can be carried into the next cell.”

Scientists suspect that a mother’s nutrition while pregnant or a child’s diet during early life can cause epigenetic changes that persist into adulthood. “For the diabetes population, this is important because [the pancreas’s insulin-producing] beta cells replicate very early in life and then no longer replicate,” says Simmons. “So a cell with epigenetic changes [from early life] just stays there.” And if epigenetic changes are transferred between cells through replication, then these changes in early life may have an even greater effect since they will be passed from the mother cell to the daughter cell throughout growth.

Research in epigenetics took off after a 2003 study published in Molecular Cell Biology found that giving nutritional supplements to female mice during pregnancy could affect the color of a mother’s offspring’s fur as well as their risk of developing obesity, diabetes, and cancer. These changes were linked to the methylation of a single gene.

Such changes may eventually explain the development of diabetes in an individual. But even more tantalizing is new research suggesting that the epigenetic modifications in parents’ sperm and eggs may persist in their offspring and affect those children’s health. If true, then epigenetic inheritance across generations may turn out to have a role in explaining why children of people with diabetes are more likely than others to develop diabetes themselves.

It’s hard to tease out whether a mother’s epigenetic influence on her children stems from the environment of the womb during pregnancy or from epigenetic traits in her eggs that already existed. With fathers, it’s easier. For them, “the only way environmental effects can be passed to the next generation is by sperm,” says Margaret Morris, PhD, a professor of pharmacology at the University of New South Wales in Australia. In a study published in October 2010 in the journal Nature, she found that male mice fed a high-fat diet had offspring with fewer insulin-producing cells and more resistance to insulin than mice whose fathers were given a normal diet. “They are prediabetic,” Morris says, though not overweight.

Epigenetics is a young field and a challenging one. Just identifying epigenetic changes to genes is difficult, a bit like trying to find a single out-of-place word in a long novel. Even so, researchers may someday discover through the study of epigenetics that the key to diabetes resides at the intersection of genes and environment.