Discovery of fundamental mechanism within cells that link obesity and type 2 diabetes

Researchers from the Harvard School of Public Health have discovered what they believe is the fundamental mechanism within cells that links two fast-rising public health threats: obesity and Type 2 diabetes.

In identifying a specific cell-signaling pathway through which excess fat sets in motion a series of steps culminating in diabetes, the scientists have gone farther than previous studies that provided shards of evidence but not a satisfactory whole. An article on the work appears in the October 15 issue of Science.

A series of experiments in isolated cells and in mice revealed that accumulation of excess fat put unusual demands on crucial synthetic machinery of cells. In attempting to adapt to this condition, cells activate a cascade of genes and proteins that ultimately disrupt insulin function. The result is cellular stress inflammation, and diabetes.

Type 2 diabetes – 90 to 95 percent of all diabetes cases – affects an estimated 18 million people in the United States, and causes some 200,000 deaths a year. Its description as “adult-onset” diabetes has been dropped, as it is now being diagnosed in younger and younger people including children and teenagers, most of whom are overweight.

“What we have found is an important step toward understanding the roots of Type 2 diabetes and metabolic disease,” said Gokhan Hotamisligil, chair of the Department of Genetics and Complex Diseases, who headed the research team. “It is a missing piece that integrates the mechanisms of the disease at different sites in the body, including fatty tissue, liver and the pancreas.”

Hotamisligil is the senior author; co-first authors are Harvard School of Public Health fellows Umut Özcan and Qiong Cao. Laurie H. Glimcher of the Department of Immunology and Infectious Diseases is a collaborator and provided the genetically altered mice.

Until now, scientists have obtained only a sketchy picture of how the accumulation of excess calories and millions of extra fat cells in an obese person triggers a chain of events that leads to a chronic state of inflammation and insulin resistance (when cells can no longer respond to the hormone insulin, hence are unable to import sugar from the blood). Over time, these events create a high risk of heart disease and stroke, kidney disease, amputation of feet and legs, and blindness.

Hotamisligil has done pioneering work on the discovery of inflammation as a cause of obesity and type 2 diabetes. He and others previously showed that fat cells are not just inert storage receptacles; instead, they play an important role in communicating with other organs to maintain proper metabolic balance. They also secrete chemical messengers that stimulate the immune system.

With the goal of reaching to the deeper mechanisms, Hotamisligil tested a hypothesis that the key to the obesity-diabetes connection might be found in the endoplasmic reticulum, or ER – a system of folded membranes and tubules in the cytoplasm of cells where proteins and lipids are manufactured, processed, and shipped around the cell. When unusual demands are put on the ER’s capacity, the life of the cell is threatened and it goes into emergency mode. This condition is called ER stress. It can be triggered by a viral infection, gene mutations, exposure to toxins, or a shortage of intracellular nutrients. The cell responds with a flurry of activity aimed at survival – but which suppresses the cell’s normal responsiveness to insulin and sets off inflammation.

Hotamisligil showed that turning the adaptive capacity in the ER “on or off” by regulating the levels of a gene called XBP-1 also changes insulin action. In mice, when there is less XBP-1 activity — hence susceptibility to ER stress — the animals develop insulin resistance and diabetes. The XBP-1 gene was first isolated by Glimcher.

How does obesity cause ER stress to begin with? Although the details aren’t all known, Hotamisligil says that fat cells by their nature are perpetually on the verge of ER stress. “It’s a big, spherical cell that under the best of conditions uses up all its excess capacity to be able to run,” he said. “Obesity brings a huge amount of stress to a cell that has no reserve capacity to tolerate it.”

With the missing link in hand, Hotamisligil said the discovery will open up many therapeutic possibilities by focusing on how to enhance the cell’s tolerance of ER stress. He cautions, however, that there is no treatment based on this concept on the immediate horizon, though he is “very excited” about the work’s rich potential for treating diabetes.