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.