In Type 2 Diabetes, Mitochondrial Damage Kills Insulin-Producing Cells
Joslin Researchers Identify Effect of Insulin Resistance
BOSTON - November 24, 2009 - Over time, patients with type 2 diabetes lose insulin-producing cells, a difficulty that aggravates their disease. Researchers at Joslin Diabetes Center now have identified a mechanism that triggers the problem, giving a chance to find targets for drugs to protect these crucial cells.
The failure arises when the insulin-producing "beta" cells, located in the pancreas, themselves fail to import insulin properly. Similar failures throughout the body, producing a condition known as insulin resistance, are a common cause of type 2 diabetes.
Scientists in the lab of Joslin Principal Investigator Rohit N. Kulkarni, M.D., Ph.D., found that when a beta cell can't respond to circulating insulin, an altered molecular cascade ends up damaging the normal action of a certain molecular complex on the surface of the cell's mitochondria.
Mitochondria, known as the cell's powerhouses, produce most of every cell's supply of adenosine triphosphate, the prime fuel for cellular activity. When compromised in this way, the beta-cell's mitochondria begin to destroy the cell.
In research published online in PLoS ONE on November 24, Siming Liu, Ph.D., a postdoctoral fellow in the Kulkarni lab, began by studying genetically modified mice whose beta cells, and only beta cells, lacked a receptor on their cell surface that allows insulin to act.
"Experimenting with these cell lines, Siming noticed that they kept dying over a period of time, and then discovered that this cell death was linked to mitochondrial damage," says Dr. Kulkarni, who is also an Assistant Professor of Medicine at Harvard Medical School.
When Liu genetically modified these cells to restore the insulin receptor, he was able to fix most of the defects.
Tracking down what caused the damage to the beta cells, he pinpointed a molecular complex on the mitochondrial surface that includes two key proteins. One is glucokinase, an enzyme that is key in metabolizing glucose. The other is Bcl-2-associated death promoter (BAD), a protein that is central to a pathway toward cell death.
Liu then examined beta cells from humans with type 2 diabetes and discovered that this mechanism also was at work there.
While researchers had known about the existence of the glucokinase/BAD complex, this was the first study to implicate it in the death of beta cells when the insulin signaling pathway breaks down, and to show that this mechanism also is triggered in humans with type 2 diabetes. Scientists elsewhere recently isolated a similar effect in hepatocytes, cells that make up the liver.
Following up on the discovery in beta cells, "we will try to figure out whether the proteins we isolated in the complex can be therapeutic targets," says Kulkarni. "Right now, no drugs are specifically targeted to prevent this kind of cell death, which can affect just about anyone with type 2 diabetes."
"Mitochondrial function is a very fundamental aspect of how beta cells produce insulin, and this research shows its direct relation with insulin signaling," notes co-author E. Dale Abel, M.D., Ph.D., Chief of the Division of Endocrinology and Metabolism at the University of Utah School of Medicine.
Other contributors include Terumasa Okada, Anke Assmann and Chong Wee Liew of Joslin; Jamie Soto and Heiko Bugger of the University of Utah School of Medicine in Salt Lake City; and Orian S. Shirihai of the Boston University School of Medicine. The research was funded by the National Institutes of Health.