Contact

Duke Health News

919-660-1306

DURHAM, N.C. – Before people develop type 2 diabetes, cells in the pancreas spend years churning out increasing amounts of insulin, the body's key player in maintaining normal blood sugar levels. The constant stress of creating more and more insulin eventually exhausts these cells, and they quit working – one of the hallmarks of the disease.

Duke University Medical Center researchers have shown that they can control insulin release in the pancreas by blocking a protein called Gáz (G-alpha-z). In mice, deleting the protein from cells that make insulin, called beta cells, improves their blood sugar control.

Mice missing the protein produced more insulin and cleared sugar from their bloodstreams faster than normal mice, the researchers found. This means mice without Gáz would process blood sugar, or glucose, more quickly and efficiently than normal mice after eating sweets, for example.

"A drug that targets the Gáz protein could slow or even prevent the onset of type 2 diabetes by improving how beta cells respond to glucose," said Michelle Kimple, Ph.D., a biochemist at Duke University Medical Center.

The study appears in the Feb. 22, 2008 issue of The Journal of Biological Chemistry. The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of General Medical Sciences.

About 90 percent of diabetics, or 221 million people worldwide, have type 2 diabetes, according to the International Diabetes Foundation. The disease has two distinct but related causes: 1) beta cells don't make enough insulin in response to rising blood sugar; and 2) tissues throughout the body are resistant to insulin, the hormone that helps cells use glucose for food, so it takes more insulin to make the same amount of energy.

The Duke researchers investigated the Gáz protein via a mouse that does not have the genetic code for making the protein in any of its cells. Compared to normal mice, the genetically-altered mice (called knockout mice) had the same levels of blood glucose and insulin both when fed and during fasting. They weighed about the same and their pancreatic cells were similar in size and structure. The knockouts also didn't show any negative effects on other parts of the body, nor did the mice develop diabetes.

But a big difference appeared when the two sets of mice were given a large dose of glucose. The altered mice produced more insulin and cleared sugar from their bloodstreams significantly faster than normal mice.

"In the knockout mice, the glucose concentration in blood goes down faster and doesn't peak as high, which suggests that they were secreting more insulin," said Kimple, lead study author and a research scientist in the laboratory of Patrick Casey, Ph.D., James B. Duke professor of pharmacology and cancer biology.

Further experiments in laboratory cell cultures revealed the knockout mice beta cells only made extra insulin when faced with a big increase in glucose. It turns out that removing the protein interferes with the cell signals that control insulin production in response to glucose.

"You don't have increased insulin secretion unless there is a higher glucose load. And you don't want to have increase insulin secretion all the time, because that could lead to insulin resistance," Kimple said.

She said a Gáz-targeted drug could treat a diabetic's dysfunctional beta cells by changing how the cells manufacture and release insulin in response to glucose, reviving tired cells or preventing them from wearing out in the first place.

There is already evidence that a drug targeting the pathway that the Gáz protein inhibits could be a therapy for type 2 diabetes, Kimple explains. The Food and Drug Administration has approved a diabetes medication, called Byetta, that activates certain chemical signals in beta cells, leading to more insulin.

Kimple and her colleagues have received a grant from the NIDDK to further test whether removing Gáz protein will protect against developing type 2 diabetes. They plan to feed the altered mice a high-fat diet, based on what the average American eats, and monitor how many develop diabetes. "This is the necessary next step in showing that this might be a potential drug target," Kimple said.

Collaborators on the study include Candice Bailey, Patrick Fueger, Christopher Newgard and Patrick Casey, all of Duke; Jamie Joseph of the University of Waterloo in Ontario, Canada; and Ian Hendry of Australian National University in Canberra, Australia.