Insulin Toppled As Ruler of Diabetes

Andy Coghlan, New Scientist Magazine

A pioneering hormone treatment may be the secret to an easy life for diabetics, consigning insulin shots and regular glucose monitoring to the medical history books.

Most people associate diabetes with insulin, the pancreatic hormone that dictates how much glucose circulates in blood. Type 1 diabetics have to inject the hormone because they can't make it themselves. Now, the spotlight is turning on insulin's lesser-known pancreatic twin, glucagon, as a treatment that could control blood glucose levels without the need for daily monitoring.

Whereas insulin clears surplus glucose from the blood after meals, squirreling it away in the liver, muscles and elsewhere, glucagon does the opposite when we are hungry, ordering the liver to release stores of glucose "fuel" into the blood or to make more if none is available.

To investigate glucagon's role, Roger Unger at the University of Texas Southwestern Medical Center in Dallas and colleagues engineered mice to lack glucagon receptors so they couldn't respond to the hormone. Surprisingly, the mice had normal levels of blood glucose. Then, when the team used a toxin to destroy the pancreatic beta cells that make insulin, the mice remained diabetes-free.

"The bottom line is that without glucagon, you can't get diabetes," says Unger. Even more mystifying, when the mice consumed huge amounts of sugar in so-called "glucose tolerance" tests, their blood glucose levels remained normal, irrespective of whether or not they could make insulin (Diabetes).

"The implication for humans is that (without glucagons) you could drink 10 bottles of sugary drinks and your blood sugar would remain the same, with or without insulin," he says. "This was a huge surprise."

So theoretically, if glucagon could be safely neutralized in people with type 1 diabetes, their blood glucose levels would stay normal without them having to take insulin or constantly check that level.

"The only potential downside is too little glucose in the blood, or hypoglycemia," says Unger. But this would only likely become an issue if a person was due to run a marathon, or do something equally energy-sapping. "The answer would be to take a sugary drink with you," he says.

The results in mice are so encouraging that a trial has already begun to see if suppressing glucagon has similar benefits in people with diabetes. Amylin Pharmaceuticals of San Diego, Calif., is attempting to do this with leptin, a hormone that controls fat uptake by cells but which also dampened the action of glucagon in studies on mice by Unger's team in 2008.

"It's the first time that researchers will test leptin, in the form of an analogue called metreleptin, in people with type 1 diabetes to see if it can improve glucose control," a company spokeswoman told New Scientist. The volunteers will not go without insulin, but will receive the minimum safe amount.

Other diabetes researchers are encouraged, but cautious about the developments.

"If you get rid of the glucagon receptor, you get these dramatic changes," says Alan Cherrington of Vanderbilt University School of Medicine, Nashville, Tenn. "But is it more relevant in rodents than in humans?" he asks.

Cherrington says that the study leaves important questions unanswered. Firstly, where does surplus glucose go in the mice lacking glucagon and insulin? Unger agrees that this urgently needs investigation and says that tracer studies are under way with labeled glucose so its fate in the animals can be tracked. The most likely destination, according to Cherrington, is the liver, but if so, what happens when it is "full up"?

The key question is: how are the mice managing to regulate glucose if insulin is not involved? Cherrington's hunch is that glucagon-like peptide-1 (GLP-1), a hormone made in the gut, may be deputising. "GLP-1 may affect the liver and muscle in an insulin-like way, ordering them to store glucose," he says.

Daniel Drucker at the Samuel Lunenfeld Research Institute in Toronto, Canada, who investigates GLP-1 and glucagon, agrees. "Animal models show elimination of glucagon is associated with increased circulation of GLP-1, so this hormone may certainly be playing a role," he says.

Drucker also says that suppressing glucagon levels, as expected in the leptin treatment, is probably safer than completely blocking the receptors. That's because blocking causes the cells that make glucagon to multiply rapidly to increase glucagon output, potentially resulting in the development of a pancreatic tumor. This shouldn't happen if glucagon action is only dampened.

Another question, of course, is how the finding will translate to people with type 1 diabetes, says Robert Henry of the University of California at San Diego, head of medicine and science for the American Diabetic Association. "The animals don't have any glucagon activity from birth, so would blocking the hormone have different effects in animals or humans already producing it?" he says.

Although cautious, most commentators were confident that the finding could lead to new treatments, or at the very least to new insights challenging the historical pre-eminence of insulin.

"It raises a large number of issues challenging the classic dogma that insulin is the most important hormone in diabetic control," says Henry.

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