UT Southwestern researcher ready to test new diabetes treatment in humans
04:23 PM CST on Monday, March 1, 2010
By JEFFREY WEISS / The Dallas Morning News
jweiss@dallasnews.com
A longtime diabetes researcher at UT Southwestern Medical School is setting up human tests for a new treatment he says might have fewer side effects than standard insulin therapy.
Dr. Roger Unger, former director of the Director of the Touchstone Center for Diabetes Research at UT Southwestern Medical School, is quick to warn that a novel method that worked in mice with Type 1 diabetes may not help people.
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"You can't make any claims until the tests have been done," he said.
The tests using leptin, a natural hormone produced by fat cells, would build on results of experiments performed by Unger's research team and published today in a major scientific journal, Proceedings of the National Academy of Sciences.
The paper, titled "Leptin monotherapy in insulin dependent type 1 diabetes," describes studies done on diabetic mice. The journal cites the new paper as "reporting findings of exceptional interest."
The new work is a follow-up to a paper published in 2008 by Unger's team that reported about diabetic mice and rats that were genetically modified to produce extra leptin and thrived without insulin. The 2008 paper was the research equivalent of a talking dog – startling even to experts, whether or not it said anything practical.
Genetic modification is not an option for humans, so Unger's team next tried treating mice using a technique well-known to people with diabetes: leptin injections delivered by a pump. Not only did the leptin-treated mice thrive, Unger said today, but they did so without some of the side effects familiar to people using insulin.
"I think today's paper is much bigger, because the last one was just academic," said Unger, who has been researching diabetes for more than 50 years. "This is a translatable paper into something that might be useful for people. The other was not."
Unger's team first asked permission to start human trials almost a year ago, he said. The hospital is prepared, they have an ample supply of potential volunteers, and they've lined up funding. What's holding the process up, Unger said, is getting the manufacturers of leptin to set up the logistics to guarantee the supply.
"We thought it would happen six months ago," he said. "And it hasn't happened yet."
Why is his claim about leptin such a surprise? Since 1921, when researchers first linked what is now known as Type 1 diabetes to a lack of insulin, doctors have assumed that the only successful treatment replaced insulin, usually through multiple daily injections. Insulin is used by more than a million Type 1 diabetics in the United States.
Insulin is normally produced by specialized "beta" cells in the pancreas that respond to the level of sugar in the bloodstream. The hormone has at least two functions:
• It acts like a key to a locking gas cap, letting many kinds of cells absorb sugar from the blood to use for fuel.
• Insulin also sits on the opposite side of a biochemical teeter-totter from a hormone called glucagon. Glucagon tells liver cells to dump storage supplies of sugar into the bloodstream, providing more fuel as needed. At higher levels, it signals cells to convert amino acids and fats into fuel – basically telling the body to "burn" muscle and fat.
In Type 1 diabetes, which affects about a million people in the United States, the body's immune system mistakenly kills the beta cells – and the ability of the body to produce insulin.
Without insulin on the other side of the teeter-totter, excess glucagon over-triggers the consumption of muscle and fat, which produces the wasting and rapidly fatal symptoms associated with untreated Type 1 diabetes, Dr. Unger said.
But Unger said that the dosage of insulin needed to treat Type 1 diabetes is much higher than what is normally produced, and therefore causes unwanted side effects – including hard-to-avoid large swings in blood sugar levels and possible increases in the effects of bad cholesterol on blood vessels in the heart. Those problems seem to be reduced in the leptin-injected mice, Unger said, even when a small amount of insulin was added to the treatment.
Leptin, discovered in 1994, has been tied to a wide range of body functions that range from appetite control to regulation of menstrual cycles. Several prior studies hinted at its ability to affect blood sugar, but Unger's team was the first to see if it worked without insulin.
Dr. Jeffrey Friedman, the researcher who first identified leptin, was the editor for the paper published today. For him, the most surprising part of the new paper is an indication that relatively low doses of leptin might be enough for treatment.
"It's an interesting result," he said.
Unger's research was funded by the Veterans Administration, the National Institute of Diabetes and Digestive and Kidney Diseases, and several private donors.
But he and other diabetes experts agree that leptin is a long way from becoming a practical treatment. Dr. Barbara Kahn, a diabetes expert at Harvard Medical School and chief of endocrinology at Beth Israel Deaconess Medical Center, was asked to co-author a commentary to run with Unger's new paper.
Among the challenges that Kahn says leptin therapy might face:
• Mice snack frequently on slow-digesting food. People eat meals a few times a day. Leptin levels that kept blood sugar stable in mice may not be able to handle the rapid ups and downs in blood sugar created by the human eating pattern.
• The mice used in the tests had a shortage of leptin. Most Type 1 diabetics have normal leptin levels. The amount of additional leptin needed to control blood sugar in people may induce significant side effects that are more damaging than those associated with insulin.
• Extra leptin could make it harder for a Type 1 diabetic to be aware of the dangerous condition of low blood sugar – and make it harder to return low blood sugar to normal levels.
And Kahn said that Unger's claim that leptin might reduce the risk of coronary artery disease rests on assumptions and a chain of reasoning that has not been proven in humans.
Despite all that, Kahn says there could be value in leptin treatment for diabetics if Unger's results prove out in people, perhaps used in addition to insulin. Maybe it could lower appetite or reduce the amount of insulin that diabetics now need to take, she said.
But the only way to find out is to test it.
"I would say it should be tried, but very cautiously," she said.
She and other experts agree that leptin is not likely to help people with the much more common Type 2 diabetes, a condition that mostly affects people who are overweight and have developed a resistance to both leptin and insulin.
Those issues aside, Unger's paper doesn't explain why leptin (or something else in those leptin-treated mice) works to handle one of insulin's key tasks: Getting sugar from the bloodstream into muscle and fat cells.
"We don't know the answer to that," Unger admitted.
[Abstract of the PNAS article. I was able to retrieve the full article without payment, perhaps because "This Feature Article is part of a series identified by the Editorial Board as reporting findings of exceptional significance."]
Leptin therapy in insulin-deficient type I diabetes
May-yun Wanga, Lijun Chena, Gregory O. Clarka, Young Leea, Robert D. Stevensb, Olga R. Ilkayevab, Brett R. Wennerb, James R. Bainb, Maureen J. Charronc, Christopher B. Newgardb, and Roger H. Ungera,d,1
+ Author Affiliations
aTouchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
bSarah W. Stedman Nutrition and Metabolism Center and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710;
cDepartment of Biochemistry and the Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461; and
dDepartment of General Medical Research, VA North Texas Health Care System, Dallas, TX 75216
Edited by Jeffrey M. Friedman, Howard Hughes Medical Institute/Rockefeller University, New York, NY, and approved January 12, 2010 (received for review October 7, 2009)
Abstract
In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes.
pnas.org |
