Designing safer glucocorticoid drugs

ScienceDaily (Dec. 1, 2010) ? Glucocorticoid drugs are used widely to treat numerous conditions, including rheumatoid arthritis, allergic reactions, asthma, and some forms of cancer, and transplant recipients. The beneficial effects of these drugs are their potent antiinflammatory and immunosuppressive properties. However, their long-term use is limited by severe side effects, including high blood levels of glucose, fatty liver, and type 2 diabetes.

A team of researchers, led by Carolyn Cummins, at the University of Toronto, Ontario, has now shown that the protein LXR-beta is required in mice for glucocorticoid drugs to elicit many of their negative side effects. Importantly, although mice lacking LXR-beta did not develop high levels of blood glucose or fatty liver when administered a glucocorticoid drug, they did show all the signs of immunosuppression.

The authors therefore suggest that glucocorticoid drugs designed to selectively target the glucocorticoid receptor and not LXR-beta should be safer than those currently in clinical use.

The research appears in the Journal of Clinical Investigation.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Journal of Clinical Investigation, via EurekAlert!, a service of AAAS.

Journal Reference:

Rucha Patel, Monika Patel, Ricky Tsai, Vicky Lin, Angie L. Bookout, Yuan Zhang, Lilia Magomedova, Tingting Li, Jessica F. Chan, Conrad Budd, David J. Mangelsdorf, Carolyn L. Cummins. LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. Journal of Clinical Investigation, 2010; DOI: 10.1172/JCI41681

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HIV Drugs Interfere With Blood Sugar, Lead To Insulin Resistance

Main Category: HIV / AIDS
Also Included In: Endocrinology;??Biology / Biochemistry;??Diabetes
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The same powerful drugs that have extended the lives of countless people with HIV come with a price insulin resistance that can lead to diabetes and cardiovascular disease.

Now, researchers at Washington University School of Medicine in St. Louis have determined why that happens. Their research shows that HIV protease inhibitors directly interfere with the way blood sugar levels are controlled in the body. This leads to insulin resistance, a condition that occurs when the body produces enough insulin but doesn't use it properly.

This confirmation provides the potential to develop safer antiviral drugs.

Paul Hruz, MD, PhD, assistant professor of pediatrics and of cell biology and physiology at the School of Medicine, and his team found that first-generation protease inhibitors, including the drug ritonavir, block GLUT4, a protein that transports glucose from the blood into the cells where it is needed. This raises blood sugar levels a hallmark of diabetes.

"Our lab has established that one of the effects of these drugs is blocking glucose transport, one of most important steps in how insulin works," says Hruz, senior author of the study published in the Nov. 19 Journal of Biological Chemistry. "Now that we've identified the main mechanism, we will look to develop new drugs that treat HIV but don't cause diabetes."

Hruz's lab made the discovery in mice that lacked the GLUT4 protein. When researchers gave these mice ritonavir, the drug had no effect on their glucose tolerance. However, when they gave the drug to normal mice, their blood glucose shot up very quickly, showing that the drugs impair glucose tolerance and promote insulin resistance.

"What we saw were very acute effects on insulin sensitivity that we could reverse in the mice," Hruz says. "But when insulin resistance goes on for a long time, secondary changes develop, such as high triglycerides, and those are harder to reverse," he says.

The finding will help researchers better understand the role of glucose transporters in health and disease, including the epidemic of type 2 diabetes in HIV negative patients, says Hruz. He expects the results will help scientists better understand how to develop new diabetes drugs and the role of glucose transport in diseases such as heart failure.

Hruz and his team are now studying at the molecular level how the HIV drugs inhibit GLUT4.

"We'd like to figure out exactly how these drugs interact with the transporter to aid the development of better HIV drugs," he says. "We want to find problems in glucose transport that lead to diabetes in the preclinical stage of drug development."

The team already is working with a drug developer to create a new HIV drug that the virus does not develop resistance to and does not block GLUT4.

Source: Washington University in St. Louis

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HIV drugs interfere with blood sugar, lead to insulin resistance

ScienceDaily (Nov. 23, 2010) ? The same powerful drugs that have extended the lives of countless people with HIV come with a price -- insulin resistance that can lead to diabetes and cardiovascular disease.

Now, researchers at Washington University School of Medicine in St. Louis have determined why that happens. Their research shows that HIV protease inhibitors directly interfere with the way blood sugar levels are controlled in the body. This leads to insulin resistance, a condition that occurs when the body produces enough insulin but doesn't use it properly.

This confirmation provides the potential to develop safer antiviral drugs.

Paul Hruz, MD, PhD, assistant professor of pediatrics and of cell biology and physiology at the School of Medicine, and his team found that first-generation protease inhibitors, including the drug ritonavir, block GLUT4, a protein that transports glucose from the blood into the cells where it is needed. This raises blood sugar levels -- a hallmark of diabetes.

"Our lab has established that one of the effects of these drugs is blocking glucose transport, one of most important steps in how insulin works," says Hruz, senior author of the study published in the Nov. 19 Journal of Biological Chemistry. "Now that we've identified the main mechanism, we will look to develop new drugs that treat HIV but don't cause diabetes."

Hruz's lab made the discovery in mice that lacked the GLUT4 protein. When researchers gave these mice ritonavir, the drug had no effect on their glucose tolerance. However, when they gave the drug to normal mice, their blood glucose shot up very quickly, showing that the drugs impair glucose tolerance and promote insulin resistance.

"What we saw were very acute effects on insulin sensitivity that we could reverse in the mice," Hruz says. "But when insulin resistance goes on for a long time, secondary changes develop, such as high triglycerides, and those are harder to reverse," he says.

The finding will help researchers better understand the role of glucose transporters in health and disease, including the epidemic of type 2 diabetes in HIV negative patients, says Hruz. He expects the results will help scientists better understand how to develop new diabetes drugs and the role of glucose transport in diseases such as heart failure.

Hruz and his team are now studying at the molecular level how the HIV drugs inhibit GLUT4.

"We'd like to figure out exactly how these drugs interact with the transporter to aid the development of better HIV drugs," he says. "We want to find problems in glucose transport that lead to diabetes in the preclinical stage of drug development."

The team already is working with a drug developer to create a new HIV drug that the virus does not develop resistance to and does not block GLUT4.

Vyas A, Koster J, Tzekov A, Hruz, P. Effects of the HIV Protease Inhibitor Ritonavir on GLUT4 Knock-out Mice. Journal of Biological Chemistry. Nov. 19, 2010.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Washington University School of Medicine.

Journal Reference:

A. Kalla Vyas, J. C. Koster, A. Tzekov, P. W. Hruz. Effects of the HIV protease inhibitor ritonavir in GLUT4 knockout mice. Journal of Biological Chemistry, 2010; DOI: 10.1074/jbc.M110.176321

Note: If no author is given, the source is cited instead.

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Scientists learn more about how kidneys fail and how new drugs may intervene

ScienceDaily (Nov. 16, 2010) ? Scientists are learning more about how protein gets in the urine when the kidneys begin to fail and how a new drug blocks it.

"We have known for a long time that renal failure comes with protein in your urine, especially in diabetes," said Dr. David Pollock, renal physiologist at the Medical College of Georgia Vascular Biology Center. It's also known that a new class of drugs called endothelin A receptor antagonists reduce protein in the urine.

New research published in the journal Hypertension connects the two, providing more information about how new drugs under study for kidney failure work.

The scientists have shown in rats that increased levels of the peptide endothelin 1 -- characteristic of conditions such as diabetes and high-salt diets -- increase the permeability of tiny kidney filters. The filters recycle key components such as red and white blood cells and proteins, including albumin, that help keep blood vessels from leaking fluid.

The increased permeability causes the proteins to be eliminated in the urine, resulting in a double whammy that likely includes generalized body swelling and further kidney damage. "Without albumin, the fluid just goes into your tissue," Pollock said.

"This filter, which is like cheesecloth, gets damaged in kidney failure and so you get more of these proteins in your urine. Filters start scarring over, you lose the nephron (the filter and its associated kidney cells) and so the kidneys slowly die," he said.

And that's just part of the damage. High endothelin levels also trigger inflammation, sending out proinflammatory molecules that attract inflammatory cells like white blood cells and macrophages to the kidneys, MCG researchers have shown. They also have shown that endothelin A receptor antagonists reduce this inflammatory response.

"There has been no drug that really targets diabetic nephropathy," said Mohamed A. Saleh, MCG graduate student and the study's first author. The study provides more scientific evidence that the new endothelin A receptor antagonists may be the first class of drugs to fit that bill, said Saleh, noting that his native Egypt, like the United States, has an increasing problem with diabetes.

The positive results were achieved without affecting blood pressure, the scientists noted. Endothelin receptor antagonists are known to have health benefit but precisely why was an unknown, said Pollock, corresponding author on the study. "A lot of people thought they just lower blood pressure and anything that lowers blood pressure is going to make your kidneys feel better," he said.

Endothelin 1 has A and B receptors and whether the peptide hurts or helps generally depends on which receptor it activates. The B receptor is considered the good guy, helping the kidney eliminate excess sodium, for example. The A receptor is generally considered a trouble maker that interferes with sodium excretion, constricts blood vessels and promotes inflammation.

The MCG scientists want to compare A inhibitors to another new class of drugs that blocks both the A and B receptors.

The research was funded by the National Heart, Lung and Blood Institute and an American Heart Association predoctoral fellowship and Egyptian government grant to Saleh.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Medical College of Georgia, via EurekAlert!, a service of AAAS.

Journal Reference:

M. A. Saleh, E. I. Boesen, J. S. Pollock, V. J. Savin, D. M. Pollock. Endothelin-1 Increases Glomerular Permeability and Inflammation Independent of Blood Pressure in the Rat. Hypertension, 2010; DOI: 10.1161/HYPERTENSIONAHA.110.156570

Note: If no author is given, the source is cited instead.

View the original article here