HIV Drugs Interfere With Blood Sugar, Lead To Insulin Resistance

Main Category: HIV / AIDS
Also Included In: Endocrinology;??Biology / Biochemistry;??Diabetes
Article Date: 23 Nov 2010 - 2:00 PST window.fbAsyncInit = function() { FB.init({ appId: 'aa16a4bf93f23f07eb33109d5f1134d3', status: true, cookie: true, xfbml: true, channelUrl: 'http://www.medicalnewstoday.com/scripts/facebooklike.html'}); }; (function() { var e = document.createElement('script'); e.async = true; e.src = document.location.protocol + '//connect.facebook.net/en_US/all.js'; document.getElementById('fb-root').appendChild(e); }()); email to a friend ? printer friendly ? opinions ?

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

Please rate this article:
(Hover over the stars
then click to rate)

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

All opinions are moderated before being added.

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

View the original article here

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.

View the original article here

Combining aerobic and resistance training appears helpful for patients with diabetes

ScienceDaily (Nov. 23, 2010) ? Performing a combination of aerobic exercise and resistance training was associated with improved glycemic levels among patients with type 2 diabetes, compared to patients who did not exercise, according to a study in the November 24 issue of JAMA. The level of improvement was not seen among patients who performed either aerobic exercise or resistance training alone.

Although it is generally accepted that regular exercise provides substantial health benefits for individuals with type 2 diabetes, the exact exercise type (aerobic vs. resistance vs. both) has been unclear. "Given that the 2008 Federal Physical Activity Guidelines recommend aerobic exercise in combination with resistance training, the unanswered question as to whether for a given amount of time the combination of aerobic and resistance exercise is better than either alone has significant clinical and public health importance," the authors write.

Timothy S. Church, M.D., M.P.H., Ph.D., of Louisiana State University System, Baton Rouge, La., and colleagues conducted the HART-D trial, which compared among 262 sedentary women and men with type 2 diabetes the effect of aerobic training, resistance training, and a combination of both on change in hemoglobin A1c levels (HbA1c; a minor component of hemoglobin [the substance of red blood cells that carries oxygen to the cells] and to which glucose [blood sugar] is bound; HbA1c levels are used to monitor the control of diabetes mellitus). Study participants were 63.0 percent women, 47.3 percent nonwhite, average age of 56 years, HbA1c level of 7.7 percent and duration of diabetes of 7.1 years. The individuals were enrolled in the 9-month exercise program between April 2007 and August 2009. Forty-one participants were assigned to the nonexercise control group; 73 to resistance training sessions; 72 to aerobic exercise sessions; and 76 to combined aerobic and resistance training.

The researchers found that the absolute change in HbA1c in the combination training group vs. the control group was -0.34 percent. In neither the resistance training (-0.16 percent) nor the aerobic (-0.24 percent) groups were changes in HbA1c significant compared with those in the control group. The prevalence of increases in hypoglycemic medications were 39 percent in the control, 32 percent in the resistance training, 22 percent in the aerobic, and 18 percent in the combination training groups.

"Only the combination exercise group improved maximum oxygen consumption compared with the control group. All exercise groups reduced waist circumference from [-.75 to -1.1 inches] compared with the control group," the authors write. The resistance training group lost an average of 3.1 lbs. fat mass and the combination training group lost an average of 3.7 lbs., compared with the control group.

"The primary finding from this randomized, controlled exercise trial involving individuals with type 2 diabetes is that although both resistance and aerobic training provide benefits, only the combination of the 2 were associated with reductions in HbA1c levels," the researchers write. "It also is important to appreciate that the follow-up difference in HbA1c between the combination training group and the control group occurred even though the control group had increased its use of diabetes medications while the combination training group decreased its diabetes medication uses."

Editorial: Combined Aerobic and Resistance Exercise for Patients With Type 2 Diabetes

Ronald J. Sigal, M.D., M.P.H., of the University of Calgary, Alberta, Canada, and Glen P. Kenny, Ph.D., and Dr. Sigal of the University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, write in an accompanying editorial that this study provides important evidence on the effects of aerobic and resistance training on improving hemoglobin A1c levels.

"Based on the results of the HART-D trial, patients with type 2 diabetes who wish to maximize the effects of exercise on their glycemic control should perform both aerobic and resistance exercise. The HART-D trial clarifies that, given a specific amount of time to invest in exercise, it is more beneficial to devote some time to each form of exercise rather than devoting all the time to just one form of exercise."

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 JAMA and Archives Journals.

Journal Reference:

Timothy S. Church, MD, MPH, PhD; Steven N. Blair, PED; Shannon Cocreham, BS; Neil Johannsen, PhD; William Johnson, PhD; Kimberly Kramer, MPH; Catherine R. Mikus, MS; Valerie Myers, PhD; Melissa Nauta, BS; Ruben Q. Rodarte, MS, MBA; Lauren Sparks, PhD; Angela Thompson, MSPH; Conrad P. Earnest, PhD. Effects of Aerobic and Resistance Training on Hemoglobin A1c Levels in Patients With Type 2 Diabetes. JAMA, 2010;304(20):2253-2262 DOI: 10.1001/jama.2010.1710

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

View the original article here

Liver hormone is a cause of insulin resistance

ScienceDaily (Nov. 2, 2010) ? Researchers have identified a hormone produced and secreted by the liver as a previously unknown cause of insulin resistance. The findings, in the November issue of Cell Metabolism, a Cell Press publication, suggest a new target for the treatment of insulin resistance and type 2 diabetes, the researchers say.

"The current study sheds light on a previously underexplored function of the liver; the liver participates in the pathogenesis of insulin resistance through hormone secretion," said Hirofumi Misu of Kanazawa University Graduate School of Medical Science in Japan.

The researchers had discovered earlier that genes encoding secretory proteins are abundantly expressed in the livers of people with type 2 diabetes. On the basis of those findings, Misu and colleagues began to suspect that, similar to the role of fat tissue, the liver might contribute to the development of type 2 diabetes and insulin resistance via secretory proteins they call "hepatokines."

Now, the researchers report the results of comprehensive gene expression analyses, revealing that the liver expresses higher levels of the gene encoding selenoprotein P (SeP) in people with type 2 diabetes who are more insulin resistant. Blood levels of SeP are also increased in people with diabetes compared to healthy people.

Further studies in mice added support to the notion that the connection between SeP and insulin resistance is causal. When the researchers gave normal mice SeP, they became insulin resistant and their blood sugar levels rose. A treatment that blocked the activity of SeP in the livers of diabetic and obese mice improved their sensitivity to insulin and lowered blood sugar levels.

Misu said that SeP was known previously as a protein produced mainly in the liver, where it transports the essential trace element selenium from the liver to other parts of the body. But the protein's clinical significance and, more specifically, its role in glucose homeostasis weren't known.

In the development of insulin resistance, the researchers don't think SeP acts on its own. It is well known, they explain, that fat tissue is a main contributor to the development of insulin resistance by producing fat-derived hormones called adipokines. But they say they have preliminary evidence for a connection between SeP and adipokine production, which will be the subject of further investigation.

The new findings suggest that there may be other hormones derived from the liver with important and varied roles in the body, Misu and his colleague Toshinari Takamura add. "Our study raises the possibility that the liver functions as an endocrine organ by producing a variety of hepatokines and that the dysregulation or impairment of hepatokine production might contribute to the development of various diseases."

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 Cell Press, via EurekAlert!, a service of AAAS.

Journal Reference:

Hirofumi Misu, Toshinari Takamura, Hiroaki Takayama, Hiroto Hayashi, Naoto Matsuzawa-Nagata, Seiichiro Kurita, Kazuhide Ishikura, Hitoshi Ando, Yumie Takeshita, Tsuguhito Ota, Masaru Sakurai, Tatsuya Yamashita, Eishiro Mizukoshi, Taro Yamashita, Masao Honda, Ken-ichi Miyamoto, Tetsuya Kubota, Naoto Kubota, Takashi Kadowaki, Han-Jong Kim, In-kyu Lee, Yasuhiko Minokoshi, Yoshiro Saito, Kazuhiko Takahashi, Yoshihiro Yamada, Nobuyuki Takakura, Shuichi Kaneko. A Liver-Derived Secretory Protein, Selenoprotein P, Causes Insulin Resistance. Cell Metabolism, 2010; 12 (5): 483-495 DOI: 10.1016/j.cmet.2010.09.015

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

View the original article here

Insulin resistance may be associated with stroke risk

ScienceDaily (Oct. 12, 2010) ? Insulin resistance, a condition in which insulin produced by the body becomes less effective in reducing blood glucose levels, appears to be associated with an increased risk of stroke in individuals without diabetes, according to a report in the October issue of Archives of Neurology, one of the JAMA/Archives journals.

Insulin resistance originates from several factors, including genetics, a sedentary lifestyle and obesity, according to background information in the article. The condition contributes significantly to the risk of cardiovascular disease, but whether it predicts ischemic stroke (interruption in blood flow to the brain due to a blood clot or another artery blockage) is still a matter of debate.

One widely used tool to estimate insulin sensitivity is the homeostasis model assessment (HOMA), calculated using fasting blood glucose and fasting insulin levels. Tatjana Rundek, M.D., Ph.D., of Miller School of Medicine, University of Miami, and colleagues assessed insulin resistance using HOMA for 1,509 non-diabetic participants in the Northern Manhattan Study, a study assessing stroke risk, incidence and prognosis in a multi-ethnic urban community. Participants were followed for an average of 8.5 years.

During the follow-up period, vascular events occurred in 180 participants, including 46 who had fatal or non-fatal ischemic strokes, 45 who had fatal or non-fatal heart attacks and 121 who died of vascular causes. Individuals in the top one-fourth (quartile) of HOMA index had an increased risk of stroke compared to those in the other three quartiles of the HOMA index. Adjusting for established cardiovascular risk factors -- including glucose level, obesity and metabolic syndrome -- did not diminish the association. The relationship between insulin resistance and the risk of first stroke was stronger in men than women but did not vary by racial or ethnic group.

Individuals in the top quarter of insulin resistance had a 45 percent greater risk of any type of vascular event. However, insulin resistance was not associated with heart attack or vascular death separately.

"There are several possible reasons for the stronger effect of insulin resistance on the risk of ischemic stroke than of myocardial infarction in the present study compared within other studies," the authors write. It may be because individuals with a history of heart attack were excluded from this study, or because factors associated with insulin resistance -- including high blood pressure, high triglyceride levels and low HDL or "good" cholesterol levels -- are more significant risk factors for stroke than for heart attack.

"These findings emphasize the need to better characterize individuals at increased risk for ischemic stroke and the potential role of primary preventive therapies targeted at insulin resistance," the authors conclude.

Editorial: Insulin Resistance Can Be Used to Refine Risk Stratification

"The implications of these findings are exciting if insulin resistance can be proven to be a causal risk factor for stroke (rather than a marker of increased risk) because insulin resistance cannot only be measured but also treated," write Graeme J. Hankey, M.D., F.R.C.P., F.R.C.P.(Edin), F.R.A.C.P., of University of Western Australia, Perth, and Tan Ze Feng, M.D., of the First Affiliated Hospital of Jinan University, Guangzhou, China, and both also of Royal Perth Hospital, Perth, Australia, in an accompanying editorial.

"To establish a causal relationship between insulin resistance and stroke, it is necessary to not only show that insulin resistance is an independent, significant risk factor for stroke, as reported by Rundek et al, but also that removing or minimizing exposure to insulin resistance is associated with a reduction in the incidence of stroke," they write.

Clinical trials to establish this relationship are under way, they note. In the meantime, "we can take confidence from the study of Rundek et al that measuring insulin resistance may help refine prognostic estimates of future risk of stroke obtained by means of traditional risk stratification schemes. Although it is premature to widely screen for insulin resistance as a means to prevent stroke, its measurement may have a role in particular cases in which traditional risk stratification schemes suggest that the patient is at intermediate risk of stroke (rather than high or low risk) and in whom an additional finding of insulin resistance may be sufficiently compelling to supplement lifestyle advice with pharmacological interventions to lower stroke risk."

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 JAMA and Archives Journals.

Journal References:

T. Rundek, H. Gardener, Q. Xu, R. B. Goldberg, C. B. Wright, B. Boden-Albala, N. Disla, M. C. Paik, M. S. V. Elkind, R. L. Sacco. Insulin Resistance and Risk of Ischemic Stroke Among Nondiabetic Individuals From the Northern Manhattan Study. Archives of Neurology, 2010; 67 (10): 1195 DOI: 10.1001/archneurol.2010.235G. J. Hankey, T. Z. Feng. Insulin Resistance a Possible Causal and Treatable Risk Factor for Ischemic Stroke. Archives of Neurology, 2010; 67 (10): 1177 DOI: 10.1001/archneurol.2010.252

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

View the original article here