Diabetes may clamp down on cholesterol the brain needs

ScienceDaily (Dec. 1, 2010) ? The brain contains more cholesterol than any other organ in the body, has to produce its own cholesterol and won't function normally if it doesn't churn out enough. Defects in cholesterol metabolism have been linked with Alzheimer's disease and other neurodegenerative conditions. Now researchers at Joslin Diabetes Center have discovered that diabetes can affect how much cholesterol the brain can make.

Scientists in the laboratory of C. Ronald Kahn, M.D., head of Joslin's Integrative Physiology and Metabolism research section, found that brain cholesterol synthesis, the only source of cholesterol for the brain, drops in several mouse models of diabetes. Their work was reported online in the journal Cell Metabolism on November 30.

"Since cholesterol is required by neurons to form synapses (connections) with other cells, this decrease in cholesterol could affect how nerves function for appetite regulation, behavior, memory and even pain and motor activity," says Dr. Kahn, who is also Mary K. Iacocca Professor of Medicine at Harvard Medical School. "Thus, this has broad implications for people with diabetes." Other investigations have gathered strong evidence that people with diabetes may display varying types of alterations in brain function or ways of responding to stress, he points out.

"It is well known that insulin and diabetes play an important role in regulating cholesterol synthesis in the liver, where most of the cholesterol circulating in blood comes from," Dr. Kahn adds. "But nobody had ever suspected that insulin and diabetes would play an important role in cholesterol synthesis in the brain."

In addition to its potential role in Alzheimer's disease and other forms of neurological dysfunction, the newly discovered mechanism may play a role in diabetic neuropathy, which remains a large challenge for therapy.

People with diabetes are also known to be more prone to depression, memory loss and eating disorders than people without diabetes, and imaging studies have shown that people with diabetes have altered brain function compared to those without.

Additionally, the finding raises a question about potential interactions between anti-cholesterol drugs and diabetes.

In the Joslin study, scientists first examined gene expression in the hypothalamus of a mouse model of insulin-deficient (type 1) diabetes. They found decreased expression for almost all of the genes of cholesterol synthesis, including a gene called SREBP-2, which acts as a master regulator for cholesterol production. Similar findings were present in the cerebral cortex and other regions of the brain in these animals and also found in several other mouse models of diabetes. In the insulin-deficient animals, this phenomenon was associated with decreased cholesterol synthesis. Treatment of the mice with insulin, either by normal injection or injection into the fluid surrounding the brain, reversed the process.

"Our studies showed that these effects occurred in both the neurons and supporting 'glial' cells that help provide some nutrients to the neurons," says Kahn. "Ultimately this affects the amount of cholesterol that can get into the membranes of the neuron, which form the synapses and the synaptic vesicles -- the small structures that contain neurotransmitters."

Additionally, the Joslin work showed a connection between the decrease in brain cholesterol synthesis and appetite. When the scientists took normal mice and temporarily reduced cholesterol creation in the hypothalamus with a technique known as RNA interference, the animals started eating more and gained significant weight. Previous studies by other labs have demonstrated that diabetes may affect brain hormones involved in appetite regulation.

Ryo Suzuki, Ph.D., a postdoctoral researcher in the Kahn lab, is first author on the paper. Other Joslin contributors include Kevin Lee and Enxuan Jing. Other co-authors include Sudha B. Biddinger of Children's Hospital Boston, Jeffrey G. McDonald of the University of Texas Southwestern Medical Center, and Thomas J. Montine and Suzanne Craft of the University of Washington in Seattle. The work was supported by the National Institutes for Health, the Iacocca Foundation and the Manpei Suzuki Diabetes Foundation.

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 Joslin Diabetes Center, via EurekAlert!, a service of AAAS.

Journal Reference:

Ryo Suzuki, Kevin Lee, Enxuan Jing, Sudha B. Biddinger, Jeffrey G. McDonald, Thomas J. Montine, Suzanne Craft, C. Ronald Kahn. Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism. Cell Metabolism, Volume 12, Issue 6, 567-579, 1 December 2010 DOI: 10.1016/j.cmet.2010.11.006

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

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Diabetes Affects Brain Cholesterol

Posted on: Tuesday, 30 November 2010, 14:23 CST

Researchers at Joslin Diabetes Center have discovered that diabetes is able to affect how much cholesterol the brain is able to produce.

Scientists have discovered that brain cholesterol synthesis, which is the only source of cholesterol for the brain, dropped in several mouse models of diabetes.?

"Since cholesterol is required by neurons to form synapses (connections) with other cells, this decrease in cholesterol could affect how nerves function for appetite regulation, behavior, memory and even pain and motor activity," says Dr. Kahn, who is also Mary K. Iacocca Professor of Medicine at Harvard Medical School.? "Thus, this has broad implications for people with diabetes."

Kahn wrote in the journal Cell Metabolism that other research has found that people with diabetes may display varying types of alterations in brain function or ways of responding to stress.

"It is well known that insulin and diabetes play an important role in regulating cholesterol synthesis in the liver, where most of the cholesterol circulating in blood comes from," Kahn adds. "But nobody had ever suspected that insulin and diabetes would play an important role in cholesterol synthesis in the brain."

If the brain does not produce enough cholesterol, then it can lead to Alzheimer's disease and other neurodegenerative conditions.

The newly discovered mechanism may help play a role in diabetic neuropathy, which still remains a large challenge for therapy.

People with diabetes are also known to suffer from depression, memory loss and eating disorders.?

The researchers examined gene expression in the hypothalamus of a mouse with type-1 diabetes.? They found decreased expression for almost all of the genes of cholesterol synthesis, including a gene called SREBP-2, which acts as a master regulator for cholesterol production.?

The team also discovered that similar findings were present in the cerebral cortex and other regions of the brain in these animals.?

This phenomenon was associated with decreased cholesterol synthesis.? Treating the mice with insulin helps to reverse the process.

"Our studies showed that these effects occurred in both the neurons and supporting 'glial' cells that help provide some nutrients to the neurons," Kahn wrote. "Ultimately this affects the amount of cholesterol that can get into the membranes of the neuron, which form the synapses and the synaptic vesicles?the small structures that contain neurotransmitters."

He said that the results raise the prospect that cholesterol-lowering statins might have unintended consequences for the brain and its function.? The researchers said that earlier studies designed to look for a potential effect of statins on cognitive function in patients have yielded conflicting results.

---

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Diabetes may clamp down on brain cholesterol

Public release date: 30-Nov-2010
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Contact: Eric Bender
eric.bender@joslin.harvard.edu
617-309-2418
Joslin Diabetes Center

BOSTON ? November 30, 2010 ? The brain contains more cholesterol than any other organ in the body, has to produce its own cholesterol and won't function normally if it doesn't churn out enough. Defects in cholesterol metabolism have been linked with Alzheimer's disease and other neurodegenerative conditions. Now researchers at Joslin Diabetes Center have discovered that diabetes can affect how much cholesterol the brain can make.

Scientists in the laboratory of C. Ronald Kahn, M.D., head of Joslin's Integrative Physiology and Metabolism research section, found that brain cholesterol synthesis, the only source of cholesterol for the brain, drops in several mouse models of diabetes. Their work was reported online in the journal Cell Metabolism on November 30.

"Since cholesterol is required by neurons to form synapses (connections) with other cells, this decrease in cholesterol could affect how nerves function for appetite regulation, behavior, memory and even pain and motor activity," says Dr. Kahn, who is also Mary K. Iacocca Professor of Medicine at Harvard Medical School. "Thus, this has broad implications for people with diabetes." Other investigations have gathered strong evidence that people with diabetes may display varying types of alterations in brain function or ways of responding to stress, he points out.

"It is well known that insulin and diabetes play an important role in regulating cholesterol synthesis in the liver, where most of the cholesterol circulating in blood comes from," Dr. Kahn adds. "But nobody had ever suspected that insulin and diabetes would play an important role in cholesterol synthesis in the brain."

In addition to its potential role in Alzheimer's disease and other forms of neurological dysfunction, the newly discovered mechanism may play a role in diabetic neuropathy, which remains a large challenge for therapy.

People with diabetes are also known to be more prone to depression, memory loss and eating disorders than people without diabetes, and imaging studies have shown that people with diabetes have altered brain function compared to those without.

Additionally, the finding raises a question about potential interactions between anti-cholesterol drugs and diabetes.

In the Joslin study, scientists first examined gene expression in the hypothalamus of a mouse model of insulin-deficient (type 1) diabetes. They found decreased expression for almost all of the genes of cholesterol synthesis, including a gene called SREBP-2, which acts as a master regulator for cholesterol production. Similar findings were present in the cerebral cortex and other regions of the brain in these animals and also found in several other mouse models of diabetes. In the insulin-deficient animals, this phenomenon was associated with decreased cholesterol synthesis. Treatment of the mice with insulin, either by normal injection or injection into the fluid surrounding the brain, reversed the process.

"Our studies showed that these effects occurred in both the neurons and supporting 'glial' cells that help provide some nutrients to the neurons," says Kahn. "Ultimately this affects the amount of cholesterol that can get into the membranes of the neuron, which form the synapses and the synaptic vesicles?the small structures that contain neurotransmitters."

Additionally, the Joslin work showed a connection between the decrease in brain cholesterol synthesis and appetite. When the scientists took normal mice and temporarily reduced cholesterol creation in the hypothalamus with a technique known as RNA interference, the animals started eating more and gained significant weight. Previous studies by other labs have demonstrated that diabetes may affect brain hormones involved in appetite regulation.

Ryo Suzuki, Ph.D., a postdoctoral researcher in the Kahn lab, is first author on the paper. Other Joslin contributors include Kevin Lee and Enxuan Jing. Other co-authors include Sudha B. Biddinger of Children's Hospital Boston, Jeffrey G. McDonald of the University of Texas Southwestern Medical Center, and Thomas J. Montine and Suzanne Craft of the University of Washington in Seattle. The work was supported by the National Institutes for Health, the Iacocca Foundation and the Manpei Suzuki Diabetes Foundation.

About Joslin Diabetes Center

Joslin Diabetes Center is the world's preeminent diabetes research and clinical care organization. Joslin is dedicated to ensuring that people with diabetes live long, healthy lives and offers real hope and progress toward diabetes prevention and a cure. Founded in 1898 by Elliott P. Joslin, M.D., Joslin is an independent, nonprofit institution affiliated with Harvard Medical School. For more information about Joslin, visit www.joslin.org. Keep up with Joslin research and clinical news at Inside Joslin at www.joslin.org/news/inside_joslin.html, friend Joslin on Facebook at www.facebook.com/joslindiabetes and follow on Twitter at www.twitter.com/JoslinDiabetes.

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Diabetes May Clamp Down On Cholesterol The Brain Needs

Main Category: Diabetes
Also Included In: Neurology / Neuroscience;??Cholesterol
Article Date: 01 Dec 2010 - 3:00 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 brain contains more cholesterol than any other organ in the body, has to produce its own cholesterol and won't function normally if it doesn't churn out enough. Defects in cholesterol metabolism have been linked with Alzheimer's disease and other neurodegenerative conditions. Now researchers at Joslin Diabetes Center have discovered that diabetes can affect how much cholesterol the brain can make.

Scientists in the laboratory of C. Ronald Kahn, M.D., head of Joslin's Integrative Physiology and Metabolism research section, found that brain cholesterol synthesis, the only source of cholesterol for the brain, drops in several mouse models of diabetes. Their work was reported online in the journal Cell Metabolism on November 30.

"Since cholesterol is required by neurons to form synapses (connections) with other cells, this decrease in cholesterol could affect how nerves function for appetite regulation, behavior, memory and even pain and motor activity," says Dr. Kahn, who is also Mary K. Iacocca Professor of Medicine at Harvard Medical School. "Thus, this has broad implications for people with diabetes." Other investigations have gathered strong evidence that people with diabetes may display varying types of alterations in brain function or ways of responding to stress, he points out.

"It is well known that insulin and diabetes play an important role in regulating cholesterol synthesis in the liver, where most of the cholesterol circulating in blood comes from," Dr. Kahn adds. "But nobody had ever suspected that insulin and diabetes would play an important role in cholesterol synthesis in the brain."

In addition to its potential role in Alzheimer's disease and other forms of neurological dysfunction, the newly discovered mechanism may play a role in diabetic neuropathy, which remains a large challenge for therapy.

People with diabetes are also known to be more prone to depression, memory loss and eating disorders than people without diabetes, and imaging studies have shown that people with diabetes have altered brain function compared to those without.

Additionally, the finding raises a question about potential interactions between anti-cholesterol drugs and diabetes.

In the Joslin study, scientists first examined gene expression in the hypothalamus of a mouse model of insulin-deficient (type 1) diabetes. They found decreased expression for almost all of the genes of cholesterol synthesis, including a gene called SREBP-2, which acts as a master regulator for cholesterol production. Similar findings were present in the cerebral cortex and other regions of the brain in these animals and also found in several other mouse models of diabetes. In the insulin-deficient animals, this phenomenon was associated with decreased cholesterol synthesis. Treatment of the mice with insulin, either by normal injection or injection into the fluid surrounding the brain, reversed the process.

"Our studies showed that these effects occurred in both the neurons and supporting 'glial' cells that help provide some nutrients to the neurons," says Kahn. "Ultimately this affects the amount of cholesterol that can get into the membranes of the neuron, which form the synapses and the synaptic vesicles-the small structures that contain neurotransmitters."

Additionally, the Joslin work showed a connection between the decrease in brain cholesterol synthesis and appetite. When the scientists took normal mice and temporarily reduced cholesterol creation in the hypothalamus with a technique known as RNA interference, the animals started eating more and gained significant weight. Previous studies by other labs have demonstrated that diabetes may affect brain hormones involved in appetite regulation.

Ryo Suzuki, Ph.D., a postdoctoral researcher in the Kahn lab, is first author on the paper. Other Joslin contributors include Kevin Lee and Enxuan Jing. Other co-authors include Sudha B. Biddinger of Children's Hospital Boston, Jeffrey G. McDonald of the University of Texas Southwestern Medical Center, and Thomas J. Montine and Suzanne Craft of the University of Washington in Seattle. The work was supported by the National Institutes for Health, the Iacocca Foundation and the Manpei Suzuki Diabetes Foundation.

Source:
Joslin Diabetes Center

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Brain Might Be Key To Leptin's Actions Against Type 1 Diabetes, UT Southwestern Researchers Find

Main Category: Diabetes
Also Included In: Clinical Trials / Drug Trials
Article Date: 21 Oct 2010 - 1:00 PDT 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 ?

New findings by UT Southwestern Medical Center researchers suggest a novel role for the brain in mediating beneficial actions of the hormone leptin in type 1 diabetes.

"Our findings really pave the way for understanding the mechanism by which leptin therapy improves type 1 diabetes," said Dr. Roberto Coppari, assistant professor of internal medicine at UT Southwestern and senior author of the study involving laboratory mice. "Understanding the mechanism is important, because if we can determine how leptin drives these benefits, then we may be able to develop drugs that eliminate the need for insulin."

The findings are available online and will be published in a future issue of the Proceedings of the National Academy of Sciences.

Prior research by Dr. Roger Unger, professor of internal medicine at UT Southwestern, has shown that subcutaneous administration of leptin, a hormone produced by the body's fat cells, can restore terminally ill rodents with type 1 diabetes to full health. The underlying cellular mechanisms that caused that effect, however, have been unclear.

In the current study, the researchers injected leptin continuously into the brains of mice that lacked any naturally produced insulin. Lack of or reduced insulin production is the hallmark of type 1 diabetes in humans.

They found that infusing leptin into the lateral ventricle of the animals' brains reversed the lethal consequences of type 1 diabetes. The results establish the brain as a potentially critical site for mediating the metabolism-improving actions of leptin, Dr. Coppari said.

The team's findings also indicate the smallest amount of leptin required to normalize the animals' food intake, body weight and blood sugar levels.

A human clinical trial currently under way at UT Southwestern aims to determine whether adding leptin to standard insulin therapy might help rein in the tumultuous blood-sugar levels of people with type 1 diabetes.

"It might be that leptin treatment is not going to be effective or well-tolerated or that it might cause unwanted effects," Dr. Coppari said. "However, if we understand the mechanisms and how leptin improves type 1 diabetes, then perhaps we can develop alternatives to harness those mechanisms."

The next step, Dr. Coppari said, is to determine which specific nerve cells in the brain are responsible for the anti-type 1 diabetic actions of leptin.

"Living without insulin was once considered impossible, but our results have shown that it is possible when leptin receptor signaling in the brain is enhanced. If we can identify which neurons are responsible for driving the anti-type 1 diabetic actions of leptin, we may eventually develop better therapies for individuals with type 1 diabetes."

Other UT Southwestern researchers involved in the study were Dr. Teppei Fujikawa, lead author and postdoctoral researcher in internal medicine; and Drs. Jen-Chieh Chuang, Giorgio Ramadori and Ichiro Sakata, postdoctoral researchers in internal medicine.

The National Institutes of Health and the American Heart Association funded the study.

Source:
Kristen Holland Shear
UT Southwestern Medical Center

Please rate this article:
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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.

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

View the original article here

Brain might be key to leptin's actions against type 1 diabetes, researchers find

ScienceDaily (Oct. 19, 2010) ? New findings by UT Southwestern Medical Center researchers suggest a novel role for the brain in mediating beneficial actions of the hormone leptin in type 1 diabetes.

"Our findings really pave the way for understanding the mechanism by which leptin therapy improves type 1 diabetes," said Dr. Roberto Coppari, assistant professor of internal medicine at UT Southwestern and senior author of the study involving laboratory mice. "Understanding the mechanism is important, because if we can determine how leptin drives these benefits, then we may be able to develop drugs that eliminate the need for insulin."

The findings are available online and will be published in a future issue of the Proceedings of the National Academy of Sciences.

Prior research by Dr. Roger Unger, professor of internal medicine at UT Southwestern, has shown that subcutaneous administration of leptin, a hormone produced by the body's fat cells, can restore terminally ill rodents with type 1 diabetes to full health. The underlying cellular mechanisms that caused that effect, however, have been unclear.

In the current study, the researchers injected leptin continuously into the brains of mice that lacked any naturally produced insulin. Lack of or reduced insulin production is the hallmark of type 1 diabetes in humans.

They found that infusing leptin into the lateral ventricle of the animals' brains reversed the lethal consequences of type 1 diabetes. The results establish the brain as a potentially critical site for mediating the metabolism-improving actions of leptin, Dr. Coppari said.

The team's findings also indicate the smallest amount of leptin required to normalize the animals' food intake, body weight and blood sugar levels.

A human clinical trial currently under way at UT Southwestern aims to determine whether adding leptin to standard insulin therapy might help rein in the tumultuous blood-sugar levels of people with type 1 diabetes.

"It might be that leptin treatment is not going to be effective or well-tolerated or that it might cause unwanted effects," Dr. Coppari said. "However, if we understand the mechanisms and how leptin improves type 1 diabetes, then perhaps we can develop alternatives to harness those mechanisms."

The next step, Dr. Coppari said, is to determine which specific nerve cells in the brain are responsible for the anti-type 1 diabetic actions of leptin.

"Living without insulin was once considered impossible, but our results have shown that it is possible when leptin receptor signaling in the brain is enhanced. If we can identify which neurons are responsible for driving the anti-type 1 diabetic actions of leptin, we may eventually develop better therapies for individuals with type 1 diabetes."

Other UT Southwestern researchers involved in the study were Dr. Teppei Fujikawa, lead author and postdoctoral researcher in internal medicine; and Drs. Jen-Chieh Chuang, Giorgio Ramadori and Ichiro Sakata, postdoctoral researchers in internal medicine.

The National Institutes of Health and the American Heart Association funded the study.

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 UT Southwestern Medical Center, via EurekAlert!, a service of AAAS.

Journal Reference:

T. Fujikawa, J.-C. Chuang, I. Sakata, G. Ramadori, R. Coppari. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proceedings of the National Academy of Sciences, 2010; 107 (40): 17391 DOI: 10.1073/pnas.1008025107

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

View the original article here