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Potential Diabetes Treatment Selectively Kills Autoimmune Cells From Human
Patients
ScienceDaily (Aug. 26, 2008) -
In experiments using blood cells from human patients with diabetes and other
autoimmune disorders, Massachusetts General Hospital (MGH) researchers have
confirmed the mechanism behind a potential new therapy for type 1 diabetes.
A team led by Denise Faustman, MD, PhD, director of the MGH Immunobiology
Laboratory, showed that blocking a metabolic pathway regulating the immune
system specifically eliminated immune cells that react against a patient's
own tissues.
Faustman and her colleagues previously discovered a technique that reversed
type 1 disease in a mouse model. The current study, which will appear in the
Proceedings of the National Academy of Sciences and has been released
online, is the first demonstration of this strategy in human cells and
supports the viability of a clinical trial that is currently underway.
"Our studies in mice showed that we could selectively kill the defective
autoimmune cells that were destroying insulin-producing islets," says
Faustman. "These results show that the same selective destruction can occur
in humans cells and connect what we saw in our animal studies with the
protocol we are pursuing in our Phase I clinical trial."
Type 1 diabetes and other autoimmune diseases are caused when the body's
immune cells mistakenly attack an individual's=2 0own cells. In several
studies over the past decade, Faustman's team showed that triggering the
expression of the immune-system modulator tumor necrosis factor (TNF) in
diabetic mice led to the death of the T cells responsible for destroying
insulin-producing pancreatic islets. After receiving this treatment, the
animals were able to regenerate healthy islet cells that produced normal
levels of insulin, effectively curing the animals' diabetes.
The current study used T cells from more than 1,000 patients with type 1
diabetes, other autoimmune disorders and healthy controls. First the
researchers found that treatment with TNF killed CD8 T cells, the immune
system's "killer" cells, from diabetic patients but not CD4 "helper" T
cells. TNF treatment also induced the death of CD8 T cells from other
autoimmune disease patients but had no negative effect on cells from healthy
controls.
Since TNF interacts with immune cells through two different receptors -
TNFR1 and TNFR2, which activate different signaling pathways - the
researchers next tested several TNF agonists, substances that mimic the
molecule's actions. One of those TNF agonists acts through TNFR1, which is
expressed on all T cells, and three act through TNFR2, only found on
subpopulations of T cells. While neither the TNFR1 agonist nor two of the
three substances that activate the TNFR2 pathway had any significant
effects, a third TNFR2 agonist induced cell death in particular CD8 cells
from patients with diabetes and other autoimmune disorder s. As with TNF
treatment, no cell death occurred in cells from healthy participants.
Further experiments with blood samples from several diabetic patients
revealed that the population of CD8 T cells responsible for the autoimmune
destruction of pancreatic islets consistently died after treatment with the
TNFR2 agonist, while similar cells from a non-diabetic proliferated.
However, CD8 cells from diabetic participants that were targeted against two
common viruses were not killed by exposure to the TNFR2 agonist, confirming
that the protocol only leads to the death of T cells responsible for an
autoimmune reaction.
The clinical trial based on Faustman's earlier studies is testing whether
use of bacillus Calmette-Guerin (BCG), a generic drug that temporarily
elevates TNF levels, will reduce autoimmune T cells in patients with type 1
diabetes. The current Phase 1 trial, which has been approved by the FDA and
is directed by David M. Nathan, MD, director of the MGH Diabetes Center,
focuses on determining the optimal dose and timing of BCG administration.
More information on the 18-month trial, which began in March, is available
at
http://www.faustmanlab.org/
Terminally Ill Rodents With Type 1 Diabetes Restored To Full Health With
Single Dose Of Leptin
ScienceDaily (Aug. 26, 2008) -
Terminally ill rodents with type 1 diabetes have been restored to fu ll
health with a single injection of a substance other than insulin by
scientists at UT Southwestern Medical Center.
Since the discovery of insulin in 1922, type 1 diabetes (insulin-dependent
diabetes) in humans has been treated by injecting insulin to lower high
blood sugar levels and prevent diabetic coma.
New findings by UT Southwestern researchers, which appear online and in a
future issue of the Proceedings of the National Academy of Sciences, suggest
that insulin isn't the only agent that is effective. Leptin, a hormone
produced by the body's fat cells, also lowers blood glucose levels and
maintains them in a normal range for extended periods, they found.
"The fact that these animals don't die and are restored to normal health
despite a total lack of insulin is hard for many researchers and clinicians
to believe," said Dr. Roger Unger, professor of internal medicine and senior
author of the study. "Many scientists, including us, thought it would be a
waste of time to give leptin in the absence of insulin. We've been
brainwashed into thinking that insulin is the only substance that can
correct the consequences of insulin deficiency."
The mechanism of leptin's glucose-lowering action appears to involve the
suppression of glucagon, a hormone produced by the pancreas that raises
glucose levels. Normally, glucagon is released when the glucose, or sugar,
level in the blood is low. In insulin deficiency, however, glucagon levels
are inappropriately high and cause t he liver to release excessive amounts
of glucose into the bloodstream. This action is opposed by insulin, which
tells the body's cells to remove sugar from the bloodstream.
In type 1 diabetes, which affects about 1 million people in the U.S., the
pancreatic islet cells that produce insulin are destroyed. Type 1 diabetics
must take insulin multiple times a day to metabolize blood glucose and
regiment their diets. In comparison, patients with non-insulin dependent, or
type 2, diabetes make insulin, but their bodies don't respond well to it.
Type 2 diabetes affects between 18 million and 20 million people in this
country.
In the current study, researchers tested for the first time whether a single
injection of the leptin gene given to insulin-deficient mice and rats on the
verge of death from diabetic coma could reverse the severe condition and
prevent the animals from dying. The animals that received the leptin gene
began producing excessive amounts of leptin, which reversed all the
measurable consequences of type 1 diabetes including weight loss,
hyperglycemia and ketoacidosis, a potentially fatal condition that develops
when the body doesn't have enough insulin to meet basic metabolic
requirements. Much of the effect was mediated by complete suppression of the
high glucagon levels, said Dr. Xinxin Yu, assistant instructor of internal
medicine and lead author of the study.
"These animals were actually dying," Dr. Yu said. "But if we gave them the
leptin gene, within two weeks, the terminally ill rodents were restored to
full health without any other treatment."
Dr. Unger said it's too premature to know whether leptin might someday
replace insulin as a treatment for diabetic patients, but this study
demonstrates that leptin could at least handle some of insulin's job
requirements and do it for longer periods of time. Injected insulin is
biologically active for only three to four hours.
"My hope is that you could give leptin for one type of action - glucagon's
suppression, for example - and insulin for another. Or perhaps give a
substance other than insulin entirely," Dr. Unger said. "What would be a
tremendous advance would be the ability to give an oral agent that
suppresses glucagon without injections."
Dr. Yu said the research team hypothesizes that leptin combats diabetes not
only be suppressing glucagon's action on the liver, but also by boosting the
insulin-like actions of IGF-1 (insulin-like growth factor-1), a hormone that
promotes growth and mimics insulin.
"One of the things that happens when a child gets type 1 diabetes is their
growth is stunted until they're given insulin," Dr. Unger said. "The same is
true with these mice. However, we found that if you take a diabetic rat
that's not receiving insulin and make it hyperleptinemic, it almost catches
up growthwise."
While the treated animals' blood glucose levels inched back up over time,
their hyperglycemia (high blood sugar) consistently remained well=2 0below
the elevated pre-treatment levels. The untreated rodents, on the other hand,
died within two or three days. The researchers tracked the treated rodents
for 25 weeks.
The next step is to study other potential glucagon suppressants and begin
leptin clinical trials within the next year.
Other UT Southwestern researchers involved in the study were Dr. May-Yun
Wang, assistant professor of internal medicine; Dr. Zhao Wang, postdoctoral
researcher in internal medicine; and former postdoctoral fellow Dr.
Byung-Hyun Park.
The work was supported by the National Institute of Diabetes and Digestive
and Kidney Diseases, the Department of Veterans Affairs, and the Juvenile
Diabetes Research Foundation.
Adapted from materials provided by UT Southwestern Medical Center
http://www.swmed.edu/
Patients
ScienceDaily (Aug. 26, 2008) -
In experiments using blood cells from human patients with diabetes and other
autoimmune disorders, Massachusetts General Hospital (MGH) researchers have
confirmed the mechanism behind a potential new therapy for type 1 diabetes.
A team led by Denise Faustman, MD, PhD, director of the MGH Immunobiology
Laboratory, showed that blocking a metabolic pathway regulating the immune
system specifically eliminated immune cells that react against a patient's
own tissues.
Faustman and her colleagues previously discovered a technique that reversed
type 1 disease in a mouse model. The current study, which will appear in the
Proceedings of the National Academy of Sciences and has been released
online, is the first demonstration of this strategy in human cells and
supports the viability of a clinical trial that is currently underway.
"Our studies in mice showed that we could selectively kill the defective
autoimmune cells that were destroying insulin-producing islets," says
Faustman. "These results show that the same selective destruction can occur
in humans cells and connect what we saw in our animal studies with the
protocol we are pursuing in our Phase I clinical trial."
Type 1 diabetes and other autoimmune diseases are caused when the body's
immune cells mistakenly attack an individual's=2 0own cells. In several
studies over the past decade, Faustman's team showed that triggering the
expression of the immune-system modulator tumor necrosis factor (TNF) in
diabetic mice led to the death of the T cells responsible for destroying
insulin-producing pancreatic islets. After receiving this treatment, the
animals were able to regenerate healthy islet cells that produced normal
levels of insulin, effectively curing the animals' diabetes.
The current study used T cells from more than 1,000 patients with type 1
diabetes, other autoimmune disorders and healthy controls. First the
researchers found that treatment with TNF killed CD8 T cells, the immune
system's "killer" cells, from diabetic patients but not CD4 "helper" T
cells. TNF treatment also induced the death of CD8 T cells from other
autoimmune disease patients but had no negative effect on cells from healthy
controls.
Since TNF interacts with immune cells through two different receptors -
TNFR1 and TNFR2, which activate different signaling pathways - the
researchers next tested several TNF agonists, substances that mimic the
molecule's actions. One of those TNF agonists acts through TNFR1, which is
expressed on all T cells, and three act through TNFR2, only found on
subpopulations of T cells. While neither the TNFR1 agonist nor two of the
three substances that activate the TNFR2 pathway had any significant
effects, a third TNFR2 agonist induced cell death in particular CD8 cells
from patients with diabetes and other autoimmune disorder s. As with TNF
treatment, no cell death occurred in cells from healthy participants.
Further experiments with blood samples from several diabetic patients
revealed that the population of CD8 T cells responsible for the autoimmune
destruction of pancreatic islets consistently died after treatment with the
TNFR2 agonist, while similar cells from a non-diabetic proliferated.
However, CD8 cells from diabetic participants that were targeted against two
common viruses were not killed by exposure to the TNFR2 agonist, confirming
that the protocol only leads to the death of T cells responsible for an
autoimmune reaction.
The clinical trial based on Faustman's earlier studies is testing whether
use of bacillus Calmette-Guerin (BCG), a generic drug that temporarily
elevates TNF levels, will reduce autoimmune T cells in patients with type 1
diabetes. The current Phase 1 trial, which has been approved by the FDA and
is directed by David M. Nathan, MD, director of the MGH Diabetes Center,
focuses on determining the optimal dose and timing of BCG administration.
More information on the 18-month trial, which began in March, is available
at
http://www.faustmanlab.org/
Terminally Ill Rodents With Type 1 Diabetes Restored To Full Health With
Single Dose Of Leptin
ScienceDaily (Aug. 26, 2008) -
Terminally ill rodents with type 1 diabetes have been restored to fu ll
health with a single injection of a substance other than insulin by
scientists at UT Southwestern Medical Center.
Since the discovery of insulin in 1922, type 1 diabetes (insulin-dependent
diabetes) in humans has been treated by injecting insulin to lower high
blood sugar levels and prevent diabetic coma.
New findings by UT Southwestern researchers, which appear online and in a
future issue of the Proceedings of the National Academy of Sciences, suggest
that insulin isn't the only agent that is effective. Leptin, a hormone
produced by the body's fat cells, also lowers blood glucose levels and
maintains them in a normal range for extended periods, they found.
"The fact that these animals don't die and are restored to normal health
despite a total lack of insulin is hard for many researchers and clinicians
to believe," said Dr. Roger Unger, professor of internal medicine and senior
author of the study. "Many scientists, including us, thought it would be a
waste of time to give leptin in the absence of insulin. We've been
brainwashed into thinking that insulin is the only substance that can
correct the consequences of insulin deficiency."
The mechanism of leptin's glucose-lowering action appears to involve the
suppression of glucagon, a hormone produced by the pancreas that raises
glucose levels. Normally, glucagon is released when the glucose, or sugar,
level in the blood is low. In insulin deficiency, however, glucagon levels
are inappropriately high and cause t he liver to release excessive amounts
of glucose into the bloodstream. This action is opposed by insulin, which
tells the body's cells to remove sugar from the bloodstream.
In type 1 diabetes, which affects about 1 million people in the U.S., the
pancreatic islet cells that produce insulin are destroyed. Type 1 diabetics
must take insulin multiple times a day to metabolize blood glucose and
regiment their diets. In comparison, patients with non-insulin dependent, or
type 2, diabetes make insulin, but their bodies don't respond well to it.
Type 2 diabetes affects between 18 million and 20 million people in this
country.
In the current study, researchers tested for the first time whether a single
injection of the leptin gene given to insulin-deficient mice and rats on the
verge of death from diabetic coma could reverse the severe condition and
prevent the animals from dying. The animals that received the leptin gene
began producing excessive amounts of leptin, which reversed all the
measurable consequences of type 1 diabetes including weight loss,
hyperglycemia and ketoacidosis, a potentially fatal condition that develops
when the body doesn't have enough insulin to meet basic metabolic
requirements. Much of the effect was mediated by complete suppression of the
high glucagon levels, said Dr. Xinxin Yu, assistant instructor of internal
medicine and lead author of the study.
"These animals were actually dying," Dr. Yu said. "But if we gave them the
leptin gene, within two weeks, the terminally ill rodents were restored to
full health without any other treatment."
Dr. Unger said it's too premature to know whether leptin might someday
replace insulin as a treatment for diabetic patients, but this study
demonstrates that leptin could at least handle some of insulin's job
requirements and do it for longer periods of time. Injected insulin is
biologically active for only three to four hours.
"My hope is that you could give leptin for one type of action - glucagon's
suppression, for example - and insulin for another. Or perhaps give a
substance other than insulin entirely," Dr. Unger said. "What would be a
tremendous advance would be the ability to give an oral agent that
suppresses glucagon without injections."
Dr. Yu said the research team hypothesizes that leptin combats diabetes not
only be suppressing glucagon's action on the liver, but also by boosting the
insulin-like actions of IGF-1 (insulin-like growth factor-1), a hormone that
promotes growth and mimics insulin.
"One of the things that happens when a child gets type 1 diabetes is their
growth is stunted until they're given insulin," Dr. Unger said. "The same is
true with these mice. However, we found that if you take a diabetic rat
that's not receiving insulin and make it hyperleptinemic, it almost catches
up growthwise."
While the treated animals' blood glucose levels inched back up over time,
their hyperglycemia (high blood sugar) consistently remained well=2 0below
the elevated pre-treatment levels. The untreated rodents, on the other hand,
died within two or three days. The researchers tracked the treated rodents
for 25 weeks.
The next step is to study other potential glucagon suppressants and begin
leptin clinical trials within the next year.
Other UT Southwestern researchers involved in the study were Dr. May-Yun
Wang, assistant professor of internal medicine; Dr. Zhao Wang, postdoctoral
researcher in internal medicine; and former postdoctoral fellow Dr.
Byung-Hyun Park.
The work was supported by the National Institute of Diabetes and Digestive
and Kidney Diseases, the Department of Veterans Affairs, and the Juvenile
Diabetes Research Foundation.
Adapted from materials provided by UT Southwestern Medical Center
http://www.swmed.edu/
How I wish it would work on our doggies
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