Scientists Step Closer To Helping Diabetics Regenerate Insulin Making Cells

[From Scientists Step Closer To Helping Diabetics Regenerate Insulin Making Cells]

Scientists Discover Leptin Can Also Aid Type 1 Diabetics

Terminally ill rodents with type 1 diabetes have been restored to full health with a single injection of a substance other than insulin by UT Southwestern Medical Center scientists.

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 appears in 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.”

[From Scientists Discover Leptin Can Also Aid Type 1 Diabetics]

Diabetes researchers convert pancreas cells to produce insulin – Los Angeles Times

Injecting a cocktail of proteins directly into the bodies of diabetic mice, researchers have converted normal pancreas cells into insulin-producing cells — a genetic transformation that could pave the way for treating intractable diseases and injuries using a patient’s own supply of healthy tissue.

The Harvard University scientists activated a trio of dormant genes that commanded the cells to transform themselves, much as a person might upload a new operating system onto a computer to change a PC into a Mac.

Within 10 days, the pancreas cells ceased their normal function — making gut enzymes to digest food — and instead produced insulin to regulate blood sugar, according to a study published online Wednesday in the journal Nature.

Doug Melton, co-director of the Harvard Stem Cell Institute and the study’s senior author, said the same approach could be used to generate motor neurons for patients with amyotrophic lateral sclerosis, to make cardiac muscle cells for heart attack victims or to create other crucial cells that can repair damage wrought by a range of illnesses.

“We were able to flip the cell from one state into another,” Melton said, adding that the approach should be useful in treating disorders in “any case where there’s a cell type missing and there are neighboring cells that are still healthy.”

The method has been tested only in mice and is at least two to five years from being tried in humans, he said. Applying the technique to other diseases will involve a tedious process of searching for the right combinations of dormant genes and the most effective means of turning them on.

Still, Patricia Kilian, who heads regeneration therapy research at the Juvenile Diabetes Research Foundation, said the technique would sidestep some of the complexities inherent in the highly touted but controversial research involving embryonic stem cells.

“You wouldn’t be transplanting cells, so you wouldn’t be dealing with immune issues,” she said, calling the research remarkable and “very unexpected.”

The process, which the researchers call direct reprogramming, relies on the fact that all cells contain a complete library of genes in their DNA.

As cells mature, different genes are turned on and off through a still-mysterious process that ultimately leads to the creation of a muscle fiber, neuron, cardiomyocyte or some other type of cell.

When certain types of cells are damaged or destroyed, there is no easy way to replace them.

Over the last decade, scientists have focused on stem cells as a solution because of their natural ability to grow into new tissues that can be transplanted into patients.

Of particular interest were embryonic stem cells, which can grow into any type of cell in the body with the proper chemical prodding — though figuring out those regimens has not always been easy. The research was also controversial because the cells had to be harvested from days-old embryos, which were destroyed in the process.

In recent months, researchers have embraced a new technique that involves rewinding adult cells to an embryonic state by turning on a set of four genes that are active during early development.

The Harvard researchers wondered if they could find a shortcut.

“We just asked, sort of like an undergraduate, the simple question, ‘Why should you have to go all the way back to the beginning? Could you go directly from one cell type to another?’ ” Melton said.

They chose to study diabetes, a disease that has been a central focus of stem cell research.

Patients with Type 1 diabetes need new beta cells to make insulin because their original beta cells have been destroyed by their immune systems.

Insulin is crucial for metabolizing sugar, and without it, patients must monitor their blood-sugar levels every few hours and inject themselves with insulin up to five times a day.

Melton said he is obsessed with finding a way to treat patients with Type 1 diabetes, including his own children Emma and Sam.

“I wake up every day thinking about how to make beta cells,” he said.

Once he decided to try direct reprogramming, his team identified nine key genes that are active in mature beta cells and their close relatives.

They started turning them on and off using specialized proteins, known as transcription factors, that bind to specific parts of DNA. Every possible combination was tried to determine which were necessary to make insulin-producing cells. The researchers ultimately determined that only three were essential to the process, and they were activated by the proteins Ngn3, Pdx1 and Mafa.

The researchers injected mice with a virus that specifically infects pancreatic exocrine cells, the type that make up about 95% of the pancreas. The proteins carried by the virus turned on the dormant genes.

Three days later, the cells started making small amounts of insulin. After 10 days, up to 20% of the exocrine cells had lost their cobblestone appearance and took on the distinctive spindle shape of beta cells. Their insulin production was comparable to that of normal beta cells, the study said.

To test their therapeutic potential, the researchers turned dozens of mice into Type 1 diabetics by wiping out their beta cells. Animals that were treated with the three proteins showed a significant improvement in their fasting blood glucose levels compared with controls that got a placebo.

The process turned out to be faster and more efficient than methods involving stem cells, the study found.

The transformation should also be safer than methods involving immature stem cells, which have a tendency to grow into tumors, said Konrad Hochedlinger, a scientist at the Harvard Stem Cell Institute who was not involved in the research.

He said he expected to see “many more examples” of direct reprogramming that target diseases and injuries, although each would require its own search for the exact combination of tissues, proteins and genes needed to create the biological repair kits.

[From Diabetes researchers convert pancreas cells to produce insulin - Los Angeles Times]

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 full 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 the 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 below 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.

Diabetes without insulin injections

A research team headed by Prof. Park Byung-hyun of Korea’s Chonbuk University and Prof. Roger Unger of the Southwestern Medical Center at the University of Texas said they observed drops in the blood sugar levels of mice infected with type 1 diabetes through the injection of leptin, a protein hormone, in an article published Tuesday in the Proceedings of the National Academy of Sciences.

The lowered blood sugar level was maintained 10 to 80 days, and the result implies leptin can be a key factor in controlling blood sugar metabolism, thus laying the foundation to finding a way to control diabetes without using insulin, the team said.

Leptin, secreted from fat tissues of the body, is known to be significant in regulating energy intake in appetite and expenditure through metabolism.

In the study, the increased leptin level in the mice seems to work for sugar control in the blood by constraining the formation and secretion of glucagons, a hormone involved in carbohydrate metabolism, it said.

Glucagon is produced in the pancreas and released when the glucose level in the blood is low, causing the liver to convert stored glycogen into glucose and release it into the bloodstream to raise the sugar level.

“This means the activity of glucagons can be restrained or blocked by leptin and, in other words, that type 1 diabetes can be preventable or curable with its use,” Prof. Park said.

Type 1 diabetes is characterized by loss of the insulin-producing beta cells, leading to a deficiency of insulin. The cell loss is mainly attributable to an autoimmune attack mediated by T-cells, which play a pivotal role in cell immunity. No specific preventive measure has been found yet against type 1 diabetes.

The disease is commonly referred to “juvenile diabetes” even though it affects both children and adults.

http://www.koreatimes.co.kr/www/news/biz/2008/08/123_30031.html

hckim@koreatimes.co.kr

Unique Drug Combination May Hold The Key To Reversing Type I Diabetes

ScienceDaily (June 12, 2008) — Promising results from a study that tested a new approach for reversing Type 1 diabetes are being presented at the American Diabetes Association’s 68th Annual Scientific Session in San Francisco.

The study tested the combination of Lisofylline (LSF), a drug that is being developed to halt immune damage to insulin producing cells, and Islet Neogenesis Associated Protein peptide (INGAP), a drug based on a naturally occurring protein produced by the pancreas.

The study was conducted at the University of Virginia by a team of scientists led by Jerry L. Nadler, M.D. Currently Director of Endocrinology and Metabolism at the University of Virginia, Nadler will join the faculty at Eastern Virginia Medical School (EVMS) in July as chair of the Department of Internal Medicine and head of the EVMS Strelitz Diabetes Center.

[From Unique Drug Combination May Hold The Key To Reversing Type I Diabetes]

Diabetes vaccine shows promise in mice: study

By Will Boggs, MD Thursday, Jun. 26, 2008; 3:27 AM

NEW YORK (Reuters Health) – A novel experimental vaccine targeting key immune system cells prevents and reverses “new-onset” diabetes in a mouse model, researchers report.

“Certainly, (this vaccine) will not ‘reverse’ disease in a person who has had diabetes for more than 5 years,” Dr. Nick Giannoukakis from University of Pittsburgh School of Medicine, Pennsylvania cautioned in comments to Reuters Health.

In the journal Diabetes, Giannoukakis and associates report that a single injection of the vaccine significantly delayed the onset of diabetes in the mice and 8 consecutive injections prevented the onset of diabetes altogether.

Similar studies in mice with established hyperglycemia (elevated blood sugar) showed that injection of the vaccine twice weekly for no more than 25 days could reverse new-onset hyperglycemia and maintain normal blood sugar levels after vaccine discontinuation.

The protein bits contained in the vaccine were previously shown to effectively enable human immune system cells called dendritic cells to suppress diabetes.

The vaccine will be tested for safety in volunteers with type 1 diabetes pending the completion of preliminary studies now in progress, Giannoukakis said. Once safety is confirmed, the vaccine’s ability to reverse newly diagnosed diabetes and to abrogate the evolution of silent type 1 diabetes into full-blown diabetes will be tested. “This we predict to begin by the end of 2010, early 2011,” Giannoukakis said.

SOURCE: Diabetes, June 2008.

Diabetes vaccine shows promise in mice: study

CTV.ca | Diabetes breakthrough may end insulin injections

Bioengineers at the University of Calgary have successfully grown insulin producing cells in a lab, marking a major breakthrough in diabetes research.

The team of scientists hope to eventually transplant lab grown, insulin producing cells directly into the bodies of patients with Type 1 diabetes.

Type 1 diabetes makes the body unable to produce enough insulin, requiring those suffering from the disease to inject themselves with the hormone.

In theory, the transplant would eliminate the need for daily insulin injections by patients who suffer from the disease.

“This transplant procedure

[From CTV.ca | Diabetes breakthrough may end insulin injections]

Type 1 diabetes vaccine goes into human studies – FierceVaccines

Researchers have begun human studies of a new vaccine that is designed to block or reverse type 1 diabetes. A team at Children’s Hospital in Pittsburgh is loading microspheres with nucleic acid. In an animal study, the spheres were injected into mice and absorbed by dendritic cells, preventing the cells from producing proteins that spur T cells to attack beta cells. That allowed the pancreas to make more insulin-producing beta cells, correcting the disease.

The researchers say this is a simpler dendritic-cell strategy that could conceivably only require a shot and annual booster injections to manage type 1 diabetes. Data is from human trials is expected in 2010.

“This is a very exciting approach because in many ways it simplifies what the dendritic-cell approach is all about,” Dr. Michael Clare-Salzler, a University of Florida endocrinologist, told the Pittsburgh Post-Gazette. “We’ve been the crazies in left field, but for me it makes ultimate sense.”

- check out the press release
- read the article in the Post-Gazette

New Vaccine Approach Prevents, Reverses Diabetes In Lab Study

ScienceDaily (May 29, 2008) — Microspheres carrying targeted nucleic acid molecules fabricated in the laboratory have been shown to prevent and even reverse new-onset cases of type 1 diabetes in animal models. The results of these studies were reported by diabetes researchers at the John G. Rangos Sr. Research Center at Children’s Hospital of Pittsburgh of UPMC and Baxter Healthcare Corporation.