RxPG News : NIDDM

Data support role for adult spleen cells in regeneration of beta cells

Fri, 24 Nov 2006 22:42:07 PST

( from http://www.rxpgnews.com ) New data published in the Nov. 24 issue of Science provide further support for a protocol to reverse type 1 diabetes in mice and new evidence that adult precursor cells from the spleen can contribute to the regeneration of beta cells. In 2001 and 2003, researchers at Massachusetts General Hospital (MGH) demonstrated the efficacy of a protocol to reverse of type 1 diabetes in diabetic mice. Three studies from other institutions published in the March 24, 2006 issue of Science confirmed that the MGH-developed protocol can reverse the underlying disease but were inconclusive on the role of spleen cells in the recovery of insulin-producing pancreatic islets. The new data from a study performed at the National Institutes of Health (NIH), published as a technical comment, provides additional confirmation of the ability to reverse type 1 diabetes and on the role of the spleen cells in islet regeneration.

"This data from the NIH and the earlier studies have added significantly to the understanding of how diabetes may be reversed," says Denise Faustman, MD, PhD, director of the Immunobiology Laboratory at Massachusetts General Hospital, primary author of the 2001 and 2003 studies and co-corresponding author of the current report. "It is still early, but it appears that there are multiple potential sources for regenerating islets. As a research community we should pursue all avenues. We're excited to see what will happen in humans."

In the 2001 and 2003 studies, Faustman and colleagues treated end-stage nonobese diabetic (NOD) mice with Freund's complete adjuvant, a substance that suppresses the activity of the immune cells that destroy islets in type 1 diabetes. They also introduced donor spleen cells to retrain the immune system not to attack islets and found that the protocol not only halted the immune destruction caused by diabetes but also allowed the insulin-producing pancreatic islet cells to regenerate. Evidence indicated that the spleen cells were the source of at least some of the regenerated islet cell and hastened the restoration of blood sugar levels.

The direct contribution of spleen cells to islet recovery, first described in the 2003 study, is confirmed in the current work. NIH researchers used cell lineage tracking in the form of Y-chromosomal fluorescence in situ hybridization (FISH), in combination with insulin staining, to follow the fate of male spleen cells transplanted into female recipients. The female mice that received male donor cells consistently showed Y-chromosome-positive insulin-producing islet cells, indicating that the introduced spleen cells contribute to islet recovery. The current study also showed that the degree of spleen cell contribution is influenced by mouse age at the start of treatment. Spleen cells appear to contribute to islet recovery more in mice who are older and with more advanced diabetes compared with younger mice with less advanced diabetes, in which regeneration of remaining islets may be the dominant mechanism.

Researchers reveal mechanisms behind Thiazolidinediones in type 2 diabetes

Sat, 11 Mar 2006 00:50:37 PST

( from http://www.rxpgnews.com ) Thiazolidinediones (TZD's) are drugs commonly prescribed to patients with type 2 diabetes, the most common form of diabetes. Current U.S. Food and Drug Administration-approved agents are known as Actos (pioglitazone) and Avandia (rosiglitazone). These oral agents improve blood glucose levels in people with diabetes by improving insulin action in the body. While it is known that these drugs work primarily by binding to a receptor in the nucleus of cells called Peroxisome Proliferator Activated Receptor-gamma (PPARg), all of the molecular signaling events important for the drugs to work are not completely understood.

A new study by researchers at Joslin Diabetes Center in Boston helps to explain how these drugs work. The manuscript appears in the March edition of the American Diabetes Association's journal Diabetes.

In a clinical research study, Joslin researchers Allison B. Goldfine, M.D., Sarah Crunkhorn, Ph.D., and Mary-Elizabeth Patti, M.D., examined muscle and fat tissue from patients with type 2 diabetes before and after they took the drug rosiglitazone. The researchers found that levels of two proteins called Necdin and E2F4, which are important in regulating cell replication, are altered in muscle and fat after patients took the drug for two months. Dr. Goldfine is an Investigator in Joslin's Section on Cellular and Molecular Physiology, Assistant Director of Clinical Research at Joslin and Assistant Professor of Medicine at Harvard Medical School. Dr. Patti is Director of Joslin's Genomics Core Lab and also an Investigator in Cellular and Molecular Physiology and Assistant Professor of Medicine, Harvard Medical School. Dr. Crunkhorn is a postdoctoral fellow in Dr. Patti's laboratory.

"Because the proteins are important in regulating the cell cycle, the findings suggest that the thiazolidinediones may work, in part, by altering the cell differentiation state, or level of cell maturity. Additionally, the two proteins Necdin and E2F4 may represent new drug targets that may be useful in the future for treatment of patients with diabetes," says Dr. Goldfine

High-fat diet supresses GnT-4a activity to cause type 2 diabetes

Fri, 30 Dec 2005 15:40:38 PST

( from http://www.rxpgnews.com ) Howard Hughes Medical Institute researchers have discovered a molecular link between a high-fat, Western-style diet, and the onset of type 2 diabetes. In studies in mice, the scientists showed that a high-fat diet disrupts insulin production, resulting in the classic signs of type 2 diabetes.

In an article published in the December 29, 2005, issue of the journal Cell, the researchers report that knocking out a single gene encoding the enzyme GnT-4a glycosyltransferase (GnT-4a ) disrupts insulin production. Importantly, the scientists showed that a high-fat diet suppresses the activity of GnT-4a and leads to type 2 diabetes due to failure of the pancreatic beta cells.

The experiments point to a mechanistic explanation for why failing pancreatic beta cells don't sense glucose properly and how that can lead to impaired insulin production, said Jamey Marth, a Howard Hughes Medical Institute investigator at the University of California, San Diego (UCSD). Marth and first author Kazuaki Ohtsubo at UCSD collaborated on the studies with researchers from the Kirin Brewery Co. Ltd., and the University of Fukui, both in Japan.

The discovery of the link between diet and insulin production offers new information that may aid in the development of treatments that target the early stages of type 2 diabetes. In its earliest phases, the disease causes failure of insulin-secreting beta cells in the pancreas, which leads to elevated blood glucose levels. As the disease progresses, the insulin-secreting beta cells overcompensate for the elevated blood glucose, and eventually pump out too much insulin. This leads to insulin resistance and full-blown type 2 diabetes.

The new studies suggest that people with an inherited predisposition to type 2 diabetes might have variations in the gene for GnT-4a, said the researchers. Worldwide, more than 200 million people have type 2 diabetes, and close to 20 million people in the United States have been diagnosed with the disorder.

Marth and his colleagues began their studies hoping to learn more about the function of protein glycosylation in the pancreas. They focused on the function of GnT-4a, in part, because it is highly expressed in the pancreas. GnT-4a is a type of enzyme known as a glycosyltransferase that attaches sugar-like molecules called glycans to proteins in a process called glycosylation. Glycans are essential for the proper function of many proteins.

GnT-4a was known to maintain glucose transporters on the surface of beta cells in the pancreas. Those transporters, such as Glut-2, play a crucial role in allowing the beta cell to sense how much glucose is in the blood. Transport of glucose across the cell membrane into pancreatic beta cells triggers insulin secretion.

The new studies showed that in the absence of sufficient GnT-4a enzyme, Glut-2 lacks an attached glycan that is required for it to be expressed at the cell membrane. Without that glycan, Glut-2 leaves the cell surface and becomes internalized, where it can no longer transport glucose into the cell. In turn, this failure impairs insulin secretion, causing type 2 diabetes in the mice.

"What was really astounding to us, however, was that when we fed normal mice a high-fat diet, we saw this same mechanism of pathogenesis with attenuation of GnT-4a enzyme levels, reduced Glut-2 glycosylation, and loss of cell surface Glut-2 expression," said Marth. "This finding may explain the loss of Glut-2 commonly observed in type 2 diabetes. For example, transcriptional control of GnT-4a expression may underlie the pathogenesis of type 2 diabetes in human mature onset diabetes of the young (MODY), and perhaps in response to leptin signaling deficiency in db mice."

In addition, variations in susceptibility to type 2 diabetes may result from inherited differences in the gene for GnT-4a that may ultimately affect its level or activity. These findings could have important clinical implications because reduced GnT-4a expression has been observed by other researchers in tissue samples from humans with diabetes. "If you could somehow stimulate production of this enzyme, you might be able to render animals, and perhaps humans, resistant to high-fat diet-induced diabetes," said Marth.

To explore such possible clinical applications, Marth and his colleagues are now testing whether over-expression of the GnT-4a gene in transgenic mice makes them resistant to diabetes induced by a high-fat diet or by transcriptional factor mutations that cause MODY.

"If our findings can be applied to humans, they should give us important insights into how type 2 diabetes may be prevented and treated," he said.

While a deficiency of insulin can cause diabetes, too much insulin can also be harmful, and has been found to contribute to the pathogenesis of cancer, cardiovascular disease, ovarian diseases, and Alzheimer's disease. "It may be that suppressing insulin production to some degree could be beneficial in such disorders, and that could theoretically be achieved by inhibiting the GnT-4a glycosyltransferase," Marth said.

Low blood glucose levels may complicate gastric bypass surgery

Tue, 25 Oct 2005 13:55:38 PST

( from http://www.rxpgnews.com ) Physicians monitoring patients who have undergone gastric bypass surgery should be on the alert for a new, potentially dangerous hypoglycemia (low blood glucose) complication that, while rare, may require quick treatment, according to a new study by collaborating researchers at Joslin Diabetes Center, Beth Israel Deaconess Medical Center (BIDMC), and Brigham and Women's Hospital (BWH) and published in the October issue of the journal Diabetologia. The paper follows on the heels of a Mayo Clinic report on six similar case studies published in July in the New England Journal of Medicine. About 160,000 people undergo gastric bypass surgery every year.

The study details the history of three patients, who did not have diabetes, who suffered such severe hypoglycemia following meals that they became confused and sometimes blacked out, in two cases causing automobile collisions. The immediate cause of hypoglycemia was exceptionally high levels of insulin following meals. All three patients in the collaborative study failed to respond to medication, and ultimately required partial or complete removal of the pancreas, the major source of insulin, to prevent dangerous declines in blood glucose.

"Severe hypoglycemia is a complication of gastric bypass surgery, and should be considered if the patient has symptoms such as confusion, lightheadedness, rapid heart rate, shaking, sweating, excessive hunger, bad headaches in the morning or bad nightmares," says Mary-Elizabeth Patti, M.D., Investigator in Joslin's Research Section on Cellular and Molecular Physiology and Assistant Professor of Medicine at Harvard Medical School. "If these symptoms don't respond to simple changes in diet, such as restricting intake of simple carbohydrates, patients should be evaluated hormonally, quickly," she adds. Dr. Patti and Allison B. Goldfine, M.D., also an Investigator at Joslin and Assistant Professor of Medicine at Harvard Medical School, were co-investigators of the study.

The study reported on three patients a woman in her 20s, another in her 60s and a man in his 40s. All three lost significant amounts of weight through gastric bypass surgery, putting them in the normal Body Mass Index (BMI) range. Each, however, developed postprandial hypoglycemia (low blood glucose after meals) that failed to respond to dietary or medical intervention. As a result, all patients required removal of part or all of the pancreas. In all three cases, it was found that the insulin-producing islet cells in their pancreases had proliferated abnormally.

A potential cause of this severe hypoglycemia in these patients is "dumping syndrome," a constellation of symptoms including palpitations, lightheadedness, abdominal cramping and diarrhea, explains Dr. Patti. Dumping syndrome occurs when the small intestine fills too quickly with undigested food from the stomach, as can happen following gastric bypass surgery. But the failure to respond to dietary and medical therapy, and the conditions worsening over time suggested that additional pathology was needed to explain the symptoms' severity, Dr. Patti adds. "The magnitude of the problem was way beyond what doctors typically call dumping syndrome," she says.

Other causes of postprandial hypoglycemia can include overactive islet cells, sometimes caused by excess numbers of cells, a tumor in the pancreas that produces too much insulin, or familial hyperinsulinism (hereditary production of too much insulin), which in severe cases can necessitate removal of the pancreas.

In patients following bariatric surgery, additional mechanisms may contribute to overproduction of insulin. "First, insulin sensitivity (responsiveness to insulin) improves after weight loss of any kind, and can be quite significant after successful gastric surgery," says Dr. Patti. "Second, weight gain and obesity are associated with increased numbers of insulin producing cells in the pancreas, and so some patients may not reverse this process normally, leaving them with inappropriately high numbers of beta cells."

Finally, after gastric bypass surgery, GLP1 (glucagon-like peptide 1) and other hormones are secreted in abnormal patterns in response to food intake, since the intestinal tract has been altered. High levels of GLP1 may stimulate insulin secretion further and cause increased numbers of insulin-producing cells. "In our patients, the fact that the post-operative onset of hyperinsulinemia was not immediate suggests that active expansion of the beta cell mass contributed to the condition," Dr. Patti adds.

Other researchers participating in the study included S. Bonner-Weir, Ph.D., of Joslin; E.C. Mun, M.D., J.J. Holst, M.D., J. Goldsmith, M.D., D.W. Hanto, M.D., Ph.D., M. Callery, M.D., of Beth Israel Deaconess Medical Center. Collaborating investigators from the Brigham and Women's Hospital included R. Arky, M.D., who also is a Joslin Overseer, G.T. McMahon, M.D., M.M.Sc., A. Bitton, M.D., and V. Nose, M.D. All participants are on faculty at the Harvard Medical School. Funding for the study was provided by the National Institutes of Health, the Julie Henry Fund of BIDMC and the General Clinical Research Centers.

Besides helping afflicted gastric bypass patients, the research has hopeful implications for treating people with diabetes, says Dr. Patti. The gastric bypass patients have what many of those with diabetes lack ample insulin and perhaps an understanding of this phenomenon could be harnessed to help those with diabetes. "If we can understand what processes are responsible for too much insulin production and too many islet cells in these patients, we may be able to apply this information to stimulate insulin production in patients with diabetes, who lack sufficient insulin," Dr. Patti says.

Muraglitazar found to increase adverse cardiovascular events

Tue, 25 Oct 2005 05:04:38 PST

( from http://www.rxpgnews.com ) A new medication under review by the Food and Drug Administration that may regulate blood glucose levels and have a beneficial effect on blood cholesterol and lipid levels for patients with Type 2 diabetes appears to increase the risk for major adverse cardiovascular events and death, according to a new study in JAMA. The study and an accompanying editorial were released early online at www.JAMA.com because of their timeliness and potential importance for public health.

The medication, muraglitazar, is in a class of drugs called dual peroxisome proliferator-activated receptors (PPARs), that affect lipid levels and glycemic control in diabetic patients. The studies on muraglitazar were reviewed by an FDA advisory committee on September 9, 2005, resulting in a vote of 8 to 1 recommending approval for its use as a monotherapy in controlling blood glucose levels in patients with type 2 diabetes. On October 18, 2005, the FDA issued an "approvable letter" for muraglitazar, indicating that the drug could be approved once the FDA receives and reviews additional information.

Steven E. Nissen, M.D., and colleagues from the Cleveland Clinic Foundation, reviewed the FDA briefing documents available via the FDA website for the September 9 public hearing. The researchers analyzed the muraglitazar trials performed in diabetic patients, publicly released by the sponsor and FDA for the advisory panel meeting. The documents provided data for five clinical trials that assessed safety and efficacy in diabetic patients. The researchers restricted their analysis to treatment groups using muraglitazar doses of 5 mg/d or less. The analysis yielded 2,374 patients exposed to muraglitazar and 1,351 patients exposed to other agents, of which 823 received pioglitazone (a currently available PPAR) and 529 placebo. The patients were relatively young (average age 55 years or less) and obese (average body mass index greater than 30). The studies included both men and women participants and the diabetes control among the participants was relatively poor.

"In the muraglitazar-treated patients, death, MI (heart attack), or stroke occurred in 35 of 2,374 (1.47 percent) patients compared with 9 of 1,351 (0.67 percent) patients in the combined placebo and pioglitazone treatment groups (controls)," the authors found.

"The results of this analysis are concerning," the authors write. "For the most widely accepted composite end point of death, MI (heart attack), and stroke the RR (relative risk) for muraglitazar was 2.23. Other end points using narrower definitions (including only cardiovascular death) or broader composites (including CHF [congestive heart failure] and TIA [transient ischemic attack] events) showed similar risks." The researchers note that the results are particularly concerning because the excess of adverse events was observed after the study participants had limited drug exposure ranging from 24 to 104 weeks.

The researchers state that "atherosclerotic cardiovascular disease is particularly common in patients with type 2 diabetes, representing the cause of death in approximately 80 percent of diabetic patients. Thus, any drug used to treat diabetes requires careful scrutiny for its effects on atherosclerosis-related outcomes, such as MI and stroke." The researchers also note there are some limitations to their analysis as they did not have access to original trial databases.

"Nonetheless, some important conclusions are warranted. Muraglitazar appears to increase the risk for morbidity and mortality in diabetic patients during relatively short-term treatment. The estimated magnitude of this risk is substantial with RRs indicating a doubling for irrevocable, major end points and composite outcomes. The consistency of these RRs suggests that this result is not due to chance. Accordingly, muraglitazar should not be used or approved to treat patients with diabetes until an appropriate dedicated trial to assess cardiovascular outcomes is performed," the authors conclude.

In an accompanying editorial, James M. Brophy, M.D., F.R.C.P., Ph.D., from McGill University, Montreal, Canada, writes, "muraglitazar is the first dual PPAR agonist to be considered for general marketing both as mono and combined therapy by the U.S. Food and Drug Administration. Given the emerging epidemic of diabetes, it is easy to understand the enthusiasm for this new class of drugs."

"Last month, a FDA advisory committee reviewed muraglitazar's efficacy and safety data and recommended approval. However, in this issue of JAMA, Nissen and colleagues have re-analysed this data and challenge the advisory board's recommendation."

In addition to underscoring the cardiovascular risks evident in the analysis by Nissen et al, Dr. Brophy notes that carcinogenicity (cancer) also has been a concern in animal studies involving other PPAR agonists. "While the manufacturer's presentation to the advisory committee concluded that cancer rates were not increased, there were 34 cancers reported in the muraglitazar group and one in the control group." He goes on to question some of the methodological decisions in the sponsor's FDA application that "may foster an illusion of safety" including the selection of the study population that is not representative of potential future users; underpowered studies increasing the failure rate to detect meaningful safety differences; and concentrating on reductions in surrogate laboratory values rather than in meaningful patient health outcomes.

"In conclusion, while muraglitazar may yet prove to be a valuable addition to our clinical armamentarium, Nissen and colleagues are to be congratulated for their meticulous examination of the current evidence and for drawing our attention to its potential cardiovascular risks. Residual safety concerns surrounding carcinogenicity also have not been completely resolved. The question now is which safety message will the FDA buy?"

Insulin's role in blocking release of energy

Thu, 22 Sep 2005 04:50:38 PST

( from http://www.rxpgnews.com ) Chronically high levels of insulin, as is found in many people with obesity and Type II diabetes, may block specific hormones that trigger energy release into the body, according to researchers at the University of California, San Diego (UCSD) School of Medicine.

The research team, led by Roger Y. Tsien, professor in UCSDs Departments of Pharmacology and Chemistry and Biochemistry and a Howard Hughes Medical Institute investigator, found that high levels of insulin can block stress hormones known as catecholamines, which normally cause the release of cellular energy. Adrenaline is the best known example of a catecholamine. For normal metabolism to occur, the body needs a balanced input of insulin and catecholamines. One of the actions of insulin --, the main energy storage hormone, is to block activation of the protein kinase A (PKA) enzyme. After a meal, insulin levels go up, and the body stores energy primarily as triglycerides, or fat, in adipose tissue to be used later. When energy is needed, catecholamine triggers activation of PKA, and energy is released. But in people with Type II diabetes, the hormonal balance has been thrown off, because the body continues to produce and store more triglyceride instead of breaking down the fat as released energy.

Somehow, insulin knows how to specifically block catecholamine-induced PKA, but not other molecules, said Christopher Hupfeld, assistant professor of Medicine in the UCSD Division of Endocrinology and Metabolism and a co-author of the paper. When the body has a constantly high level of insulin, this energy- release stimulus is lost.

The teams findings provide new understanding to the cause and effect occurring when insulin levels are too high. It also underscores the goal of physicians to bring down insulin levels in Type II diabetes using medicines called insulin sensitizers, so that the body becomes more sensitive to using its own insulin, rather than compensating for insulin resistance by making more.

In order to understand the mechanisms of insulin resistance present in Type II diabetes, the researchers used a new breed of cellular enzyme reporter to track PKA. The reporter is a marker protein, created with special fluorescent tags so that scientists can physically view the protein under a microscope and watch how the live cell activates PKA in real time. The PKA is normally activated inside the adipocyte cell, the major site of energy storage in the body where many aspects of metabolism are controlled. There, energy is stored in the form of triglycerides, commonly known as fat. If a person is obese, excess triglycerides are stored in the adipocytes. The new study shows that insulin weakens the normal linkage between catecholamine receptors and the turn-on of PKA.

If insulin levels get too high for too long a time which happens in many patients with type II diabetes the normal catecholamine signal that triggers fat breakdown and energy release can be drowned out. This can lead to excessive energy storage in the adipocyte, said Hupfeld. This may be one reason why chronic obesity and Type II diabetes are often seen together.

By correcting this hormonal imbalance, researchers may at some point improve treatment options for both obesity and Type II diabetes, said Hupfeld.

TORC2 - Key regulator of blood glucose levels discovered

Sat, 10 Sep 2005 23:13:38 PST

( from http://www.rxpgnews.com ) In many patients with type 2 diabetes, the liver acts like a sugar factory on overtime, churning out glucose throughout the day, even when blood sugar levels are high. Scientists at the Salk Institute for Biological Studies discovered a key cellular switch that controls glucose production in liver cells.

This switch may be a potential new target for the development of highly specific diabetes drugs that signal the liver to reduce the production of sugar. The Salk researchers, led by Marc Montminy, a professor in the Clayton Foundation Laboratories for Peptide Biology, published their findings in the Sept. 7th online issue of Nature.

It is very exciting to understand how glucose production in the liver is regulated. Now, we can try to improve the way how type 2 diabetics handle blood sugar, says Montminy.

The newly discovered switch, a protein named TORC2, turns on the expression of genes necessary for glucose production in liver cells.

When describing glucoses role in health and disease, Montminy compares the human body to a hybrid car that runs on a mix of fuels depending on its activity status: gas, or glucose, is used for high-energy activities, and battery power, or body fat, for low-energy activities. During the day, when food refuels the gas tank, the body burns mainly glucose, and during sleep, it burns primarily fat.

The body switches from glucose to fat burning mainly in response to two key hormones -- insulin and glucagon -- that are produced by the pancreas. During feeding, the pancreas releases insulin, which promotes the burning of glucose. At night, however, the pancreas releases glucagon into the bloodstream, which signals the body to fire up the fat burner.

But even during sleep, our brain needs a constant supply of glucose to function properly. For that reason, our body actually manufactures glucose during sleep or when we are fasting. That process, called gluconeogenesis, is carried out mainly in the liver.

Insulin normally shuts down the ability of the liver to produce glucose. In individuals with Type II diabetes, however, insulin is unable to inhibit sugar production in the liver, either because the pancreas is not producing enough insulin or because insulins signal cant be heard, says Montminy. When the liver is unable to hear the insulin signal, excess glucose builds up in the bloodstream.

In addition to so-called insulin sensitizing drugs that allow insulin to work better, researchers are looking for alternative ways to shut down the production of glucose in the liver of diabetics. Figuring out how to control glucose production in the liver is critical because many complications of diabetes, such as heart disease, kidney failure and blindness, can be reduced by maintaining a very tight control over blood sugar levels, he says.

As glucose levels run low during fasting, the pancreas sends out the hormone glucagon and instructs the liver to produce glucose. This increase in glucagon turns on the TORC2 switch and allows the liver to make more glucose. Mice that were genetically modified to make more or less TORC2 produced more or less glucose depending on the amount of available TORC2 (transducer of regulated CREB activity).

Most of the time, TORC2 sits in the cellular compartment that surrounds the nucleus, where all the genes are located. When a glucagon signal arrives, the TORC2 switch crosses the nuclear membrane, teams up with the transcriptional activator CREB and turns on all the genes necessary for gluconeogenesis. Being located in a different part of the cell is what keeps the TORC2 switch off, explains Montminy.

The researchers also discovered that a chemical modification on TORC2 itself sequesters the protein in the cytoplasm, the viscous substance inside the cell that surrounds the nucleus. Since we now know the molecular mechanism by which TORC2 is inactivated we can start looking for small molecules that do the same thing, says Montminy.

Panel Recommends Muraglitazar for the Treatment of Type 2 Diabetes

Sat, 10 Sep 2005 22:26:38 PST

( from http://www.rxpgnews.com ) Bristol-Myers Squibb and Merck & Co., Inc. jointly announced today that the U.S. Food and Drug Administration's (FDA) Endocrinologic and Metabolic Drugs Advisory Committee voted to recommend approval of PARGLUVA(TM) (muraglitazar), the companies' investigational oral medicine for the treatment of type 2 diabetes, for use as monotherapy and in combination with metformin. The committee voted not to recommend its use in combination with a sulfonylurea.

PARGLUVA is an investigational oral medication that, if approved, would become the first marketed agent in a new class of compounds called glitazars. PARGLUVA is a dual alpha/gamma PPAR (peroxisome proliferator-activated receptor) activator. Activation of PPAR-gamma is associated with reductions in plasma glucose levels, while activation of PPAR-alpha is associated with reductions in plasma triglyceride levels and increases in high-density lipoprotein, or "good" cholesterol (HDL-C) levels.

Bristol-Myers Squibb and Merck are collaborators in the global development and commercialization of PARGLUVA. The New Drug Application (NDA) for PARGLUVA was submitted to the FDA in late December 2004.

"Bristol-Myers Squibb and Merck are encouraged by this recommendation," said Elliott Sigal, M.D., Ph.D., chief scientific officer and president, Pharmaceutical Research Institute, Bristol-Myers Squibb. "We are committed to bringing important medicines to patients with type 2 diabetes and look forward to further discussions with the FDA."

Persons at risk for type 2 diabetes have lower rate of cellular energy production

Mon, 05 Sep 2005 13:40:38 PST

( from http://www.rxpgnews.com ) The rate of insulin-stimulated energy production is significantly reduced in the muscles of lean, healthy young adults who have already developed insulin resistance and are at increased risk of developing diabetes later in life, according to a Yale School of Medicine study.

The new research by Gerald Shulman, M.D., professor of internal medicine, endocrinology, and senior author of the study, indicates that a decreased ability to burn sugars and fats efficiently is an early and central part of the diabetes problem. The new data also suggest that the basic defect lies within the mitochondria, which are the energy factories inside cells that produce most of the chemical power needed to sustain life.

The young adults studied by the research team are the offspring of parents who have type 2 diabetes, adding support to the idea that the risk can be inherited and that the problem begins well before diabetes symptoms become evident. The researchers observed that the mitochondria in the subjects' muscle cells responded poorly to insulin stimulation. Normal mitochondria react to insulin by boosting production of an energy-carrying molecule, ATP, by 90 percent. But the mitochondria from the insulin-resistant people they tested only boosted ATP production by five percent.

Among their findings was also evidence for a severe reduction in the amount of insulin stimulated phosphorus transport into the muscle cells of the insulin-resistant participants. This also points to a dramatic defect in insulin signaling and may explain the observed abnormalities in insulin-stimulated power production in the insulin-resistant study subjects. Phosphorus is a key element in the mithochondrion's complex energy-production process.

Sirt1 protein enhances the secretion of Insulin

Thu, 18 Aug 2005 02:22:38 PST

( from http://www.rxpgnews.com ) Opening the possibility of new therapies for type 2 diabetes, researchers at Washington University School of Medicine in St. Louis have found that a protein called Sirt1 enhances the secretion of insulin in mice and allows them to better control blood glucose levels. Their study will appear in the August 17 issue of Cell Metabolism.

According to senior author Shin-ichiro Imai, M.D., the finding suggests that therapies that increase the activity of Sirt1 could be of benefit in type 2 diabetes. "We are especially interested in how we can activate Sirt1 in a natural way," says Imai, assistant professor of molecular biology and pharmacology. "One option we are investigating is increasing the body's synthesis of NAD, a necessary cofactor for Sirt1's function. Because Vitamin B3, often called niacin, is a building block of NAD, it has interesting potential."

Sirt1 is referred to as Sir2 in lower organisms where it has previously proven to be a key to aging and longevity: Increasing the amount of Sir2 dramatically extends life spans in experimental yeast, worms and flies.

"Researchers, such as myself, who study aging are enthusiastically investigating Sir2," Imai says. "In 2000, I found that Sir2 responds to the level of energy in the form of NAD available in cells. Further research has shown that Sir2 connects nutrient status and longevity."

In mammals, scientists have shown that restricting calories can extend life span and also leads to an increase in Sirt1, the mammalian version of Sir2. Sirt1 reacts to changes in nutrient availability in a wide variety of tissues.

Uptake of the basic nutrient glucose is controlled by insulin, and Imai's research group found that the cells responsible for secreting insulin--Beta cells in the pancreas--also produce Sirt1. So they investigated the effects of increasing the amount of Sirt1 in pancreatic Beta cells in mice to better understand the link between Sirt1 and glucose metabolism.

They designed transgenic mice with a genetic switch that turned up the gene that makes Sirt1 in Beta cells. "We confirmed that the mice overexpress Sirt1 proteins specifically in pancreatic Beta cells, not in other kinds of pancreatic cells, and not in brain, liver, kidney, fat or muscle," says Kathryn Moynihan, graduate research assistant.

Compared to wild-type mice, the transgenic mice had the same levels of blood glucose and insulin both when well-fed and during fasting. They were of similar weights and their pancreatic cells looked very similar in size and structure.

But when the two sets of mice were given a large dose of glucose, a difference became apparent. The transgenic mice produced more insulin and cleared glucose from their blood streams significantly faster than did wild-type mice.

Challenging the mice's systems with glucose in this manner mimics the glucose tolerance tests used to check for diabetes in human patients. Diabetic patients clear glucose more slowly than do non-diabetics in these tests.

"If your system reacted like that of these transgenic mice, you could process sugar more quickly and much more efficiently after eating sweets," Imai says.

The research group found that the transgenic mice retained their unique Beta cell function as they aged from three months to eight months, the equivalent of middle age in humans. The researchers are continuing to track the progress of the mice, which are now about 20 months old.

An analysis of the activity of genes in the Beta cells showed that several genes linked to insulin secretion were affected by the increased expression of Sirt1. Most prominently, Sirt1 turned down the activity of a gene that decreases insulin secretion.

"The gene makes uncoupling protein 2, which is intimately connected to ATP production," Imai says. "ATP is a fundamental source of energy for metabolism, and by downregulating uncoupling protein 2, Sirt1 not only enhances insulin secretion, but increases ATP energy. This is a further indication of the connection between Sirt1 and energy status."

Imai feels that Sirt1 is probably a very important regulator that integrates cellular response to different types of nutrients, such as glucose, amino acids, and fatty acids. Continued research in the lab will use the transgenic mice to further investigate Sirt1's role in this response.