One Molecule, Many More Insulin-Producing Cells To Treat Diabetes

With a single stimulatory molecule, human insulin-producing beta cell replication can be sustained for at least four weeks in a mouse model of diabetes, according to researchers at the University of Pittsburgh School of Medicine in Diabetes, a journal of the American Diabetes Association.

They also found several cocktails of molecules that drive human beta cells to replicate, as well as important differences between mouse and human beta cells that could influence how these approaches are best used to treat diabetes, which is caused by insufficient insulin production leading to abnormal blood sugar levels.

"Our team was the first to show that adult human beta cells can be induced to proliferate or grow at substantial rates, which no one thought possible before," said senior author Andrew F Stewart, MD, professor of medicine and chief of the Division of Endocrinology and Metabolism, Pitt School of Medicine. "Now our effort has been to unravel these regulatory pathways to find the most effective strategy that will allow us to treat - and perhaps cure - diabetes by making new insulin-producing cells."

In a series of experiments, lead author Nathalie M Fiaschi-Taesch, PhD., assistant professor of endocrinology, and the team discovered that combining elevated amounts of the regulatory molecules cdk4 or cdk6 with a variety of D-cyclin proteins, particularly cyclin D3, stimulates human beta cell replication in test tubes.

"We didn't expect cyclin D3 to ramp up beta cell replication so strongly when it was used with either cdk4 or cdk6," Dr Fiaschi-Taesch said. "There was no known role for cyclin D3 in human beta cell physiology."

Cyclin D2 is present in and essential for rodent beta cell replication and function, but the team showed that molecule is barely detectable in human cells, and beta cell replication could be sustained for at least four weeks in a model in which mice were transplanted with human beta cells engineered to overproduce cdk6. Blood sugar normalized in the diabetic mice transplanted with surprisingly small numbers of human beta cells, indicating that the cells functioned properly to produce needed insulin.

Mice don't appear to make cdk6 naturally, but they do have cdk4 and cyclins D1 and D2, so standard rodent studies of beta replication might have led scientists to pursue the wrong molecules in their quest to stimulate human beta cell replication, Dr Stewart noted.

He and his colleagues continue to explore many other regulatory proteins that could play a role in encouraging or thwarting beta cell replication.

Courtesy: University of Pittsburgh

Scientists Uncover Novel Anti-Diabetes Mechanism

In a joint study, scientists from The Scripps Research Institute and the Dana-Farber Cancer Institute at Harvard University have uncovered a novel mechanism that dramatically increases insulin sensitivity and reduces the risk of developing type 2 diabetes and cardiovascular disease.

These findings offer a potent new target in the continuing search for new and improved anti-diabetic treatments. 

The new study, which focuses on controlling a fat-regulating protein known as PPARy, was published July 22, 2010, in the journal Nature (Volume 466, Issue 7304).

"The field has become interested in finding drugs that can promote increased insulin sensitization but not activate the classical fat cell generating pathway of PPARγ," said Patrick R. Griffin, chairman of the Department of Molecular Therapeutics at Scripps Florida who headed up the Scripps Research part of the study.

"We examined the mechanism of action of compounds that bind to PPARγ that improve insulin sensitivity but have minimal induction of fat. It was clear from the studies that these compounds have a unique but overlapping mechanism with the class of drugs used clinically that target PPARγ."

Adipose or fat tissue lies at the center of the metabolic syndrome, a cluster of risk factors that increases the possibility of type 2 diabetes, as well as stroke, coronary artery disease, even certain cancers. Of those risk factors, excessive body fat is considered the most problematic.

PPARγ can be considered the master gene of fat cell biology because it drives the conversion of cellular precursors into fat cells.

The collaborative studies showed obesity causes a modification on PPARγ that leads to alterations in the expression of a number of genes, including a reduction in the production of an insulin-sensitizing protein (adiponectin). This leads to an increase in insulin resistance.

The reprogramming of genes controlled by PPARγ occurs when it undergoes phosphorylation (a phosphate group is added to a protein) by the cdk5 kinase, an enzyme that is involved in a number of important sensory pathways and that can be activated by pro-inflammatory proteins.

The scientists were able to use both full and partial agonists (compounds that activate a cellular response) to reverse these phosphorylation effects and improve the production of adiponectin.

These results strongly suggest that cdk5-mediated phosphorylation is involved in the development of insulin-resistance and open the door to a novel opportunity for creating an improved generation of anti-diabetic drugs.

In 2007, Griffin and his colleagues published a study in the journal Structure (October 16, 2007, Volume 15, Number 10, pp.1258-1271) that explained the difference between how full and partial agonists interacted with PPARγ. Full agonists interacted strongly with a region of the receptor known to be important for the classical fat generation program.

On the other hand, partial agonists, which are poor agonists of the receptor, did not interact with this region at all but interacted more strongly with a potentially critical region of the receptor. From a drug development point of view, these results offered a new area of the protein to focus on to optimize therapeutic molecules that would be potent insulin sensitizers without driving fat generation.

"Bruce Spiegelman at Dana-Farber was starting to uncover the fact that the phosphorylation of PPARγ takes place in the very region where MRL-24, one of the partial agonists interacted," Griffin said. "I suggested that compounds like MRL24 might be better at antagonizing the cdk5 site given their strong interaction in this region of the receptor. For the new study, we provided significant amounts of compound to support the animal studies and provided an plausible mechanism for how partial agonists might recruit co-activator proteins to the cdk5 surface of PPARg."

While the team found that PPARγ phosphorylation effects were reversed by both full and partial agonists, partial agonists indeed accomplished this as well or better than the full agonists. Mimicking the effects of just blocking the phosphorylation event by mutation of the site on the receptor showed improvements in the production of adiponectin.

The new study also suggests a unified framework for understanding the relationship between fat cell dysfunction in obesity and anti-diabetic therapies based on PPARγ. In animal studies, high fat diets activate the cdk5 kinase, initiating phosphorylation, disrupting a number of key metabolic regulators including adiponectin and adipsin, a fat cell-selective gene whose expression is altered in obesity.

"The great paradox of this whole effort is we're targeting a receptor critical for fat production to offset the problem of fat overproduction," Griffin said. "Unfortunately, current drugs that target PPARg increase fat as one of their unwanted long-term side effects."

While the study is a big step forward, important questions still remain such as does a high fat diet and obesity lead to activation of cdk5 in non-fat tissues, Griffin said, since the negative effects of obesity extend far beyond metabolic syndrome to diseases like cancer and neurodegeneration.

More information: "Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5," Jang Hyun Choi, et al. Nature Volume 466, Issue 7304

Courtesy: The Scripps Research Institute

Two Therapies May Slow Diabetic Retinopathy in Type 2 Diabetes

In high-risk adults with Type 2 diabetes, researchers have found that two therapies may slow the progression of diabetic retinopathy, an eye disease that is the leading cause of vision loss in diabetics.

Intensive blood-sugar control reduced the progression of diabetic retinopathy, compared with standard blood-sugar control, and combination lipid therapy with a fibrate and statin also reduced disease progression, compared with statin therapy alone. However, intensive blood pressure control provided no additional benefit to patients compared with standard blood pressure control.

Results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study, supported by the National Institutes of Health, recently were published in the New England Journal of Medicine and presented at the 70th Scientific Sessions of the American Diabetes Association.

"This is the largest study to date examining the effects of blood sugar, combination lipid therapy, and blood pressure control on the prevention of diabetic retinopathy progression using retinal photographs," stated Walter Ambrosius, a professor of biostatistical sciences in the Division of Public Health Sciences at Wake Forest University Baptist Medical Center and principal investigator of the ACCORD Eye study's coordinating center, in a July 23 release.

"Many people with diabetes have microvascular problems, which can result in problems with the kidneys and amputation of toes and feet, and the only place that you can directly observe the microvasculature is in the back of the eyes. What we have seen in the eyes is potentially an indicator of what is happening in other parts of the body."

"The ACCORD Eye Study clearly indicates that intensive glycemic control and fibrate treatment added to statin therapy separately reduce the progression of diabetic retinopathy," added Emily Chew, chair of the Eye Study and chief of the Clinical Trials Branch of the Division of Epidemiology and Clinical Applications at the National Eye Institute.

"The main ACCORD findings showed that fibrate treatment added to statin therapy is safe for patients like those involved in the study. However, intensive blood sugar control to near normal glucose levels increased the risk of death and severe low blood sugar, so patients and their doctors must take these potential risks into account when implementing a diabetes treatment plan."

The ACCORD study was a landmark clinical trial that included 10,251 adults with Type 2 diabetes who were at especially high risk for heart attack, stroke or cardiovascular death. The study evaluated three intensive strategies, compared with standard treatments for lowering cardiovascular risks associated with diabetes.

Michael Johnsen/DrugStore News

Lack Of Zinc Linked To Diabetes

A US researcher says zinc may play a role in blood sugar regulation and in avoiding type 2 diabetes, reports UPI.

Ayyalusamy Ramamoorthy of the University of Michigan suggests in type 2 diabetes -- a protein called amylin forms dense clumps that shut down insulin-producing cells. However, in the presence of zinc, amylin does not form clumps.

"We found that one of the likely factors stopping amylin from attacking the insulin-producing islet cells of the pancreas is zinc, which normally is found in high amounts in these cells, but is deficient in people with type 2 diabetes," Ramamoorthy says in a statement. "By understanding what stops amylin from attacking islet cells in normal people, we hope we'll be able to understand how it is attacking them in people with diabetes."

The research, published in the Journal of the American Chemical Society, suggests zinc prevents amylin - also known as Islet Amyloid Polypeptide - from forming harmful clumps.

Ramamoorthy and colleagues looked at how amylin acts with and without zinc present using several methods, including nuclear magnetic resonance spectroscopy.

"Ultimately, we want to understand how the whole scenario leads to type 2 diabetes," Ramamoorthy says.

Diabetes Alert: Avandia May Be Banned In Europe

European regulators will decide by September if Avandia will be allowed to stay on the market there. The European Medicines Agency (EMEA) said on July 23 that it is still reviewing GlaxoSmithKline’s controversial diabetes drug, which has been linked to an increased risk of heart attacks.

Since 2000, the EMEA has contra-indicated Avandia for anyone with heart failure or a history of heart failure. Since then, use of Avandia, as well as Avandame (Avandia in combination with metformin) and Avaglim (Avandia in combination with glimepiride), has been further restricted several times by the EMA by new warnings and contra-indications on their use in patients with heart problems.

The EMEA initiated a new review of Avandia earlier this month on the request of the European Commission following publication of studies questioning the cardiovascular safety of the medicine.

In the US, a Food & Drug Administration (FDA) advisory panel took up Avandia last week. Since 2007, Avandia has borne a black box label – the FDA’s most urgent safety warning – regarding its heart attack risks. An FDA advisory panel met last week to consider further restrictions on the controversial diabetes drug.

According to a report in The New York Times, 12 of the panel’s 33 members voted that Avandia should be withdrawn; 10 voted that its sales should be restricted and the warnings on its label enhanced; 7 voted only to support enhanced warnings on the drug’s label; and 3 voted that the drug should continue to be sold with its present warnings unchanged.

The FDA is not required to follow the recommendations of such panels, but does so in most cases. However, the lack of unity among panel members in the case of Avandia makes it hard to predict what the agency will do, The Times said.

As I reported yesterday, the FDA has ordered GlaxoSmithKline to halt enrollment in a study called TIDE (Thiazolidinedione Intervention With Vitamin D Evaluation) over safety concerns. TIDE was designed to compare the long-term effects of Avandia with another diabetes drug called Actos.

Actos has not raised as many safety concerns as Avandia. For some time now, scientists inside and outside the FDA have opposed TIDE, saying it is unethical to compare Avandia, with its known cardiac risks, with a seemingly safer alternative.

Incidentally, India has already suspended all participation in the TIDE trial in the country. In India, at least 20 cities including Mumbai, Bangalore, Chennai and Hyderabad had enrolled over 150-200 subjects earlier this year for conducting these clinical trials, which are part of the global post-marketing studies to asses its safety risks.

According to The Boston Globe, the FDA said it halted recruitment in TIDE because it needs time to study new evidence of the Avandia’s risks. The agency is demanding that Glaxo update physicians and ethics oversight boards involved in the trial regarding all new safety information about the drug. The agency has not indicated how long the enrollment halt would last.

Diabetes: Safety Concerns Force FDA To Halt Enrollment For Avandia Trials

The FDA On July 21 ordered drug maker GlaxoSmithKline to stop enrolling new patients in a controversial clinical trial of its widely marketed diabetes drug, Avandia (rosiglitazone).

The clinical trial, called TIDE, was mandated by the FDA to assess safety risks of the drug, which is prescribed to treat type-2 diabetes.

But it has been highly controversial because Avandia has been linked in a variety of studies to an increased risk of heart attack and other adverse cardiovascular effects.

Critics, including one of the Food and Drug Administration’s own safety researchers, have said publicly that the trial should be stopped immediately, asserting that it is unethical to expose patients to risks that have been shown statistically to be quite real.

GlaxoSmithKline recently announced that India has already suspended all participation in the TIDE trial in the country.

In India, at least 20 cities including Mumbai, Bangalore, Chennai and Hyderabad had enrolled over 150-200 subjects earlier this year for conducting these clinical trials, which are part of the global post-marketing studies to asses its safety risks.

This development is significant in the wake of the fact that a total of around 2,000 diabetics were to be enrolled from India.

A debate has been raging on the blockbuster drug, Avandia since studies reported serious side-effects like heart attacks and strokes associated with its use, in 2007. It is widely-prescribed by doctors here in India, with 9-10 companies marketing it.

The country's drug controller general recently halted the trials, for which subjects were being enrolled since February, across various hospitals and clinics all over.

Dr Anoop Misra, director and head diabetes, Fortis Hospitals in New Delhi said: "This step taken by FDA of stopping this unethical trial is welcome, though belated. I hope further step of banning this drug is taken soon. I am also happy to note that DCGI (India) stopped this trial in India before FDA decision, and such efficient steps and regulations are required in India."

The FDA on its part said its action does not mean the drug will be removed from the market. But the agency is demanding that GlaxoSmithKline update physicians and ethics oversight boards involved in the trial regarding all new safety information about the drug.

It said the information "can be used’’ to update consent forms for new patients and current participants. Critics, including members of Congress, have said the current consent forms in use in the trial are inadequate given the extent of the scientific warning signs.

The potential dangers of Avandia have already discouraged enrollment in the trial.

The trial’s design called for global enrollment of 16,000 patients, with about a third in the United States. But the trial’s lead investigator, Hertzel Gerstein, of McMaster University in Ontario, Canada, said last week only about 1,120 patients had been recruited worldwide, because of the widespread safety concerns.

By a vote of 20 to 12, an FDA advisory panel last week recommended that the drug be permitted to remain on the market. But half of the members who voted to keep it on the market also supported strong restrictions on prescribing, including education programs about the risks for doctors and patients, which specialists predict will dramatically cut into GSK sales figures.

GlaxoSmithKline said in a statement that new enrollment in the trial would be stopped "pending FDA review of recommendations from its Advisory Committee meeting July 13-14. Patients already enrolled may continue in the trial."

"This pause in enrollment will give clinical trial investigators and patients time to learn about the data presented to the FDA Advisory Committee and the Committee’s recommendations," said Dr Ellen Strahlman, GSK’s Chief Medical Officer. "We are committed to working with the FDA in the best interest of diabetic patients."

Avandia, which was approved for the market in 1999, was prescribed 2 million times by US doctors in 2009. It was once the largest-selling drug in its class, with more than $3 billion in global sales. It sold around $1 billion in 2009, with half of that revenue in the US.

Killer Drug Gets Safety Certificate From FDA - GSK Claims "Victory"

This week the US Food and Drug Administration voted not to ban GlaxoSmithKline's diabetes drug rosiglitazone (brand name Avandia). Their vote has been reported as a victory for the company. I don't think so: this saga tells an ugly story about our collective medical incompetence.

Rosiglitazone was first marketed in 1999. From the outset it was a magnet for disappointing behaviour. That first year Dr John Buse discussed an increased risk of heart problems at a pair of academic meetings. He was silenced. GSK made direct contact, then moved on to his head of department.

Buse felt pressured to sign various legal documents and after wading through documents for several months, in 2007 the US Senate committee on finance released a report describing the treatment of Dr Buse as "intimidation".

In 2003, the Uppsala drug monitoring group of the World Health Organisation contacted GSK about an unusually large number of reports associating rosiglitazone with heart problems. GSK conducted two internal meta-analyses of their data in 2005 and 2006.

These showed the risk was real, but although both GSK and the FDA had these results, neither made any public statement, and they were not published until 2008.

Why then? In 2004 GSK were caught ‑ famously - hiding data showing side effects of the antidepressant paroxetine in children: a court settlement required them to post all clinical trial results voluntarily on a public website.

Using this data source, cardiologist Prof Steve Nissen and colleagues published a landmark meta-analysis in 2007 showing a 43% increase in the risk of heart attack on rosiglitazone. People with diabetes are already at increased risk of heart problems.

The FDA found a similar risk in their own calculations, but voted in 2007 to keep the drug on the market. This is not insane: diabetes is tricky, 300 million people have it worldwide, a great many die from it, and rosiglitazone is unusually good at controlling blood sugar. Lots of dangerous drugs are kept on the market and then used less frequently, in extreme circumstances.

A consensus algorithm from the American Diabetes Association and the European Association for the Study of Diabetes, meanwhile, unanimously recommended against rosiglitazone. Although annual sales for rosiglitazone fell, they still remained over $1bn (£650m). Concerns continued to mount. So did the bad behaviour. In 2007, Nissen caught GSK out discussing a copy of his unpublished paper, which they had obtained improperly.

Then on 28 June this year Nissen published an updated meta-analysis of 56 trials in over 35,000 patients. Again it found an increased risk of heart problems. GSK's response to all this has been like the responses you get from homeopaths.

There are seven trials since 2007, they said, showing no excess risk: fine, except there are 56 which collectively do show an excess risk. There is this other meta-analysis, they said, which looked at 164 trials: fine, except it's published in a fairly obscure journal, and it looked at trials lasting more than four weeks, when the others set the bar at trials over 24 weeks, because a heart risk takes time to develop.

In any case, this other meta-analysis is not brilliant for GSK's case, since it points out that the company denied access to data from six trials which we know to have taken place. There is no excuse for companies withholding data from academics and doctors. But most revealingare the deep-rooted flaws this story exposes in our rather ad hoc systems for gathering, analysing, and disseminating evidence on risks and benefits of treatments.

This drug has been on the market since 1999, and it has seen billions of dollars of sales every year. There has been plenty of real patient experience of this treatment, but we have failed to capture it for analysis. Most of the trials included in these meta-analyses were not specifically designed to look at heart problems, and so the data on these is unpredictably inaccurate.

In an ideal world, for every patient, wherever possible, we could be gathering anonymised outcome data and comparing this against medication history. In an ideal world, wherever there is genuine uncertainty about which treatment is best, a patient would be randomised to one treatment, and their progress monitored. In an ideal world, these notions would be so embedded in our notion of what healthcare looks like that no patient would be bothered by it.

This isn't fanciful, or difficult, or disproportionately expensive. Instead we have a hotchpotch of incomplete monitoring systems and unforgivable secrecy.

Courtesy: Ben Goldacre/The Guardian