Risk Of Developing Liver Cancer After HCV Treatment

Monday, April 9, 2012

Monday EASL Updates And Hepatitis C Headlines

EASL

Bristol-Gilead Hep C Drug Data Leaks
TheStreet.com - 6 minutes ago
By Adam Feuerstein 04/09/12 - 09:03 AM EDT BOSTON (TheStreet) -- An early peek at data from a closely watched mid-stage study combining hepatitis C drugs from Bristol-Myers Squibb(BMY) and Gilead Sciences(GILD) has leaked in advance of the European ...

Promising hepatitis C data continues to be one of the hottest products in biotech, as we saw this morning after Jefferies analyst Thomas Wei posted some positive results from an all-oral combo of Gilead Sciences' ($GILD) 7977 and Bristol-Myers Squibb's ($BMY) daclatasvir (BMS-52). Among the genotype 1 patients enrolled in the Phase II trial, 97% had no detectable levels of the hepatitis C virus after 12 weeks of treatment. And in genotype 2/3 patients 90% of patients achieved the same virus-free status.

Analysts pounce on positive Phase II data on hep C combo - FierceBiotech
Promising hepatitis C data continues to be one of the hottest products in biotech, as we saw this morning after Jefferies analyst Thomas Wei posted some positive results from an all-oral combo of Gilead Sciences' ($GILD) 7977 and Bristol-Myers Squibb's ($BMY) daclatasvir (BMS-52). Among the genotype 1 patients enrolled in the Phase II trial, 97% had no detectable levels of the hepatitis C virus after 12 weeks of treatment. And in genotype 2/3 patients 90% of patients achieved the same virus-free status.
TheStreet's Adam Feuerstein--a careful student of all things hep C related...
TheStreet.com - 57 minutes ago
By Nathan Sadeghi-Nejad 04/09/12 - 08:09 AM EDT FOSTER CITY, Calif. (TheStreet) -- Amongst the hubbub over hepatitis C and the upcoming EASL conference, it can seem as though Gilead Sciences'(GILD) very existence hinges on whether or not the company ...

Abbott Hepatitis C Combo Impressive in Small Study
A combination of experimental oral hepatitis C treatments being developed by Abbott Laboratories led to cure rates of more than 90% in previously untreated patients....
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In The News

Hepatitis C: The deadly drill
The use of unster­ilised dental instru­ment is the second larges­t cause of the spread of hepati­tis in Pakist­an.

By Ali Usman
Published: April 9, 2012
LAHORE:
Imran Ali got the shock of his life when his blood samples tested positive for Hepatitis C. He had gone to a private clinic to donate blood to one of his friends, but instead found out that has own blood was tainted with the deadly virus. What was even more mystifying was the fact that he had tested negative for Hepatitis C when he had donated blood four months ago. It was easy for the health-conscious 22-year-old to put two and two together.

“The only thing that I could figure out which could have caused hepatitis was a dental examination I underwent,” pinpoints Ali.
“I had gone to a small clinic near my home in Iqbal Town and I was told the equipment was clinically sterilised but later I found out that using an autoclave [a steam-heated vessel where dental instruments are kept and boiled at certain heat and pressure levels to kill all viruses] is the proper way to get sterilisation done and the clinic didn’t have that procedure.”
Ali subsequently filed an application with the Health Department to take action against the private clinic, but his plea did not bear any fruit. His friends and lawyers then advised him to file a complaint with the Ombudsman’s office or file a case against the clinic in court.

“But I didn’t have any proof to substantiate my case so I didn’t consider it a viable option. Had the Health Department taken the matter seriously and seized the equipment of the clinic, it could easily have established that the equipment wasn’t sterilized properly,” he says in dismay.

Unfortunately Ali’s case is not an isolated one. According to the statistics available with the Hepatitis Prevention and Control Programme (HPCP), which gives guidelines and drafts policy for controlling hepatitis, every ninth person in Pakistan is a hepatitis patient. There are no proper figures available, but health officials say that the second largest transmission source for hepatitis in Pakistan is non-sterilised dental equipment. The number one cause is reused blades and razors at barber shops.

What puts those undergoing dental work particularly at risk is that in many dental procedures, blood will necessarily contaminate instruments. “In orthodontics (the alignment of teeth), maxillofacial surgery or root-canal treatments, instruments will definitely come in contact with blood,” explains dental surgeon Dr Anwar. “There is a small pin called the reamer which is inserted into the gums and, in many cases, it isn’t sterilised properly if it’s not put in autoclaves.”

Thus, the proper sterilisation of dental equipment is of utmost importance for preventing the spread of blood-related infection. Yet, this basic safety precaution is neglected at several dental clinics.
“There are above 30,000 unregistered so-called dental surgeons and quacks in Punjab alone, and they are the second largest source of spreading hepatitis in country,” says Pakistan Medical Association (PMA) Joint Secretary Dr Salman Kazmi. “Other than some teaching public hospitals there isn’t any Central Sterilisation Services Department (CSSD) where all surgical instruments, especially dental instruments could be properly sterilised.”

One of the reasons that autoclaves, while being of utmost importance, are severely underused, is simply because of the cost. A good autoclave costs around Rs 250,000 and runs on gas or electricity. This means that even those small clinics that actually consider sterilisation important may not be able to afford an autoclave.

In the absence of proper equipment, they use other methods which are not as effective.
“What happens here that in many small clinics dental surgeons use ovens to sterilise the instrument which isn’t at all effective in killing bacteria. Only an autoclave can do it properly and safely,” says Abid.

And even where autoclaves are available, there’s the usual problem of poor maintenance and apathy.
“There are autoclaves in all government hospitals at district headquarters, however in several cases they are not working properly,” reveals Kazmi.

Another way to disinfect instruments is by chemical sterilisation which is conducted by dipping instruments in a solution which has chemicals like gludraldehyde.

While Dr Anwar and Dr Kazmi lay the blame on the quacks, others allege that even reputed hospitals don’t have proper means of cleaning dental gear. “There are some departments at the Punjab Dental Hospital, where there isn’t any proper mechanism of sterilisation. In the scaling department, there isn’t any proper procedure for sterilization and even autoclaves are out of order,” claims a dental surgeon at the PDH. “The surgery department system is very nice, but inside every department, instruments and mouth mirrors are dipped in the same solution for the whole day for sterilisation. The same instruments go in every patient’s mouth and are likely to spread hepatitis from one person to the other.” Given that over 550 patients frequent the PDH every day, the chances for transmission are thus extremely high.

However, the Medical Superintendent (MS) of the Punjab Dental Hospital refuted the claims that dental equipment is not properly disinfected at public hospitals. “We properly steriliseequipment at public hospitals, however the problem lies with quacks and some small clinics,” she says.

A dentist surgeon at Mayo Hospital, however, claims that it’s not as simple as that. “Most of the time the sterilization of dental equipment in public hospitals depends on lower level employees, who do it during the evening or night. If they don’t do their job honestly the risk factor goes above manifold,” he explains. “There should be some training sessions to create awareness and responsibility among lower staffers who sterilisedental equipment in order to prevent hepatitis from spreading.”

However, any oversights or ommissions in this regard often go unpunished. Dr Altaf Hussain, the head of health department’s Hepatitis Preventive Control Programme (HPCP) says, “We give a policy line to control hepatitis, but we don’t have any mechanism to check or punish those who use non-sterilized instruments. The EDOs (Health) in their districts are responsible for this.”

The Punjab Government had in fact launched an anti-quackery campaign to prevent the spread of hepatitis, but it failed to show results. An official in the health department claims the problem persists because government officials have no proper mechanism to inspect instruments at private clinics and drug inspectors are only sent out to check on these clinics once in a blue moon.

According to Dr Altaf Hussain, applications regarding unsterilised instruments can be filed with the area’s EDO Health, after which the health department has to take appropriate action.

Sadly, this procedure is not really followed. “The drug inspectors mostly settle issue with quacks or small clinics on their own and the show goes on and these people keep playing with lives of innocent people,” reveals another official.

In this situation, victims like Imran really have nowhere to turn to have their complaints heard. And every day that this situation persists, more and more people fall victim to this criminal neglect.
Published in The Express Tribune, March 21st, 2012.
Source
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$1.1 M for hepatitis C screenings and treatmentBy BRANDON B. QUINN and AMANDA VERRETTE

Former Assemblyman Kenneth Zebrowski was sent by doctors to the orthopedist in 2006 for a nagging pain in his side.

Only a few months later, while still in office, Zebrowski died at the age of 61 from liver failure and cirrhosis, caused by hepatitis C.

He contracted the disease from a 1973 blood transfusion, according to his son, Assemblyman Kenneth P. Zebrowski, D-New City, who immediately succeeded his father in representing the 94th Assembly District.

Hepatitis C is a contagious liver disease that causes fibrosis of liver cells and is spread through blood contact.

Despite being diagnosed in 1996 with hepatitis C, the elder Zebrowski didn't start to exhibit symptoms, similar to the flu, until 10 years later.

Up until his last few living months, "at no time, no one told him what to do, not even recommending any types of treatment," said Zebrowski, who added that, by the time doctors matched the symptoms to the prior diagnosis, "it was already too late for my father."

Since his father's death, Zebrowski has not only followed in his father's footsteps in the Legislature, but has dedicated himself to hepatitis C awareness and advocacy, a disease that affects 300,000 New Yorkers, according to Dr. Brian Edlin, an epidemiologist at the Center for the Study of Hepatitis C.

A small victory for Zebrowski and other activist groups, including Status C Unknown, a nonprofit organization that provides hepatitis C support and education, is the inclusion of a $1.1 million line item in the Medicaid Redesign portion of the 2012-2013 budget for hepatitis C screening and treatment.

Despite this funding specifically being dedicated to hepatitis C treatment and screening, it is in the budget as part of a larger $104.5 million appropriated for the AIDS Institute, according to Morris Peters of the Division of Budget.

The AIDS Institute may ultimately designate even more money for the benefit of hepatitis C, said Peters, pointing out many programs they run would benefit both hepatitis C and HIV/AIDS patients.

The Medicaid Redesign Team suggested including $2.1 million in the budget towards hepatitis C care, coordination and service integration by adding hepatitis services to already established clinics, primary care practices and substance abuse settings, with $1.5 million coming from the state budget and the rest being federally funded.

"I think it's great that it made it in the final budget. I was happy that the governor originally put it in … and at the end of the day, all three sides recognized that it was money well spent," said Zebrowski, pointing to "exciting new treatments" as reason for funding necessity.

"We know the budgets are tight, but hepatitis C is taking a personal and financial toll on our state," said Shari Foster, founder of Status C Unknown, who praised the inclusion.

Chairman of the Assembly Health Committee and member of the Medicaid Redesign Team Richard Gottfried, D-Manhattan, said including hepatitis C care in the Medicaid program is "enormously important."

Foster said this year's funding will allow the state to adopt a plan to "combat the increasing incidence" of hepatitis C in New York state with education, testing and treatment programs.

The Centers for Disease Control and Prevention estimates hepatitis C accounts for 8,000 to 10,000 deaths each year in the United States, with Edlin placing the number at 15,000, more than the number of deaths attributed to HIV.

"The numbers crossed in 2007," said Edlin.

According to Edlin, the beginning stages of the virus, known as acute hepatitis C, can be fought off by the immune system. Centers for Disease Control and Prevention said approximately 15 to 25 percent of people who contract hepatitis C recover from the virus without treatment. If the infection is not cleared from the body, it will develop into chronic hepatitis C that will last for years.

New "extremely effective and exciting" treatment for hepatitis C is available, said Edlin and is mostly successful when given during the acute phase of the virus. But it is rarely detected in the acute phase because there are no symptoms. Usually, said Edlin, infected persons don't see symptoms of the virus until 20 to 30 years later.

"It is unconscionable that thousands of New York state residents are sick and dying every year because they don't know they have hepatitis C, when it can be identified by a simple blood test and treated," said Foster, who almost died from internal bleeding when she went into liver failure because she didn't know she had hepatitis C.

Hepatitis C is most prevalent among the baby boomer generation, said Edlin, because before 1992, blood wasn't tested for the disease. In fact, it didn't even have a name according to Shari, who said it was called "Not Hep A, Not Hep B."

Hepatitis C deaths "will only continue to get worse because baby boomers are reaching the point where they have been infected for 20 years," said Edlin.

The Centers for Disease Control and Prevention suggest those who have a had a blood transfusion or organ transplant before 1992, recipients of clotting factor concentrates before 1987, former and current injection drug users, person with HIV and children born to hepatitis C positive mothers should be screened for the virus.
Source

Staff catch hepatitis C from dirty needles while working at NHS Greater Glasgow & Clyde
 Source

EpiCept's compound EP1013 identifies as new drug candidate to treat late-stage viral hepatitis
                           
Tarrytown, New York
Saturday, April 07, 2012, 16:00 Hrs [IST]

EpiCept Corporation, a company focused on the development and commercialization of pharmaceutical products for the treatment of pain and cancer, has announced that new preclinical research for its apoptosis inhibitor drug candidate EP1013 (now renamed F573) has concluded that F573 is a new therapeutic drug candidate for the treatment of late-stage viral infection-induced hepatitis.

The data were published in the Chinese Pharmacological Bulletin (2102 Volume 28 (1):136-139). F573 was discovered by EpiCept and licensed to GNI Group Ltd. in 2008 for clinical development in Asia, Australia and New Zealand.

F573 delivered intravenously demonstrated a therapeutic effect in a study involving 60 mice with acute liver injury, including a reduction in TNF-a and cell apoptosis. GNI Group Ltd. also noted that F573 reduced mice mortality caused by acute liver injury and that these animal studies provide important proof and direction for future human studies.

EpiCept president and CEO Jack Talley commented, "This is the first published evidence of F573's activity in viral hepatitis, an inflammation of the liver caused mainly by three specific viruses (hepatitis A, B and C). According to the C. Everett Koop Institute, 3-5 million Americans are infected with hepatitis C alone, with at least 170 million people infected globally. GNI's continued progress against this disease may enable us to advance the development of the compound in other territories, particularly North America and Europe."

As part of its license agreement with GNI Group Ltd., EpiCept is eligible to receive milestone payments of more than $12 million based on the clinical advancement of F573 in Asia, Australia and New Zealand, as well as royalties on commercial sales. EpiCept retains the commercial rights to F573/EP1013 in all other markets. The next potential milestone payment would occur in conjunction with initiation of a phase I trial in any of the territories outlined in the agreement. In July 2011, Shanghai Genomics, a wholly owned subsidiary of GNI Group Ltd., filed an Investigational New Drug (IND) application for F573 in China.

F573 is a di-peptide small-molecule compound with a potent inhibitory effect on caspases, a class of enzymes involved in cell death and inflammation. Drug efficacy has been shown in animal models relating to liver failure, brain ischemia and myocardial infarction. GNI Group Ltd. has secured a series of patent rights for F573 in China, Japan other key territories from EpiCept Corporation to develop this drug for liver diseases.

Liver fibrosis increases risk of discordance in CD4 cell count and percentage in HIV-positive patients
 CD4 count >
Michael Carter
Published: 09 April 2012
Liver fibrosis is associated with discordance between CD4 cell counts and percentages in HIV-positive patients, according to US research published in the online edition of Clinical Infectious Diseases. The association was especially marked for patients with a total lymphocyte count below 1200 cells/mm3.

The investigators believe their findings have clinical significance. “From a practical standpoint, our findings suggest a relatively simple approach could be for clinicians to evaluate CD percentage in addition to CD4 number whenever a patient’s total lymphocyte count is below 1200 cells/mm3.”
Continue Reading...

Crackdown on prescription pain killers widens to Walgreens
BOSTON/NEW YORK | Fri Apr 6, 2012 2:29pm EDT

(Reuters) - The U.S. Drug Enforcement Administration said on Friday it is inspecting six Walgreens Co pharmacies and its distribution center in Florida, after the agency noticed a jump in purchases of the highly addictive pain killer oxycodone.

The DEA issued inspection warrants on Wednesday to Walgreens' distribution center in Jupiter and to retail stores in Hudson, Port Richey, Oviedo, Fort Myers and two stores in Fort Pierce, said Mia Ro, a spokeswoman for the DEA in Miami.

Under the U.S. Controlled Substances Act, a warrant may be issued for "valid public interest" and without the type of probable cause needed under criminal law, according to the warrant filed in U.S. District Court, Middle District of Florida.

"DEA is investigating Walgreens Jupiter and its top six retail pharmacies in Florida for 2011 to determine if the pharmacies are dispensing controlled substances outside the scope of their registration in violation of federal laws and regulation," the warrant said.

For instance, in 2009 there were no Walgreens retail walk-in pharmacies listed in the DEA's top 100 purchasers of oxycodone for retail pharmacies in Florida. By 2011 there were 38 and 53 in just the first two months of 2012, the warrant said.

In another example, a Walgreens in Ft. Myers, which purchased its oxycodone from the Jupiter wholesale distribution center, accounted for 67 percent of that drug purchased by all the pharmacies in the same zip code.

"The purchase of large amounts of oxycodone by a retail pharmacy is indicative of a pharmacy that fills prescription issued by physicians at pain clinics and/or a pharmacy which services primarily drug seeking individuals that abuse the medication," the warrant said.

The action follows DEA's recent move to suspend Cardinal Health Inc's license to distribute controlled substances -- drugs that are susceptible to abuse -- from its facility in Lakeland, Florida, and also intervened to prevent two CVS Caremark Corp pharmacies in Florida from selling controlled substances. The companies are fighting the orders in court.

"We are working with, and cooperating with, the DEA on this matter," Robert Elfinger, Walgreens spokesman, said in an email.

Ro said the pharmacies came to the attention of the DEA based on several red flags, primarily the volume being shipped to these outlets.

The inspection warrants will allow the DEA's diversion investigators to examine the pharmacies' records and receipts to determine whether drugs were being diverted to the illicit market.
The pharmacies are not required to stop selling controlled substances, which include narcotic painkillers, while the DEA conducts its inspection.

The DEA has been ratcheting up its focus on drug wholesalers and pharmacies in recent months as it attempts to battle what the Centers for Disease Control and Prevention call a prescription drug abuse "epidemic." Deaths from narcotic painkillers now exceed those of heroin and cocaine combined.
Florida has long been considered the epicenter of prescription drug abuse and the DEA has, over the past year, dismantled dozens of "pill mills" - sham pain clinics whose doctors write prescriptions for thousands of pain pills to drug dealers and addicts.

(Reporting by Toni Clarke and Ilaina Jonas; Editing by Lisa Shumaker)

Stem Cells

The Titanic & Dubious Adult Stem Cell Clinics
A final parallel between dubious adult stem cell therapies and the Titanic is that people can and in fact have been killed in both cases. The risks are high for biologics treatments that are not fully vetted by the FDA....Continue Reading

Indian to head world’s first trial with liver stem cells
An Indian-origin professor in the U.K. will head the world’s first trial using liver stem cells that could avoid transplant surgery.

Paediatric liver consultant Professor Anil Dhawan, who will head the trial at King’s College Hospital, has described the use of stem cells to treat liver disease as an “exciting breakthrough”, The Daily Mail reported.

Doctors have developed a pioneering treatment for liver disease that could save hundreds of lives a year and avoid the need for transplant surgery, it said.
Eighteen British children suffering from rare and life threatening liver conditions are to receive infusions of specially treated liver cells removed from the organs of dead donors, the paper said.
It said that doctors believe they will make vital stem cells — the building blocks of life — and repair the damaged organ.
“We have many very sick children and babies who need transplants. If we can cure them without a transplant that will be a fantastic development.
“We have tried using ordinary liver cells with limited success, but is the first time a treatment has been developed that gets the liver to regrow using stem cells,” Mr. Dhawan was quoted, as saying by the daily.
He added that if all goes well, the children, who are being treated with the cells, will show an improvement within a couple of months.

“We would expect those children to come off their medicines and therapy. It will mean the liver cells have done their job and corrected the defects that made them ill. “Then we will have to see how long the effect lasts and whether we have to top up these children with further infusions. I am optimistic the treatment will work,” he said.

Improved stem cell line developed at CHOP
By Serena Gordon 
THURSDAY, April 5 (HealthDay News) -- Developing stem cell lines that don't have cells that potentially grow into cancer has been one of the biggest challenges for stem cell therapies.
But researchers from the Children's Hospital of Philadelphia have generated a new line of stem cells that may solve that problem, at least for stem cells destined for the digestive system or possibly the lungs.

"The most significant use short-term will be for disease modeling. We've had to rely on mouse models, but we're different than mice. A model with human cells could be very powerful," said the study's senior author, Paul Gadue, an assistant professor in the department of pathology and laboratory medicine at the hospital's Center for Cellular and Molecular Therapeutics.
In the far future, he added, these stem cells could potentially be used as therapies for diseases such as diabetes or liver disease.

For the current research, the scientists used embryonic stem cells and induced pluripotent stem cells. Embryonic stem cells are derived from human embryos, often unused embryos from fertility treatments that are donated for research. Induced pluripotent stem cells are genetically engineered from other human cells, such as skin cells or blood cells. Both of these stem cell types can give rise to cancer.

"One of the big issues that's critical when you think about potentially transplanting embryonic stem cells or induced pluripotent stem cells is that you have to make sure there are no undifferentiated cells in that batch, because undifferentiated cells can form tumors called teratomas," said Gadue.
By stalling the development of these cells at what's called the endodermal stage, the researchers found that the cells no longer created teratomas. The endoderm is the innermost layer of cells found in an early embryo that eventually develop into the lining of the digestive and respiratory tract.
These cells are then known as endodermal progenitor cells, and they have nearly unlimited growth potential in the lab, according to the authors.

But, delaying the cells at the endodermal stage does limit the type of cell they can later become. Endodermal progenitor cells can only become cells found in the digestive tract, such as intestinal, liver or pancreatic cells, and possibly lung cells, Gadue said.

It's as if the initial stem cells are college freshmen undecided about what course of study they want to pursue. At this point, they can essentially choose any career. For stem cells, that means some choose to become cancer.

However, Gadue and his colleagues found a way to guide the cells to the school of study that might be right for them, such as a school of engineering or a school of art. And, for stem cells, that means the choice no longer includes becoming a teratoma. But, that also means that the cells' pathways are more limited, like an engineering major who chooses a subspecialty of mechanical engineering, but can no longer choose art.

Of course, while creating a stem cell line that doesn't produce teratomas is important, it's also important that cells in that line grow up (differentiate) to become other cells. And Gadue's team was able to create pancreatic beta cells that could produce some insulin. Beta cells are the cells that are damaged or destroyed in people with diabetes.

The investigators found that in the lab, the newly created beta cells produced insulin after being exposed to glucose (sugar), a function that is absent or impaired in people with diabetes. However, the cells didn't achieve full function, producing only about 20 percent of the expected insulin.
Juan Dominguez-Bendala, director of stem cell development for translation research at the Diabetes Research Institute in Hollywood, Fla., said that the 20 percent function isn't much different than what's been seen in other studies, and that getting beta cells to mature fully in the lab is very difficult. He added that beta cells will often complete maturation once they've been transplanted.

But overall, Dominguez-Bendala said, "this [research] presents two major advantages over embryonic stem cells. First, by having this 'intermediate' population, we are restricting the differentiation options of the stem cells. For applications such as liver diseases or diabetes, these cells will readily become [liver cells] or beta cells, without unwanted byproducts such as [nerve or heart cells]." And second and more importantly, he said, they don't pose the risk of forming tumors.

"If independently confirmed, this approach could certainly be of great potential to design safer and more efficient differentiation protocols for the treatment of diabetes and liver diseases, among other conditions," Dominguez-Bendala added.

Albert Hwa, scientific program manager of cure therapies at the Juvenile Diabetes Research Foundation, called the new research "very interesting and encouraging because they don't see teratomas." He also agreed that the functionality of the beta cell could be further optimized.
"This was a first try with this protocol. The function of these cells seems very promising as well," said Hwa.

Hwa also said the findings need to be replicated, but that he could see such stem cells being used for disease modeling.

However, Hwa added, a therapy for type 1 diabetes from this stem cell line is less likely "until we can look at this process consistently in a large scale. For the [U.S. Food and Drug Administration], you have to show data that you can consistently produce the same product."
Results of the study are published in the April 6 issue of the journal Cell/Stem Cell.
More information
Learn more about stem cells from the U.S. National Institutes of Health.
Source

Diabetes
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Sugar Production Switch in Liver May Offer Target for New Diabetes Therapies
Released:4/6/2012 3:20 PM EDT
Embargo expired: 4/8/2012 1:00 PM EDT

Source:Salk Institute for Biological Studies

Newswise — LA JOLLA, CA---- In their extraordinary quest to decode human metabolism, researchers at the Salk Institute for Biological Studies have discovered a pair of molecules that regulates the liver's production of glucose---- the simple sugar that is the source of energy in human cells and the central player in diabetes.

In a paper published April 8 in Nature, the scientists say that controlling the activity of these two molecules---- which work together to allow more or less glucose production---- could potentially offer a new way to lower blood sugar to treat insulin-resistant type II diabetes. They showed, through an experimental technique, that this was possible in diabetic mice.

"If you control these switches, you can control the production of glucose, which is really at the heart of the problem of type 2 diabetes," says Professor Marc Montminy, head of Salk's Clayton Foundation Laboratories for Peptide Biology.

The need for new drugs is accelerating, says Montminy, as almost 26 million Americans have type II diabetes, and an estimated 79 million people are at risk of developing the condition. Diabetes is the sixth leading cause of death in the United States, and treatment costs are estimated at $116 billion annually.

In order to develop new and effective treatments for diabetes, researchers need to understand the complex and delicate biology behind human metabolism as well as the disorders that develop when this finely tuned system is out of balance, Montminy says.

During the day, humans burn glucose, derived from the food we eat. This is the fuel that supplies the muscles and other parts of the body expending energy. At night, when we sleep, we revert to stored fat as a source of very dependable but slowly released energy. But certain parts of the body, most notably the brain, require glucose as a source of energy, even when we fast.

Pancreatic islet cells control both sides of this energy equation. Located in the pancreas, they produce glucagon, a hormone released during fasting, to tell the liver to make glucose for use by the brain. This process is reversed when we feed, and when the pancreatic islets release insulin, which tells the liver to stop making glucose.

Thus glucagon and insulin are part of a feedback system designed to keep blood glucose at a stable level.

Montminy's lab has for years focused on the central switches that control glucose production in the liver and others that control glucose sensing and insulin production in the pancreas. Among his key findings is that glucagon---- the fasting hormone---- turns on a genetic switch (CRTC2) that ramps up production of glucose in the blood. In turn, when insulin is increased in the blood, activity of CRTC2 is inhibited, and the liver produces less glucose.

"But in insulin-resistant type II diabetic individuals, the CRTC2 switch is turned on too strongly because the insulin signal is not getting through," Montminy says. "As a result, the liver produces too much glucose and the level of glucose in the blood stream is too high. Over a period of 10 to 20 years, the abnormal elevation of glucose leads to chronic complications including heart disease, blindness and kidney failure."

The new findings in the Nature study identify a relay system that explains how glucagon activates the CRTC2 switch during fasting, and how that system is compromised during diabetes.

The scientists say this relay system involves a molecular receptor (IP3) on the outside of liver cells that they call a "molecular spigot." Glucagon opens the IP3 spigot during fasting, allowing an increase in calcium, a common signaling molecule in the cell. This stimulates a molecular gas pedal, of sorts, known as calcineurin, which revs up CRTC2, activating genes that allow the liver to drive the metabolic engine by producing more glucose.

This is important, Montminy says, because the team also discovered that activity of the IP3 receptor and calcineurin in the liver are increased in diabetic insulin resistance, resulting in more blood sugar.

The findings therefore suggest that agents that can selectively damp down activity of the IP3 spigot and the calcineurin accelerator might help to shut down the CRTC2 switch and to lower blood sugar in type II diabetic patients, he says. That is precisely what happened when the researchers used these compounds on liver cells.

"We obviously have a lot of work to do to find out whether such a strategy might work in humans," he says.

The research team includes investigators from Salk Institute, Columbia University, University of California San Diego and University of Ottawa. In addition to Montminy, the coauthors on the paper are Yiguo Wang, Gang Li, Jason Goode, Jose Paz, Kunfu Ouyang, Robert Screaton, Wolfgang Fischer, Ju Chen and Ira Tabas.

The study was funded by grants from the National Institutes of Health, the Kieckhefer Foundation, the Clayton Foundation for Medical Research and the Leona M. and Harry B. Helmsley Charitable Trust.

About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.

Big Pharma

Vertex Pharmaceuticals Could See Strong Gains From Incivek
Vertex Pharmaceuticals (VRTX) is looking to be a big frontrunner in the biotech industry. With the development and mildly successful testing of Vertex's next big drug, Incivek, there is great potential for Vertex to be a major competitor against big names such as Dendreon (DNDN). I believe that as long as the Hepatitis C "cure," Incivek, continues to pass all milestones, it will be a great opportunity for investors to make some money. Incivek will be very beneficial for the future of Vertex, due to the heavy media attention that surrounds Hepatitis C...Continue Reading..

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