New-Onset Diabetes May Help Guide Pancreatic Cancer Screening

A new diagnosis of diabetes may help identify older adults who will develop pancreatic cancer while there is still time for screening and early detection, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

In an observational study of more than 20,000 older adults with pancreatic cancer, 10 antecedent diagnoses were found to be significantly associated with the cancer diagnosis.

Of these, a diagnosis of new-onset diabetes preceded the cancer diagnosis by the greatest amount of time – more than 2 years, on average – or potentially enough time to catch the cancer early with targeted screening. A diagnosis of abdominal pain was second, at 1.5 years.

Late diagnosis is a major contributor to the generally “dismal” survival of pancreatic cancer, lead investigator Dr. Elizaveta Ragulin-Coyne said in an interview.

“Colonoscopy screening works great, mammography works great. But those cancers are really a lot more common, so it makes sense to screen the whole population,” she commented.

By contrast, pancreatic cancer is relatively uncommon, so population-based screening with current tests would generate many false positives. At present, only individuals from families having hereditary pancreatic cancers associated with certain mutations are screened.

The goal of the study was therefore to identify “the factors that can precede the diagnosis of pancreatic cancer, that sort of can act as red flags to identify that population at risk,” she explained. “So we are trying to identify the risk-rich population of individuals who can benefit from potential future screening.”

The investigators analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for the years 1991-2005 and the linked Medicare database for the years 1991-2007 to identify older adults with a diagnosis of pancreatic cancer and diagnoses preceding the cancer.

They evaluated 30 possible antecedent diagnoses for their association with the pancreatic cancer diagnosis, and narrowed it down to 10 that were significantly associated (P less than .05) in a stepwise logistic regression analysis: acute pancreatitis, chronic pancreatitis, cyst-pseudocyst, other pancreatic disease, bile duct obstruction, diabetes, weight loss, jaundice, abdominal pain, and hepatomegaly.

The 22,493 study patients were 77 years old on average; 55% were women and 86% were white, according to results reported in a poster session at the meeting.

The 10 antecedent diagnoses ranged in prevalence in this population from a low of 4% for hepatomegaly to a high of 76% for abdominal pain. A diagnosis of diabetes was seen in 45%.

In most cases, the median time between the antecedent diagnosis and the pancreatic cancer diagnosis was less than 3 months. The exceptions were abdominal pain, diagnosed a median of 18 months before the cancer, and diabetes, diagnosed a median of 28 months before the cancer.

The latter intervals are long enough to provide a window of opportunity for intervention, according to Dr. Ragulin-Coyne, a surgical resident and research fellow at the University of Massachusetts Medical Center in Worcester.

“It doesn’t make sense if you have preceding diagnoses within a month before, it doesn’t really make a difference,” she explained. “But if it’s over 6 months or over a year, it is actually clinically significant because you can hypothesize that those people are potentially at an early stage and could have more interventions that give you a possibility of cure.”

The average number of antecedent diagnoses decreased with increasing stage of pancreatic cancer at diagnosis, from 3.91 among patients with stage 0 disease to 2.04 among patients with stage IV disease.

This finding initially seemed counterintuitive, Dr. Ragulin-Coyne said. But perhaps patients having more advanced cancer at diagnosis have had less contact with the health care system in general, and therefore have fewer diagnoses on record.

In a logistic regression model among just the patients with an antecedent diabetes diagnosis, the odds of the gap between that diagnosis and the pancreatic cancer diagnosis being greater than 24 months were higher for nonwhite versus white patients; for patients aged 75-84 years or aged 85 years or older, compared with those aged 65-74 years; and for patients in the Midwest versus the Northeast.

The reason pancreatic cancer is diagnosed earlier in some patients and later in others is not yet clear, but it is likely multifactorial, according to Dr. Ragulin-Coyne.

“We can make guesses, whether it is socioeconomic or cultural or there is something else in play.” For example, some patients may “tell the doctor about all their symptoms and get worked up early and get their doctors concerned more,” she said. “But if they never come to the physician or they never mention what’s going on, they get diagnosed late.”

In any case, identifying the reasons will be critical to moving all patients into the early diagnosis group. “I think that will ultimately be the best thing if, when they come, we can offer them treatments and cure and options, versus just saying, unfortunately, it’s too late,” she commented.

The investigators have obtained the SEER data for all similar older adults without a pancreatic cancer diagnosis, and using a matched analysis, plan to develop and test a prediction nomogram using the information from their study. “Stay tuned for that,” she advised.

“Screening for pancreatic cancer will be a great future tool,” Dr. Ragulin-Coyne concluded, while also cautioning that there is still much work to be done before some type of population-based screening becomes a reality.

By: SUSAN LONDON, Internal Medicine News Digital Network

Surgical Procedure Can Control Type 2 Diabetes, Claims Brazilian Surgeon

A new procedure which requires surgical intervention through Ileal Transposition (or small intestinal switch) can effectively control Type 2 diabetes, a Brazilian surgeon claimed in Hyderabad, India on August 21.

Dr Aureo Ludovico de Paula, was in the city to address the first international conference and live workshop on this procedure along with his Indian counterpart Dr Surendra Ugale.

Ugale who is also the organizing secretary of the workshop said, “the new research has shown that there are some intestinal hormones which have a great effect on the pancreas and insulin secretion especially in response to food intake. Dr Paula has devised a laparoscopic operation which he claims is proving to be a cure for Type 2 diabetes.”

Paula said, “The surgery can control diabetes without insulin, arrest the metabolic syndrome of the body organ deterioration, thus avoiding future diabetic complications.”

The doctor who has performed 700 surgeries with 95% remissions said the operation involves a long segment of ilium (ending portion of small intestine) which is shifted to the upper small intestinal area, where food particles will reach it very soon on eating a meal.

This causes an immediate secretion of good hormone GLP-1 which acts on the B cells of pancreas to secrete insulin and control blood sugar.

The fall out is a biochemical process that facilitates insulin secretion in the presence of undigested food and controls Type 2 diabetes, a metabolic disorder that is marked by the failure to absorb sugar and starch due to lack of the hormone insulin, Paula said.

Type 2 diabetes is the most common form of diabetes. In this disease, either the body does not produce enough insulin or the cells ignore it.

Ugale explained that Type 2 Diabetes affects several organs. The solution therefore is to stimulate these hormones in lower intestine that in turn secrete GLP which in turn stimulates the pancreas to stimulate the insulin and get fresh beta cells.

He said patients who already have diabetes for ten years and using medication, and are suffering from five associated diseases are ideal candidates for this kind of surgical intervention which costs less than US $10,000 (in India).

The surgery not only controls high blood pressure but also improves kidney cholesterol nerves reduces excess weight and also one need not take any medicines. He also can eat normally post surgery, including sweets.

However, doctors insist that first of all in any patient they would advise lifestyle changes, exercise followed by medication, if there is diabetes and if the patient is not doing well only then surgery is advised.

Presently a centre in Mumbai and Hyderabad are performing this surgery. A centre has also come up in Coimbatore.

Over hundred doctors from all over the country and endocrinologists are participating in the two-day seminar

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

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: Rely On Facts, Not Fiction

Several sources of information on the type two diabetes can be found almost everywhere. If you suspect that you have the diabetes type 2 condition or are at risk of acquiring it, type 2 diabetes information can be easily and conveniently found online. However, not every bit of online data may be accurately written. Therefore, it is necessary to set the facts straight about the common misconceptions about type 2 diabetes.

Fact #1: Diabetes has no remedy
Accurate and reliable data on type 2 diabetes should tell you that currently, no known 100% cure on diabetes has been developed in the medical field yet. Albeit a diabetic patient can try and even prevent the diabetes condition from worsening he or she cannot completely treat it.

It is therefore important to be cautious with information on type 2 diabetes that will offer to provide you with a cure.

Fact #2: Type 2 Diabetes is not fully understood
Many medical researchers as well as medical organizations are constantly trying to help us understand more about type 2 diabetes by conducting researches. It is a known fact though that these studies and researches will take time if we are to fully grasp, and consequently, come up with the best possible medical solution for type 2 diabetes as, even its definite causes cannot be fully identified.

Several common possible sources have been identified such as genetic heritage wherein some people are insulin resistant compared to others. This hereditary trait, combined with and unhealthy diet and lifestyle may worsen any existing diabetes condition or increase the risk of having one.

Fact #3: Too much sugar does not necessarily cause diabetes
Consuming too much sweets, by itself, does not really cause diabetes. However, diabetics prohibited from eating too much sweet food because of their body’s inability to process glucose. Facts about type 2 diabetes will tell you that type 2 diabetics’ body do not react to insulin. It is this insulin in our body which tells us to open up and take in glucose for energy production.

Sugar is not the only food item that diabetics are warned by doctor against. Other food items that diabetics should also be careful with is Carbohydrates and it should be the first thing that should be watched out for. Reliable and accurate information on type 2 diabetes should include instructions on how to count the carbohydrates level in your body so you can control your intake. This is because foods rich in carbohydrates produce just as much glucose as sugar and other sweets.

Fact #4: Not all fruits are good
People have the misconception that going on a healthy food diet of vegetables and fruits is all that is we need to address your diabetes condition. What any reliable and accurate information on type 2 diabetes should inform you, however, is that it is not about eating as much fruits and vegetables as you can to replace carbohydrates intake.

A diabetic’s diet as far as fruits are concern should be about moderation and simply making sure that you eat only within your recommended daily allowance of sugars and carbohydrates, and fruits. Fruits may still contain sugar and, as a type 2 diabetic, you should try to do away with those foods that are high in the glycemic index in your information on type 2 diabetes.

Fact #5: Not all diabetics show symptoms
Since not all people manifest signs and symptoms of being diabetic, there are some who discover their condition too late. Factors which are contributory to diabetes such as being overweight, being advanced in age and a family background on the condition should be enough warning for you to undergo regular check ups as well as enough reason for you to have a healthy change in diet and lifestyle.

Fact #6: Complications from diabetes can kill
It is not really diabetes itself that kills in most cases. Diabetics usually die because of the complications. Heart ailments for example are the number one cause of death in people with severe or uncontrolled diabetes. Others however may also suffer from kidney failure.

Thank you Andy Rowde

Diabetes: Research Team Develops Agents That Keep Insulin Working Longer

More than half a century after researchers identified a promising way to treat diabetes based on blocking the breakdown of insulin in the body, a research team led by a scientist at the Mayo Clinic campus in Florida have developed potent molecules that can do just that.

The researchers say their findings, published in the May issue of PLoS ONE, could lay the foundation for a new class of drugs for treating diabetes. The tiny molecules they developed work by inhibiting a powerful molecular machine known as insulin-degrading enzyme (IDE) from chewing up the insulin hormone. That keeps insulin in the body longer to help remove glucose (simple food sugar) from the blood.

The discovery may lead to drugs that diabetics can use to help insulin work better and longer, says the study’s lead researcher, Malcolm Leissring, Ph.D., from Mayo Clinic’s Department of Neuroscience. Diabetes affects over 200 million people worldwide, and the incidence is growing at an alarming rate, so new treatments are greatly needed, he says.

IDE is a protease, an enzyme that chops proteins or peptides into smaller pieces. According to Dr. Leissring, inhibitors have been developed for practically all biomedically important proteases in the body. “It was very surprising that IDE inhibitors had not been developed before, particularly given IDE’s special relationship with insulin, a very important hormone,” he says.

This was especially puzzling because IDE was discovered more than 60 years ago. In fact, finding an IDE inhibitor was a major goal of diabetes research in the 1950s. In a landmark study, one group of early researchers managed to purify a naturally occurring IDE inhibitor, and showed that it made insulin more effective at lowering blood glucose in animals, precisely the desired effect for treating diabetes. However, the composition of the agent was never determined.

The research team initially tried to find IDE inhibitors using sophisticated technologies. They used robots to test hundreds of thousands of compounds at the Laboratory for Drug Discovery in Neurodegeneration (LDDN), a part of Brigham and Women’s Hospital and Harvard Medical School. Surprisingly, these modern methods did not identify any good inhibitors, Dr. Leissring says.

“Our robots wound up being powerless for tackling this particular problem,” he says. “Ironically, it was an old-fashioned method that made this breakthrough possible.”

The old-fashioned approach involved using a technology invented in 1950 to figure which peptide sequence – among trillions of possible combinations – IDE chops up most efficiently. Benjamin Turk, PhD, of Yale University School of Medicine, conducted this critical step. Then, a team of chemists led by Gregory Cuny, PhD, director of Medicinal Chemistry at the LDDN, generated a compound that contained the preferred peptide sequence, together with a special chemical group that binds to zinc. The resulting compound is called “Ii1” (IDE inhibitor 1).

Ii1 is about a million times more potent than any previous IDE inhibitors, but additional work will be needed to turn it into a drug suitable for therapeutic use, Dr. Leissring says. In a key step towards this goal, Dr. Leissring, together with Wei-Jen Tang, PhD, and other colleagues from the University of Chicago, solved the 3-dimensional crystal structure of Ii1 bound to IDE. This crystal structure will facilitate the development of inhibitors that are more stable in the body than Ii1 is predicted to be.

The structure of IDE is unlike other proteases, the researchers say. It is shaped like a hinged clamshell that opens and shuts, like the well-known video game protagonist, Pac-Man.

The researchers found from their crystal structure that the Ii1 peptide acts like a magnetic latch that holds the clamshell shut. “Think of a coin purse that uses a magnet at the top to keep the purse from opening up,” Dr. Leissring says. “Ii1 is analogous to the magnetic latch, holding the two halves of IDE closed.”

If IDE is inhibited, insulin remains in the body longer. Normally, about half of the insulin produced by the pancreas is immediately destroyed by the liver; no one knows why this occurs but it may be a way to regulate how much insulin enters the bloodstream, he says.

IDE inhibitors would slow the rate of this initial destruction. However, according to a surprising finding from the study, they would also help prevent degradation of insulin at the “destination” cells that are responsible for removing sugar from the bloodstream. “When insulin reaches cells, it is normally destroyed very rapidly by IDE. We show that when you stop that process with an IDE inhibitor, insulin stays around longer inside the cell, allowing the hormone to function more efficiently,” Dr. Leissring says.

IDE inhibitors may also be beneficial for other diseases besides diabetes, the researchers suggest. “Insulin is involved in a surprisingly wide range of important processes, including memory and cognition, so IDE inhibitors may turn out to have multiple uses. They also will be very valuable as tools for basic research,” says Dr. Leissring.

Thank you Mayo Clinic

Diabetes: Preventing Hypoglycemia

A team of Boston researchers has developed an artificial pancreas that prevented blood sugar from falling perilously low blood sugar (hypoglycemia) in a trial

Boston researchers have made a major step toward the development of an artificial pancreas that overcomes the bugaboo of most previous such attempts — dangerously low blood sugar caused by injection of too much insulin.

Their experimental device secretes two hormones normally produced by the pancreas — insulin and its counterbalancing hormone, called glucagon — and has been shown to control blood sugar levels in about a dozen people for at least 24 hours, they reported Wednesday.

The team is now planning longer trials as they gear up for what they hope will be approval by the Food and Drug Administration in as little as seven years.

“This is a very important proof-of-concept study,” said Dr. Irl B. Hirsch, an endocrinologist at the University of Washington School of Medicine, who was not involved in the research. “It was becoming obvious that if we were ever going to get [an artificial pancreas], we would have to use both hormones. . . . The fact that they have been able to do so successfully is very big and very exciting news.”

Most people know that Type 1 diabetes, which affects more than a million Americans, is caused by the loss of insulin-secreting beta cells in the pancreas.

Few realize, however, that the disease also affects alpha cells of the pancreas, which secrete glucagon to raise the level of sugar in the blood. Together, the two hormones help the body in the delicate balancing act of maintaining blood sugar levels that are neither too high nor too low.

Researchers have made tremendous advances in controlling blood sugar levels with continuous monitors and insulin pumps, “but one of the challenges is that we have an accelerator but not a brake,” which means blood sugar levels can fall too much, said molecular biologist Aaron Kowalski, a vice president of the Juvenile Diabetes Research Foundation, which partially sponsored the new research. The glucagon research, reported in the journal Science Translational Medicine, may provide that brake.

The brake is crucial, Kowalski added, because low blood sugar, or hypoglycemia, can cause seizures and even be fatal. For people who have been on insulin for long periods, the risk of hypoglycemia appears to grow over time, but it is also a problem in young children. “That’s what keeps us awake at night,” said Hirsch, who has been diabetic for 46 years.

What the Boston team has invented is a computer algorithm that responds to changes in blood sugar and computes how much insulin or glucagon to inject. Biomedical engineer Edward Damiano of Boston University began developing it a decade ago when his then-11-month-old son, David, was diagnosed with diabetes. He put the algorithm in a laptop and paired it with off-the-shelf insulin pumps — which could also be used to inject glucagon — and glucose monitors that are implanted under the skin.

After Damiano proved the system would work in diabetic pigs — which are remarkably similar to humans physiologically — Dr. Steven Russell of Massachusetts General Hospital suggested that it be tested in humans. Their first trials were conducted with 11 diabetics, who were hospitalized for 27 hours for the tests.

It was “a really rigorous test,” Russell said. “We fed them three very-high-carbohydrate meals, which is the most challenging part of automated control.”

Six of the patients experienced no hypoglycemia, but five had episodes that required they drink orange juice to recover. Subsequent analysis showed that those patients absorbed and metabolized insulin more slowly than normal. When Damiano adjusted the algorithm to account for this slowed absorption, all passed a repeat of the trial with flying colors — as did the six who did well the first time around.

The next test, perhaps beginning next month, will involve a larger group who will be on the devices for at least two days in the hospital. They will use a portable form of the system that will allow them to walk around and exercise on a treadmill, which is another challenge for automated systems.

A key problem is developing a stable solution of glucagon that can be used in the pump without decomposing, an effort that is being pursued by several companies.

But because that may produce delays in commercializing a pump that uses both hormones, Damiano and Russell think an insulin-only device will be first to market, in about five years. A device that uses both hormones might follow within a couple of years.

“I am committed to trying to get something along fast enough that it could develop into a commercial product before my kid goes to college,” Damiano said.

thomas.maugh @latimes.com