Looking Beyond HbA1c: Research To Find New Diabetes Biomarkers Gains Traction

The discovery of several new biomarkers in the blood may further our understanding of exactly who’s at risk for diabetes

BETA cells within the pancreas produce and release insulin. Loss of the function of these cells compromises the body’s ability to control blood sugar and underlies the development of diabetes. So, one of the next frontiers of diabetes therapeutics is to change the progression rate of beta cell failure.

Recognizing this as a research priority, the Foundation of the National Institutes of Health (FNIH) Biomarkers Consortium announced Tuesday the launch of a multi-year clinical study to improve tools for measuring the function of insulin-producing beta cells in people with type 2 diabetes mellitus. Researchers hope the initiative will lead to improved techniques for tracking progression of the disease and pave the way for more effective treatments.

The project ‒ “Diabetes Drug Development: Identification and Validation of Markers that Predict Long-Term Beta Cell Function and Mass” ‒ is being managed by the Metabolic Disorders Steering Committee (MDSC) of the FNIH Biomarkers Consortium.

It is a three-year, $5.1 million clinical study to standardize tests for measuring beta cell function in the clinical setting that aims to improve methods for the early prediction of the long-term response to an intervention and for identification of patients at risk for rapid beta cell function deterioration, thereby enabling future clinical studies that examine diabetes progression.

A biomarker is a biochemical feature or facet that can be used to measure the progress of disease or the effects of treatment. So the validation of biomarkers to measure the progression of diabetes will greatly facilitate the development of better medicines to treat and potentially prevent this disease and its often disabling complications.

Experts believe biomarkers will become one of the major driving forces of pharmaceutical research and drug development in the coming years.

Currently, diabetes researchers are working without the benefit of agreed-upon standards for gauging beta cell function and this initiative will give researchers practical tools that can be used to measure beta cell function over time and stimulate research to maintain and improve that function.

The project was developed through a rigorous consensus-building process by a team of experts from across the entire scientific community. The pharmaceutical industry, academic, and government representatives contributed their clinical trials expertise and scientific support to the design and execution of the studies.

Utilizing a collaborative approach, the FNIH Biomarkers Consortium has brought together diabetes experts from the National Institutes of Health (NIH), Food and Drug Administration (FDA), leading academic institutions, the pharmaceutical industry, and non-profit sector to develop the project.

Biomarkers play an integral part in conducting clinical trials and treating patients. In most instances, they help medical practitioners, researchers, and regulatory officials make well-informed, scientifically sound decisions.

However, in clinical studies, there is often uncertainty in how much weight to place on biomarker results versus clinical outcomes. This uncertainty emanates from opposing goals of the drug approval process. On one hand, the process must ensure that all therapeutics tested are safe and that the benefits outweigh the risks. On the other hand, the process should allow therapies to be accessible to patients as quickly as reasonably possible.

Judicious use of biomarkers in the drug development process can bring these goals into alignment. More efficient discovery and use of biomarkers in the development of anti-diabetes drugs will depend on advancing current understanding of the pathogenesis of diabetes and especially its macrovascular (pertaining to the larger blood vessels) complications.

The idea of using biomarkers to predict diabetes is not entirely new. Glycated hemoglobin (HbA1C) values are now routinely being monitored to screen for at-risk patients. A study published in PLoS One last year shows that several new biomarkers in the blood may further our understanding of exactly who’s at risk for diabetes, and increase our knowledge of the etiology of the disease.

Veikko Salomaa and colleagues from the Department of Chronic Disease Prevention at the National Institute for Health and Welfare in Helsinki, Finland, tested nearly 13,000 people and found almost 600 cases of diabetes during routine follow-up exams.

According to the study, low levels of adiponectin, and high levels of apoB, C-reactive protein (CRP), and insulin, increase the chance that a woman will develop diabetes. When these factors were measured, proper diabetes prediction increased by 14% compared to when doctors only use classic risk factors, such as BMI and blood glucose levels, to predict disease.

The biomarkers that best predicted diabetes in men were low adiponectin, and high levels of CRP, interleukin-1 receptor antagonist (IL-1RA), and ferritin. Accounting for these biomarkers led to a 25% increase in correct diabetes detection in the cohort. Adiponectin is a hormone found in the body that modulates a number of metabolic processes, including glucose regulation and fatty acid catabolism.

The use of adiponectin, a hormone derived from fat cells, which is abundant in plasma and easy to measure through commercially available kits, was also confirmed as a robust biomarker predictive of glycemic efficacy in Type 2 diabetes and healthy subjects, after treatment with peroxisome proliferator-activated receptor-agonists (PPAR), but not after treatment with non-PPAR drugs such as metformin by the first project to be completed by the Biomarkers Consortium.

The project conducted a statistical analysis of pooled and blinded pre-existing data from Phase II clinical trials contributed by four pharmaceutical companies and analyzed under the direction of a diverse team of scientists from industry, the National Institutes of Health (NIH), U.S. Food & Drug Administration (FDA), and academic research institutions.

Source: FNIH Biomarker Consortium

A Cure for Diabetes By Implanting Insulin-Producing Islets in Abdomen

Trials on Primates Have Shown Promising Results

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DOCTORS from Hackensack University Medical Center (HUMC) in New Jersey hope to find a cure for diabetes as they embark on a partnership with one of the world’s leading researchers for the disease.

The hospital will be the first to try a procedure on humans with diabetes that is currently being tested on monkeys in Florida — a collaborative effort with Dr. Camillo Ricordi, a pioneer in the field and the scientific director and chief academy officer of the University of Miami Diabetes Research Institute.

“Dr. Ricordi wants to find a cure for diabetes, and he doesn’t care how many people are involved in the process or share in the credit,” said Dr. Michael Shapiro, Hackensack’s chief of organ transplantation and leader of the diabetes partnership. “This collaboration will do great things for diabetes research.”

“Forty percent of transplant patients have diabetes. And we know the DRI is committed to linking everyone worldwide to find a cure,” he said.

Diabetes occurs when the body cannot produce or properly use insulin, a hormone that helps the body metabolize glucose into energy and control blood sugar levels.

With Type 1 diabetes, earlier called juvenile diabetes and the most serious form of the disease, the body’s immune system destroys the cells from the pancreas that make insulin, called islets. People with Type 2 diabetes make insulin, but their body doesn’t utilize it correctly and production of it typically declines as they age. More than 25 million Americans have diabetes, and about 3 million of those suffer with Type 1.

Typical treatment for diabetic patients includes insulin pumps, injections and oral medications. Transplanting islets from deceased donors is sometimes effective, but it frequently triggers other complications because the islets need to be implanted in the liver. The number of organ donors also falls way short of the number of diabetics who would benefit from a transplant.

New Technique

Dr. Ricordi’s technique includes loading islets — the cells that make insulin and are destroyed by Type 1 diabetes — on a disc and implanting them in the abdomen. In the past, islets have been transplanted in the liver with little success.

Dr Camillo Ricordi

“The challenge is we’re dealing with an autoimmune disease so we have to replace or get cells to regenerate that were destroyed,” Ricordi told dozens of HUMC executives, physicians and health care workers last week. “And the key is to do this without a lifelong regimen of autoimmune rejection drugs.”

But successfully transplanting the islets will only be part one of the cure. Researchers need to figure out how to create islets in the lab so there will be enough to treat all diabetic patients who need them. Still, the partnership has hospital executives determined and diabetic patients hopeful. “I’m absolutely sure we’ll find a cure,” said Robert Garrett, president and chief executive of HUMC.

Because of promising results with the monkeys, Shapiro hopes to have four patients undergo the procedure in early 2012. The ideal patients will be those who aren’t responding to other treatments.

Past Success

Physicians attending the announcement highlighted Ricordi’s expertise and advances in treatment of the disease.

His creation, the Ricordi Chamber, is so well-known in the field that it was mentioned in a recent episode of the medical drama “Grey’s Anatomy.” Critical for a transplant, it is able to efficiently separate islets from the pancreas.

Stephanie Stone, who was diagnosed with diabetes at 10 and is now 18, attended the announcement with her Franklin Lakes family. “I’m optimistic for the future,” Stephanie said. “If this isn’t a cure, it sounds like it’s a better treatment before a cure is found.”

Earlier in January, the Molly and Lindsey Diabetes Research Foundation at Hackensack University Medical Center (HUMC) and the Diabetes Research Institute (DRI) at the University of Miami Miller School of Medicine had announced the formation of the Hackensack-Miami DRI Federation Project.

The project is aimed to provide a unique opportunity for funding agencies, financial institutions, and corporate entities to collaborate with the scientists and their project teams in order to provide the core competencies and infrastructure needed to move projects forward in the safest, fastest, and most efficient way possible.

“This collaboration represents an exceptional opportunity to overcome current limitations of research progress within traditional academic institutions,” said Robert C. Garrett,

“Hackensack University Medical Center is going to take the lead in diabetes research in the tri-state area,” said Dr. Shapiro. “Forty percent of transplant patients have diabetes. And we know the DRI is committed to linking everyone worldwide to find a cure.”

One of the group’s first objectives is to expand collaborative alliances with other leading research centers and to foster dynamic multidisciplinary research teams.

“There are few other collaborative projects that fully integrate basic, pre-clinical and clinical scientists to increase the rate of progress at which therapeutic solutions for type 1 diabetes can be safely and effectively brought from the bench to the bedside and eventually to a cure,” said Dr. Ricordi.

The impossible becomes possible when you bring the right people and the right resources together – especially when there is a common goal. The Molly and Lindsey Diabetes Research Foundation is the brainchild of two families who know what it means to have a child living with diabetes.

Nick Miniccuci and his wife, Susan, made a pledge more than two decades ago when they were told their nine-year-old daughter Molly had diabetes. “I vowed to do everything in my power to find a cure” explains Mr. Miniccuci, one of the philanthropists behind the alliance.  “That was a promise I intend to keep.”

“When Lindsey was diagnosed at the age of 11, we searched the world for a place that focused on curing the disease – not simply on learning to live with it –  and found theDRI,” said Bonnie Inserra, co-founder of the Foundation.  “There’s nobody like them worldwide. TheDRI team doesn’t keep research to themselves; they are experts who believe in worldwide collaborative science.  I want to see diabetes cured.”

In recognition of the endless efforts of Susan and Nick Minicucci and Bonnie and Larry Inserra, the HUMC Foundation’s Executive Vice President and Chief Operating Officer Robert L. Torre, presented a $500,000 check to the Miami-Hackensack project during a dinner held in January at the Stony Hill Inn Hackensack.  More than 50 people came together to celebrate a turning point in the history of diabetes thanks to the Minicucci and Inserra families. “We want to celebrate this new partnership – together we will find a cure,” Torre said.

About HUMC

HUMC is a nationally recognized healthcare organization offering patients the most comprehensive services, state-of-the-art technologies, and facilities. A leader in providing the highest quality patient-centered care, the medical center has been recognized for performance excellence encompassing the entire spectrum of hospital quality and service initiatives. These honors include being named one of America’s 50 Best Hospitals by HealthGrades® for four years in a row.

HUMC is the only hospital in New Jersey, New York, and New England to receive this honor. The medical center has also been ranked by U.S. News and World Report’s “America’s Best Hospitals 2010-11” in Geriatrics and Heart and Heart Surgery. NJBIZ, New Jersey’s premiere business news publication, honored HUMC as the 2010 Hospital of the Year, recognized for its excellence, innovation, and efforts which are making a significant impact on the quality of healthcare in New Jersey.

Hospital Newspaper, the leading provider of local hospitals and healthcare community news and information for hospital executives, also named HUMC Hospital of the Year in its December 2010 edition. Additionally, HUMC was named to The Leapfrog Group’s annual class of top hospitals and health systems and is one of only two hospitals in New Jersey to receive this national designation. HUMC is the hometown hospital of the New York Giants and Nets Basketball.

About the DRI

The Diabetes Research Institute, a Center of Excellence at the University of Miami Miller School of Medicine, is a recognized world leader in cure-focused research. Since its inception in the early 1970s, the DRI has made significant contributions to the field of diabetes research, pioneering many of the techniques used in islet transplantation.

The DRI is now building upon these achievements by bridging cell-based therapies with emerging technologies to restore insulin production. For the millions of families already affected by diabetes, the Diabetes Research Institute is the best hope for a cure.  Visit DiabetesResearch.org or call 800-321-3437 for more information.

Incretin Secretion, Action in the Natural History Of Type 2 Diabetes

INCRETIN hormones contribute a major portion to the insulin secretory responses after meals in healthy people. The incretin effect describes the phenomenon that oral glucose elicits approximately threefold greater insulin responses than the elevation in glucose (achieved with glucose administered intravenously) alone.

(Incretins are gastrointestinal hormones that influence insulin secretion, and which have been the basis for the development of new medications for type 2 diabetes.)

The incretin effect is the result of nutrient-stimulated secretion of the incretin hormones glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 and their insulinotropic effect (ie, the augmentation of insulin secretion at elevated plasma glucose concentrations). In patients with type 2 diabetes, this incretin effect is severely impaired or even absent.

It is the purpose of this commentary to highlight current knowledge in incretin research and to answer the question of whether and to which degree abnormalities in incretin hormone secretion and action accompany the development of type 2 diabetes or even contribute to this process.

The reduced incretin effect in patients with type 2 diabetes was first noticed in 1967 and was clearly established in 1986.

Three types of questions arose from this finding:

• What is the mechanism behind the reduced incretin effect? Is the secretion or insulinotropic action of GIP and GLP-1 at fault?

• Are defects in the enteroinsular axis (the signaling system between the gut, from where incretin hormones are secreted, and the endocrine pancreas, the main target tissue that incretin hormones act on) important for the development and/or progression of type 2 diabetes?

• Can the pathophysiological characterization of the incretin system in type 2 diabetes provide clues for the development of new approaches for the treatment of this metabolic disease?

A severe impairment in the insulinotropic (stimulating or affecting the production and activity of insulin) activity of GIP in type 2 diabetes explains the reduced incretin effect.

A large cross-sectional study by Toft-Nielsen and colleagues comparing GLP-1 responses after meal stimulation suggested a reduced release of GLP-1 in patients with type 2 diabetes and, to a lesser extent, impaired glucose tolerance (“prediabetes”).

This widely quoted study was sometimes interpreted to indicate a progressive loss in the capacity of GLP-1 secretion in the natural history of type 2 diabetes, starting from normal secretion as long as glucose tolerance was normal with slight impairments when IGT develops, with a further deterioration after the diagnosis of type 2 diabetes and little residual capacity for GLP-1 secretion when the condition has progressed.

The logical consequence was to replace a missing hormone by advocating incretin-based antidiabetic agents (GLP-1 receptor agonists [like Victoza that mimics the action of a naturally occurring substance] or DPP-4 inhibitors [medicines like like Januvia (sitagliptin), Onglyza (saxagliptin), and Galvus (vildagliptin) that contain DPP-4].

However, not all studies that have compared the secretion of GLP-1 in patients with type 2 diabetes and in matched healthy people come to the same conclusions.

A recent meta-analysis suggested no uniform reduction in L-cell secretion between healthy and type 2 diabetic patients, but a large interindividual variation, in part determined by age, obesity and plasma levels of glucagon and free fatty acids.

In nondiabetics, the amount of GIP and GLP-1 secreted is significantly correlated to the incretin effect in quantitative terms. Thus, a low secretion of GLP-1 may determine a reduced incretin effect on an individual level, but does not explain the reduced incretin effect in patients with type 2 diabetes by and large.

If secretion is not the culprit, is there any peculiarity regarding the action of incretin hormones in type 2 diabetes? As originally described using GIP of the porcine amino acid sequence, and later confirmed using synthetic human GIP, the endocrine pancreas shows very little secretory response, even if exposed to supraphysiological concentrations of GIP.

This inability to respond to GIP appears to be acquired, since populations at high risk for developing type 2 diabetes do not display a similar defect. Basically, the response to GIP seems to be normal in any form of prediabetes (first-degree relatives, patients recovering from gestational diabetes, etc.), but after diagnosis (ie, with a fasting glucose ≥126 mg/dL), the incretin effect is reduced or lost, as is the ability to respond to exogenous GIP.

Most likely, the inability to elicit insulin secretory responses with GIP, even at hyperglycemia, is explained by a generalized impairment in beta-cell secretory capacity, as is typical for type 2 diabetes, no matter which stimulus is looked at (hyperglycemia, amino acids, sulfonylureas, etc).

Furthermore, rodent studies have suggested a down-regulation of the GIP receptor by chronic hyperglycemia. The fact that this defect becomes apparent when glucose concentrations rise above the normal level has raised the question of whether this phenomenon is reversible by glucose normalization.

A recent study by Højberg and colleagues suggested that this may be the case. However, although the insulin secretory responses to GIP and GLP-1 were significantly improved, normalization was not achieved after improved glucose control.

Abnormalities in the incretin system accompany the development of type 2 diabetes and may contribute to the velocity of progression. Figure 1 depicts the natural history of developing type 2 diabetes and also the progression of the disease after the diagnosis has been made.

Changes in insulin secretory capacity, based on homeostasis model assessment (HOMA) estimation of beta-cell function, and insulin sensitivity preceding the diagnosis were taken from a recent analysis by Tabak and colleagues. The development after the diagnosis of diabetes was based on analyses from the UKPDS and ADOPT study.

Regarding the secretion of GIP and GLP-1, we refer to our recent review indicating no general abnormalities in K-cell (GIP) and L-cell (GLP-1) secretion associated with a diagnosis of type 2 diabetes.

The fact that in none of the studies examining prediabetic populations, insulinotropic GIP effectiveness was impaired, but after the diagnosis, uniformly, a severe inability to respond to GIP with secreting insulin was documented, is the basis for assuming a substantial drop in beta-cell responsiveness to GIP around the time of diagnosis, with no further changes afterward (Figure 1).

In a recent review, we have explained reasons to assume that this inability to secrete insulin in response to GIP stimulation goes along with a general impairment of beta-cell function, which is demonstrable with most other secretagogues as well.

Whether this inability of the endocrine pancreas to respond to GIP contributes to the natural history of type 2 diabetes can only be evaluated by quantitative considerations. If a mechanism to stimulate insulin secretion after meals that normally contributes two-thirds of the overall secretory responses is at fault, this almost certainly has the effect to accelerate the progression of type 2 diabetes because without the additional incretin stimulus, overall insulin secretion should be further impaired.

In the case of GLP-1, the insulinotropic activity is somewhat reduced after the diagnosis of type 2 diabetes, and even worse under the condition of uncontrolled hyperglycemia compared with healthy controls.

High pharmacological doses of GLP-1, nevertheless, have the potential to raise insulin concentrations and to suppress glucagon secretion, with the overall result of normalizing glucose concentrations in the fasting state and after meals over a wide range of patients with type 2 diabetes, ranging from those treatable with lifestyle modification (“diet and exercise”) to those requiring insulin treatments.

Thus, the “resistance” to GIP of the type 2 diabetic beta-cell can be overcome by a compensatory exposure to high concentrations of the incretin hormone, GLP-1. GLP-1 itself appears to be less important than GIP for postprandial glucose control in healthy people and does not seem to be involved in the pathogenesis (origination and development) of type 2 diabetes.

However, because of its preserved efficacy in type 2 diabetes, GLP-1 is an effective agent to treat hyperglycemia in type 2 diabetic patients, with the added benefits of inducing weight loss and avoiding hypoglycemia.

By Michael A. Nauck, MD, PhD, Irfan Vardarli, MD (Diabeteszenstrum Bad Lauterberg), and Juris J. Meier, MD (St. Josef-Hospital, Ruhr-University of Bochum, Germany)

Source: Endocrine Today

Diabetes: Artificial Pancreas Best Hope For Diabetics In Near Term

The realization that breakthroughs in biology-based therapies for diabetes are not imminent is spurring tech-based innovation in insulin delivery mechanisms

The days when ‘the only choice open to diabetes sufferers was that between death by coma and death by starvation’ passed unmourned into history in 1922, when insulin was first used therapeutically.

Even today, however, diabetes has lost none of its fearsomeness, because even today diabetics live in constant fear of overdosage or underdosage of their medicines, especially insulin, and of consequent hypoglycemic episodes and late complications that can result from inadequate treatment and prolonged elevation of blood glucose level.

Patients with diabetes whose blood glucose levels are kept close to normal by means of suitable therapeutic measures avoid the risk of dangerous hypoglycemic episodes and develop complications of diabetes considerably less frequently and later than their less successfully treated counterparts.

Artificial Pancreas Project concept

But there is realization that breakthroughs in biology-based therapies for diabetes are not imminent. Sure, there is hope that they’re going to happen, but more long-term research is needed.

In the meanwhile, technology that can meet this need is available and is spurring innovation in insulin delivery mechanisms. As a result, diabetes technology, and particularly the artificial pancreas, has become an area of very rapid academic and industrial development.

A precondition for this success is close monitoring of blood glucose levels. Therefore, a great deal of research activity has been directed towards the development of sensors that permit near-painless, continuous measurement of blood glucose level. The objective is to develop a system that pairs continuous blood glucose monitoring with an insulin pump and thus acts as an ‘artificial pancreas’.

Why Continuous Blood Glucose Monitoring Is Desirable

It is difficult to achieve good metabolic control in diabetics. Especially in patients on intensive insulin therapy, good metabolic control calls for frequent blood glucose determinations by patients themselves. The timing and dose of insulin injections have to be adapted to a variety of factors that influence blood glucose level, such as carbohydrate intake, physical exertion, sporting activities, stress (including operations, injuries and infections) and also rest periods such as periods spent asleep.

Insulin Pump

In addition to being painful and unpleasant, individual determinations of blood glucose by patients themselves using the conventional invasive techniques provide no more than a snapshot of the patient’s blood glucose level at the moment the blood sample was taken.

Continuous glucose monitoring (CGM), by contrast, would detect fluctuations in blood glucose level over a prolonged period and indicate when major deviations from the normal range occur. Every diabetic could benefit from continuous monitoring of their blood glucose level.

What Is An Artificial Pancreas?

An artificial pancreas is essentially a device that would both measure sugar levels and dispense appropriate amounts of insulin to keep blood sugar levels in optimal range. It would take much of the guesswork out of daily management of the disease and in the long-run, controlled sugar levels will help to lessen or avert the devastating complications from diabetes.

The medical equipment approach to an artificial pancreas: automatic control of an insulin pump with feedback from a continuous blood glucose sensor.

An artificial pancreas will integrate two currently available technologies ‒ continuous glucose monitors and insulin pumps ‒ with an algorithm that provides the right amount of insulin at the right time.  It will enable people with diabetes to achieve tight blood glucose control avoiding both highs and dangerous lows, thereby significantly reducing the risk of the disease’s devastating complications.

Why Is An Artificial Pancreas Needed?

The current diabetes treatment market comprises three related but distinct submarkets that address different aspects of the condition. Products in the market are currently comprised of blood glucose monitors, lancets & test strips, continuous blood glucose monitors, insulin, insulin pumps, syringes, and other insulin delivery devices & anti-diabetic drugs. Right now, the most significant growth in the U.S. market is in continuous blood glucose meters, insulin pumps, and anti-diabetic drugs.

An artificial pancreas could potentially revolutionize diabetes care and management, significantly improving the ability of people with diabetes to maintain strict blood glucose control, and ‒ as a direct result ‒ helping reduce kidney disease, heart attacks and stroke, amputations, blindness, and death from severe hypoglycemia.

Extensive research shows that glucose control is the primary factor in avoiding the devastating complications of diabetes. The landmark Diabetes Control and Complications Trial (conducted 1983-1993) showed that intensive diabetes management and improved glycemic control reduces major long-term complications of diabetes.

A later study published in the New England Journal of Medicine found that intensive diabetes therapy aimed at achieving good control reduced the risk of any heart disease event by 42 percent, and the risk of nonfatal myocardial infarction, stroke, or death from heart disease by 57 percent.

However, clinical research shows that most people with diabetes are not controlling blood glucose levels nearly well enough. The risk of complications ‒ and the economic burden placed on our health care system ‒ could be significantly lowered with devices that improve blood glucose control. And good glucose control will probably enhance the effectiveness of promising new cure therapies such as beta cell regeneration and islet transplantation.

Diabetes Technology To The Rescue

There are several classes of technologies used for diabetes care at home. In general, the devices include monitoring of blood glucose levels and delivery of insulin. The monitoring can happen with finger sticks or with the newer generation of continuous glucose monitoring that permanently attach to the person.

Insulin delivery, the old-fashioned way, is through injections several times a day. The newer devices are insulin pumps. They attach to the person with little needles under the skin that deliver insulin at continuous rates.

But the current problem with even the most advanced treatment of diabetes is that these devices don’t talk to each other. Even the most sophisticated insulin pumps will keep delivering insulin regardless of the blood sugar level of the person because it doesn’t have any information coming from the monitors. That can cause severe reactions.

Boris Kovatchev, director of the Center for Diabetes Technology at the University of Virginia, has focused on diabetes technology for more than a decade.

Dr Boris Kovatchev

His contribution to this area is to make these devices talk to each other in a smart fashion, to insert an algorithm that can take the reading from the monitoring device and tell the insulin pump to deliver insulin in a smart way.

The Artificial Pancreas Project is the most advanced application of the device. It connects the most advanced continuous monitoring device to the most advanced insulin pumps available in a continuous fashion — all the time. This is the top of the line integrated technology — and that means continuous monitoring of the person’s blood sugar levels and the reaction to changes.

The system’s “smart” algorithm, developed by Kovatchev’s team and collaborators from the University of Padova in Italy, uses existing continuous glucose monitoring and insulin pump technology to automatically regulate a patient’s insulin levels, with no action required on behalf of the user. The algorithm is currently being tested in clinical trials at the U-Va. Health System and 10 other centers spanning seven countries.

A device developed by Kovatchev and collaborators to automatically regulate a patient's insulin levels as part of the Artificial Pancreas Project (right) is shown with a continuous glucose monitor (left)

This project ‒ initiated by the Juvenile Diabetes Research Foundation (JDRF) ‒ has been going on since 2006. Kovatchev’s group was one of the first to join this project. Since then, it has grown significantly. Now, there are government initiatives in several countries and a lot of companies are interested in this technology.

The U-Va group has undertaken some extensive clinical trials on around 60 patients on that system for short periods of time for testing purposes. Besides, there are ongoing clinical trials in eight countries, all using Kovatchev’s patented technology or components of it.

The most challenging aspect of this technology is predicting the future. The reason that the future must be predicted accurately in this particular technology is that insulin delivery under the skin and glucose monitoring under the skin have delays.

“The monitoring of the blood sugar level generally works with a one-hour delay. Imagine you’re driving a car and you’re reacting to oncoming traffic with a one-minute delay. In situations like that, you have outdated data and delayed action. You have to anticipate what is going on in the next hour,” explains Kovatchev.

To make his device predict the near future for diabetes management, Kovatchev is developing a class of control strategies called model predictive control. Every human is assigned a mathematical model that mimics the functioning of the metabolic system of that person.

“Based on what that model says, we can predict the future. It’s similar to weather forecasts. But instead of weather models, we have models of a particular human,” he says with confidence.

How Insulin-Producing Cells Die – Research Offers Potential for New Diabetes Diagnostic Test

The death of insulin-producing beta cells in the pancreas is a core defect in diabetes. Scientists in Italy and Texas now have discovered a new way that these cells die — by toxic imbalance of a molecule secreted by other pancreatic cells.

“Our study shows that neighboring cells called alpha cells can behave like adversaries for beta cells. This was an unexpected finding,” said Franco Folli, M.D., Ph.D., professor of medicine/diabetes at The University of Texas Health Science Center at San Antonio. He is co-lead author on the study with Carla Perego, Ph.D., assistant professor of physiology at the University of Milan.

Alpha and beta cells are grouped in areas of the pancreas called the islets of Langerhans. Alpha cells make glucagon, the hormone that raises blood sugar during fasting. In the same environment the beta cells make insulin, the hormone that lowers sugars after a meal. Imbalance ultimately leads to diabetes.

“We found that glutamate, a major signaling molecule in the brain and pancreas, is secreted together with glucagon by alpha cells and affects beta cell integrity,” Dr. Folli said. “In a situation where there is an imbalance toward more alpha cells and fewer beta cells, as in Type 1 and Type 2 diabetes, this could result in further beta cell destruction.”

Glutamate toxicity is a new mechanism of beta cell destruction not previously known, Drs. Perego and Folli said. It has not been typically thought that alpha cells could themselves be a cause of beta cell damage, they said.

The study also found a protection for beta cells, namely, a protein called GLT1 that controls glutamate levels outside the beta cells. “GLT1 is like a thermostat controlling the microenvironment of beta cells with respect to glutamate concentration,” Dr. Perego said.

A diagnostic test for glutamate toxicity in the islets of Langerhans is being developed by the authors, Dr. Folli said. Eventually an intervention to slow the process could follow.

Glutamate poisoning is a new candidate mechanism for beta cell destruction in diabetes. Others are high glucose, buildup of a protein called amyloid, and free fatty acids, which are found in patients with type 2 diabetes.

“The vicious cycle in diabetes is that there are several substances that have been shown, also by us, to be toxic to beta cells,” Dr. Folli said. “And now we have found a new one, glutamate.”

Diabetes: Why do Doctors Miss the Wood for the Trees?

I find it very strange that when you are hospitalized, the doctors looking after you are concerned only with the problem you have reported at the time of admission and not much else. I mean what you say is wrong with need not necessarily be the only thing a doctor should be worried about – there could be other unknown reasons for your hospitalization.

Back in 1998 when I was hospitalized for “abdominal pain” (my complaint), the doctor’s (correct) prognosis was acute pancreatitis. I went through a battery of tests which confirmed this. However, the CT scan also showed the presence of a number of stones in the gallbladder.

My wife pointed this out to the doctor who dismissed the finding as a “secondary” issue that “could be tackled later. We have to treat the pancreatitis first.”

To cut the long story short, I was soon developing obstructive jaundice periodically. At the same time it was discovered that I had developed Type 2 diabetes and was put on insulin (my choice, since I had researched the problem). And, finally, 3 ERCPs and stentings later, in 2003 it was finally decided that my gall bladder had to be removed surgically (cholecystectomy) because the common bile duct was blocked by a gallstone the size of a small marble.

That is not the end of the story. Five years later, I had chronic pancreatitis and developed pancreatic abscess, and as a result, intestinal adhesions that required emergency surgery. Uncontrolled hyperglycemia added to the problems and I was in hospital for 2 months.

My saga does not end here. Fearing that I might develop an infection during the 2008 surgery (it was touch-and-go for me at that stage), the surgeon decided not to place a mesh to strengthen my abdominal wall. So a year later an incisional hernia developed, which required another surgery a few months ago.

My point is that if the gallstones had been removed laparoscopically in 1998, maybe, just maybe, I might not have developed type 2 diabetes.

I have brought this up with many doctors time and again. My argument is: Gallstones are also a cause for pancreatitis (though not necessarily in my case), which means damage to the pancreas that produce insulin. So why weren’t the gallstones attacked earlier? I may have been a healthier individual today. But, alas, I still have to get an honest, in-your-face answer. As with any profession, in the world of medicine, too, dog doesn’t eat dog.

But this just strengthens my belief – and I’ve written about this basing my argument on empirical evidence – that in the age of ‘superspeciality’, our medical schools are producing graduates who miss the wood for the trees.

I can therefore empathize with a British pensioner who developed diabetes after battling pancreatic cancer and nearly died because medics failed to diagnose the condition.

According to a news report, Raymond Ellerby, 67, lost three stone in four weeks because his diabetes was not spotted. It was only when he slipped into a diabetes-induced coma – a life-threatening condition – that doctors discovered what was wrong with him.

Diabetes is always a risk following pancreatic surgery when part of the pancreas, which produces insulin to regulate the body’s sugar levels, is removed. And Ellerby had an operation to remove part of his pancreas at Castle Hill Hospital at Hull, East Yorkshire, in December 2009. Initially, he seemed to recover well but his health then started to deteriorate late spring, with his weight plummeting and feelings of dizziness, constant nausea and pain.

“It was like being drunk all the time – I didn’t know what I was doing…I was having hallucinations and I knew I didn’t feel like myself. Eventually I was found collapsed on the floor of my lounge by my daughter. If she hadn’t found me, I wouldn’t be here now,” he recalls.

The great-grandfather was taken to Hull Royal Infirmary where doctors told his family he could die within hours. But he came round and was on the Intensive Care Unit for about a week.

Following his recovery, Ellerby complained to the UK Patient Advice and Liaison Service for Hull and East Yorkshire Hospitals NHS Trust. He has now been told procedures to identify diabetes in patients with pancreatic cancer have been “changed completely”.

A letter from Jenny Barker, assistant service manager in digestive diseases at Castle Hill Hospital, dated February 11, contained an apology from Dr Anthony Maraveyas, senior lecturer in oncology. She said: “Dr Maraveyas would like to reassure you that since this incident, the Trust has changed practice completely and all patients with a newly-diagnosed pancreatic cancer, who come to the unit, have a baseline glucose test, which is reviewed at regular intervals. He would like to apologize once again for any distress or anxiety caused due to your diabetic symptoms not being identified initially.”

Wow, even a layman would have thought that if damaged pancreas is involved, “a baseline glucose test, which is reviewed at regular intervals,” would be the first thing ANY doctor would order.

In essence, thanks to the doctor’s incompetence, Ellerby had received a death sentence. That he survived to tell the tale is another story. And all he got in return was a letter from the British NHS Trust chief executive Phil Morley, saying, “Please accept my apologies for the distress you and our family have experienced.”

So my advice to everyone is: Research your condition and take a second opinion. And DON’T put your faith in just one doctor ‒ he may be clueless about treating diabetes-related problems.

Diabetes: Do Alternative Treatments Work?

There’s something about Type 2 diabetes that inspires creativity, innovation and promises from the alternative medicine industry. People who want to control their blood sugar without medications can choose from a huge variety of pills and elixirs. “I hear new claims on a nearly daily basis,” says Dr. Daniel Einhorn, clinical professor of medicine at UC San Diego and the president of the American Assn. of Clinical Endocrinologists. “There’s a constant market for new products.”

Many current products take an herbal approach to blood sugar control. The liquid supplement Sugar Crush from NaturEra, for example, combines common sage, cinnamon, hibiscus and fenugreek, among other ingredients.

The product comes in two varieties, regular Sugar Crush and the milder Sugar Crush Daily. Users are instructed to drink 2.5 milliliters of regular Sugar Crush mixed with a glass of water right before breakfast and dinner every day. Sugar Crush Daily is recommended as a prelude to lunch and bedtime. After two or three months, users are told that they can stop taking Sugar Crush and stick with two doses of Sugar Crush Daily, one before each of the two largest meals of the day.

Sugar Crush isn’t yet sold in stores — company President Uri Man says it will be widely available starting in March — but you can buy a 125 ml bottle of either variety online for $89.95. https://shop.buysugarcrush.com/ProductDetails.asp?ProductCode=SUGARD2//

If you prefer more simplicity in your supplement, you could always try one of several products offering Cinnulin PF — an extract of cinnamon bark made by Integrity Nutraceuticals — as their sole active ingredient. Each capsule of Cinnulin PF from iVitals contains 125 milligrams of the extract. Users are instructed to take one capsule before breakfast and one before dinner for best results. A bottle of 120 capsules, available only online, costs about $30.

Nature’s Way sells a supplement called Blood Sugar that contains, among other things, 133 mg of cinnamon bark extract, 100 micrograms of chromium and 33 mg of extract of the tropical South Asian herb Gymnema sylvestre per capsule. Users are instructed to take three capsules twice daily. You can buy a bottle of 90 capsules, available at many health food stores, for about $15.

The Claims

The Sugar Crush website says that the products “are the world’s first liquid, clinically tested, completely natural dietary supplements which help maintain healthy glucose levels.” Man, the NaturEra president, says that company studies have found that the supplements, which are already very popular in Israel, have been shown to reduce blood sugar levels by up to 40% in just 30 days.

The company has not yet published any studies in medical journals, although it did present results at a recent meeting of the American Diabetes Assn. and the American Assn. of Diabetes Educators. (Both the ADA and the AADE declined to comment on Sugar Crush or any other specific products.) Adds Man, “99% of the other [diabetes] products on the market haven’t been proven to do anything.”

The iVitals website doesn’t expressly claim that Cinnulin PF can help treat diabetes. Instead, the site says the product “may support healthy glucose levels in healthy individuals.” Tim Romero, president of Integrity Nutraceuticals, says cinnamon reduces blood sugar levels by making cells more sensitive to insulin, the hormone that helps cells take in blood sugar.

The website for Nature’s Way Blood Sugar hardly makes any claims beyond the name of the supplement. The site simply says that the product contains “chromium which is an important factor for insulin.” A spokesperson for the company declined to answer any questions about the ingredients or potential benefits of the product.

The Bottom Line

There’s no doubt that diet — including supplement choices — can affect blood sugar levels. But Einhorn says there’s still no herbal supplement with a scientifically proven track record for helping people with diabetes really get their blood sugar under control. “It would be very attractive to have natural treatments,” he says. “But the scientific evidence that they work is very slim.”

Richard Anderson, a research chemist with the U.S. Department of Agriculture’s Diet, Genomics and Immunology lab in Beltsville, Md., has a more optimistic view of the potential of herbs and supplements, especially cinnamon and chromium. Anderson says research in his lab — including human trials of Cinnulin PF — suggests that each of these ingredients can increase the body’s sensitivity to insulin.

A 2006 study of 22 people with pre-diabetes published in the Journal of the International Society of Sports Nutrition found that taking 500 mg of Cinnulin PF a day for 12 weeks reduced fasting blood glucose — a measure of blood sugar after one hasn’t eaten for eight hours that is used to diagnose pre-diabetes or diabetes — by about 8%.

And in 2007, researchers at UC San Francisco reported in the journal Pharmacotherapy that cinnamon might have “modest” effects on blood sugar, but they also warned that the spice shouldn’t be used as a substitute for standard treatment of diabetes, including exercise, a healthy diet and prescription drugs.

Anderson cautions that some claims about diabetes remedies may be overblown. To his mind, it’s “hard to believe” that Sugar Crush could reduce blood sugar levels by 40%. He adds that, although cinnamon and chromium are generally safe, it would be risky for anyone to switch medications for herbs without first talking to his or her doctor.

Einhorn, meanwhile, thinks it would be unwise to expect anything from an herbal diabetic product. “I’m surprised that anyone from the USDA said that these things have any therapeutic value,” he says.

Einhorn adds that there are exactly two proven and reliable ways to control blood sugar without resorting to prescription medications: regular exercise and a healthy diet.

Groundbreaking Pancreas Transplant by Robot to Help Diabetics

The first pancreas transplant using robots has been performed in Italy. A 43-year-old mother-of-two had the three-hour procedure in Pisa Hospital, suffering no complications from the operation, with the new organ being accepted completely. The woman has suffered from type 1 diabetes since she was 24, and already received a kidney transplant . The pioneering procedure used the Da Vinci SHDI robot, which assisted in the removal of the woman’s pancreas and inserted a new one just by making just three small holes and an incision that was only seven centimetres long. The robot, designed in the Robotic Surgery centre in Pisa, is large and has several arms. It is hoped that the transplant will allow new treatments for diabetes patients, as it is a far less invasive approach than traditional surgery . Up until now, transplants of the pancreas have been extremely invasive due to the vascular structure of the organ and the fragile state of diabetes patients, as half of these cases develop post-operative problems. Ugo Boggi, who was lead surgeon for the operation, said the procedure “ends a diatribe that lasted for decades on the advisability of transplanting pancreases because of the hugely invasive nature of traditional techniques and the massive incidence of post-op complications.”

Diabetes Research: Using Molecules to Stimulate Insulin Production

Researchers from the University of Pittsburgh have discovered that the stimulation of a single molecule can result in the increased production of insulin to help manage diabetes. The study was published in the journal Diabetes published by the American Diabetes Association.

The study also found many other combinations of molecules that stimulate beta cells to replicate. When beta cells replicate, insulin is produced and this helps in the control of the amount of blood glucose in the body. Diabetes is either the body’s inability to produce insulin or the low amounts of insulin produced for the body’s needs.

“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, M.D., 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.”

The discovery was made when the team headed by Dr. Nathalie M. Fiaschi-Taesch found that the combination of elevated amounts of regulatory molecules cdk4 or cdk6 and D-cyclin proteins such as cyclin D3 results in the increased human beta cell production in test tubes. At the outset, there was no known role that cyclin D3 plays in human beta cell physiology but the discovery of its ability to increase replication overturned such notions.

When tested on rodent subjects, it was found that Cyclin D2 was essential in beta cell replication and functioning. On the other hand, the molecule was barely discernible in humans. The stimulation regimen, the study showed, can be sustained for at least four weeks in reengineered mice. These rodent subjects were transplanted with human beta cells that produce large quantities of cdk6.

This is but the start of another avenue in the treatment and management of diabetes. The use of regulatory proteins can be one of the best regimens yet available in increasing beta cell replication for diabetes worldwide.

From diabetesforum.com

Depression Sufferers Live With Higher Risk of Diabetes

Depression can heighten the risk of developing type 2 diabetes as the mental illness also increases the likelihood of obesity and failing to take enough exercise, a study carried out by the German Diabetes Association (DDG) has shown, reports DPA.

Bouts of depression can also lead to higher levels of the stress hormone cortisol in the blood. Cortisol, also known as hydrocortisone, counteracts insulin and contributes to type 2 diabetes, which is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency.

It is recommended that those suffering from depression undergo tests for the disease as they are 11 times more likely to suffer vascular complications than people battling diabetes alone. The risk of damage to arteries, which could lead to a heart attack, is between two and five times as high.

According to the DDG, not only are people with depression at increased risk of developing type 2 diabetes, those with diabetes are also at increased risk of developing depression.

The consequences can be serious as treatment for diabetes requires the active involvement of the patient. “Depression is a major barrier in such instances,” explains Bernhard Kulzer, chairman of the DDG’s psychology council.

Complications that can result from improperly managed type 2 diabetes include renal failure, blindness and arterial disease, including coronary artery disease. The DDG recommends that diabetics suffering from depression undergo psychological treatment.