Lifestyle Diseases

Can an 'Artificial Pancreas' normalise type 1 diabetes?


Researchers at Mayo Clinic in the United States have begun clinical trials on an artificial pancreas that has been years in the making. If successful, it could relieve diabetes patients from the tiresome daily testing of their blood glucose levels and help them stay healthy and lead a better life. Barbara J. Toman, Managing Editor of Discovery’s Edge, Mayo Clinic’s research magazine, speaks to two of the lead researchers on the project for Middle East Health.

Russ Stephens is an insulin-dependent diabetic. Like thousands of other people with type 1 diabetes, he injects himself with insulin before every meal and again at bedtime. He also checks his blood glucose four or five times every day by pricking his finger to obtain a drop of blood and using a compact, hand-held glucose meter.

The blood glucose levels provide critical information that he uses to adjust his insulin dose, exercise schedule and food intake to maintain good diabetic “control”, which is essential to reduce the likelihood of diabetic complications that can lead to blindness, kidney failure, nerve damage, heart attacks and strokes. Some people with diabetes prefer to use an insulin pump instead of the regular injections, but they still have to measure their blood glucose levels and adjust the rate of insulin infusion several times a day.

“They set the alarm and wake up to check. Diabetes disrupts their sleep,” says Ananda Basu, MBBS, MD, a Mayo Clinic endocrinologist. Unfortunately, even with the closest attention to detail, these conventional approaches can only approximate the perfect, real-time blood glucose control that comes from having a normal pancreas.

That burdensome routine might someday be medical history. Mayo researchers will soon start clinical trials to evaluate an “artificial pancreas” – a device that can monitor blood sugar and deliver insulin in doses calibrated to the person’s unique needs.

“This would be a seismic change in diabetes treatment,” says Yogish C. Kudva, MBBS, the Mayo endocrinologist who is leading the project with Dr Basu. “It is part of the quest for people with diabetes to lead a normal life.”

How it works

Instead of finger pricks and dose calculations, the artificial pancreas uses an abdominal patch that continuously measures blood sugar and a pager-sized pump that delivers insulin beneath the skin. Mayo’s major innovation is the sophisticated software algorithm, developed in consultation with Italian bioengineers, linking patch and pump.

“It will be loaded with information derived from the patient’s own physiology,” Dr Basu says. The result is a “closed-loop system” requiring limited input from the user. “It’s all automated,” Dr Basu says. “The constant patient decision making is minimised.”

Precise decisions are important because in type 1 diabetes, the pancreas produces little or no insulin. Abnormal blood sugar levels can lead to disabling and life-threatening complications, including heart attack, stroke, and damage to the nerves, eyes and kidneys. The artificial pancreas system might eventually be used to also treat some people with type 2 diabetes, in which the body resists the effects of insulin.

According to the International Diabetes Federation (IDF), six of the world’s top 10 countries for highest prevalence (percentage) of diabetes are in the Middle East. They include Kuwait, Lebanon, Qatar, Saudi Arabia, Bahrain and the United Arab Emirates. The IDF also indicates the region has the highest comparative prevalence of diabetes at 11%.

The prevalence of diabetes is rising at an alarming rate worldwide. In fact, the World Health Organisation projects that deaths from diabetes will double between 2005 and 2030.

The artificial pancreas is part of Mayo’s commitment to optimally treating and improving quality of life for people with diabetes. It’s designed to replicate aspects of human metabolism, the complex process that converts energy from food into energy the body can use. Metabolism involves a host of factors – including the body’s sensitivity to insulin and response to food and exercise – that vary widely among individuals and even within an individual at different times of the day. For women, menstrual and pregnancy hormones are added factors that influence sugar metabolism.

“There is tremendous variability in blood sugar levels day to day in a person with type 1 diabetes. This is why type 1 diabetes is notoriously difficult to manage,” Dr Basu says. He notes that within a single day, the blood sugar level of a person with type 1 diabetes can swing from 30 to 400 milligrams per deciliter (the normal range is 70 to 140 mg/dL). "This has a huge impact on patients' quality of life."

Incorporating that complexity into a manufactured device is an immense challenge and the culmination of years of research by Mayo scientists. Their laboratory discoveries about the physiology of metabolism are being factored into the artificial pancreas software algorithm.

Assessing physical activity

One critical set of variables involves physical activity. “Physical activity plays an important role in insulin action,” explains James A. Levine, MD, PhD, a Mayo endocrinologist. “Insulin dosing must be adjusted based on the amount of physical activity a patient does.”

Dr Levine leads a laboratory team whose work involves gauging people’s total daily activity – not just calories burned at the gym, but every fidget and sedentary moment. “We’ve worked hard over many years to develop a series of technologies to measure very precisely how active or chair-ridden an individual has been,” Dr Levine says.

This ability to “capture” an individual’s physical activity “was clearly Dr Levine’s brainchild,” Dr Kudva says. “Dr Basu and I picked it up and realised the importance this had for developing the artificial pancreas.”

As a result, the device incorporates measurements of physical activity and the individual’s metabolic response. “To bring our bench science to real folks is an honour,” Dr Levine says. “It is a fantastic example of team building and, indeed, of the translation of lab discoveries to patient care.”

Clinical trial

Clinical research studies started in the spring of 2010 and are continuing. The goal of the clinical research laboratory of Drs Kudva and Basu is to accelerate approval of the closed-loop/artificial endocrine pancreas for treatment of type 1 diabetes mellitus.

The studies have been designed to examine, among others, the role of diurnal (daily) changes to insulin effectiveness on glucose control after meals, the effects of physical activity and of stomach emptying on glucose variability, the role of dawn phenomenon and mental stress on glucose variability. A better understanding of the insulin-glucose system as it relates to meals and physical activity and other factors, such as menstrual or sleep cycles, will help inform, develop, refine and validate personalised, state-of-the-art closed-loop artificial pancreas systems to improve the quality of life in people with type 1 diabetes.

Several unexpected findings have already been discovered. For example, the diurnal pattern of how efficiently insulin works during the day varies more in people with type 1 diabetes than in healthy people. Other findings include the significant role of low-grade physical activity that mimics activities of daily living on post-meal glucose levels and the significant role of timing of physical activity in relation to meals on glucose variability. Insulin efficiency, for example, is best at breakfast in healthy people but is worst at breakfast in type 1 diabetes and even lowgrade physical activity after a meal significantly dampens glucose rise after the meal in both healthy people and those with type 1 diabetes.

“These complex physiology studies have never been attempted in people with type 1 diabetes,” says Dr Basu. “We learn and improvise at every step along the way.” Mayo’s commitment to patients and their unique needs is evident from the way the trial is structured. Unlike other studies of insulin-delivery systems, which have relied on computer simulations to predict insulin needs, Mayo’s trial uses real data from humans with type 1 diabetes. “The unique feature of our study is using information from patients to program the artificial pancreas,” Dr Kudva says. “This has not been done before at this scale.”

In the first phase, people with type 1 diabetes spend 40 hours in Mayo’s Clinical Research Unit, an inpatient facility where study protocols can be strictly followed. The participants are given precisely measured meals and have regulated exercise on a treadmill. This first stage is “open loop”; participants use conventional methods to measure blood sugar and decide, in consultation with Mayo physicians, how much insulin to take. Throughout this stage researchers collect metabolic data from each study participant.

These data are then fed into the artificial pancreas software algorithm. A few weeks later, the participants return to the research unit and follow the same meal and exercise routine. But this time, each participant uses an artificial pancreas programmed with his or her unique metabolic information. “We will see how well this personalised closed-loop system controls blood sugar levels compared to the first visit,” Dr Basu says. He and Dr Kudva hope to progress to an outpatient trial in 2014.

New research is currently starting to evaluate the relationship between glucose present in the circulation and that in the abdominal wall just under the skin. This is vital to improve the precision of currently available glucose sensors, which would be essential components of any artificial pancreas system.

Collaboration at its best

Mayo Clinic is part of a multi-institutional, international consortium to accelerate “artificial endocrine pancreas development and implementation”. This consortium is funded by the National Institutes of Health in the United States through a research grant. Mayo is the lead centre for physiology studies that are important for artificial endocrine pancreas acceleration.

The artificial pancreas highlights not only Mayo’s metabolic expertise, but also the global reach of its research efforts. The software algorithm was developed by mathematicians in Italy who have collaborated with Mayo researchers for 25 years. “They are the world’s leaders with regard to the mathematics of metabolism,” Dr Kudva says. “No one comes even close in this very specialised field,” Dr Basu adds.

Drs Kudva and Basu, who occasionally finish each other’s sentences, have collaborated on metabolic research for more than 15 years. They have finished a study of whether insulin action varies by time of day. “If you have 100 grams of carbohydrates at breakfast, lunch and dinner, does it metabolise the same way?” Dr Basu asks. The results of that research may provide yet another metabolic factor for the artificial pancreas software algorithm. “Mayo has the infrastructure to capture these complex processes accurately,” Dr Kudva says.

Indeed, that research infrastructure allows Mayo scientists to wage the war against diabetes on a number of fronts. In addition to the artificial pancreas, Dr Kudva is involved in Mayo’s efforts to use adult stem cells to regenerate insulinproducing cells in people with type 1 diabetes. Dr Kudva believes it’s important to pursue different research paths simultaneously. “We provide more choices for patients with type 1 diabetes,” he says.

Timing also is important, he adds. “Biologic solutions are sometime in the future. You could just wait, but that would be like going from a Turing computer to an iPad without doing anything in between. Whereas this translation of research into the artificial pancreas is happening as we speak.”

Improving care for patients with multimorbidity

A research review carried out by the HRB Centre for Primary Care Research, based in the Royal College of Surgeons in Ireland (RCSI) and published in the September 2012 edition of the British Medical Journal (BMJ) has focused on how we can improve care and outcomes for patients with multimorbidity (co-existence of two or more long-terms health conditions in an individual).

Multimorbidity is the norm, rather than the exception in primary care patients. Despite the increasing numbers of patients with two or more chronic conditions, the delivery of care to patients is usually built around single diseases and there is a limited level of care available to patients with multimorbidity.

Prof Susan Smith, Associate Professor of General Practice, RCSI said: “Multimorbidity is a challenging factor facing practitioners and patients; however it has attracted surprisingly little research interest. Our research focused on how we can improve care and outcomes for these patients and found that a need exists to clearly identify patients with multimorbidity in order to develop cost effective and specifically targeted interventions that can improve health outcomes for patients.”

The research indicated that interventions targeted either at specific combinations of common conditions or at specific problems for patients with multiple conditions may be the most effective method to managing patients with multimorbidity.

Prof Smith continued: “We found that the methods used had mixed effects, but they were more likely to be effective if they were targeted at specific risk factors for people with common combinations of conditions such as diabetes and depression or focused on areas where patients have difficulties, such as with activities of daily living or the management of multiple medications. The least effective approach was patient orientated interventions which dealt with patient related behaviour only but did not link this with healthcare.”

“We know from previous research studies that patients with multimorbidity are more likely to die prematurely, be admitted to hospital and have longer hospital stays than patients with single conditions. Additionally, patients with multimorbidity have a poorer quality of life, experience a loss of physical functioning and are more likely to experience depression,” Prof Smith said.

The review identified 10 studies examining interventions in 3,407 patients with multimorbidity. It highlighted the scarcity of research in to interventions to improve outcomes for patients with multimorbidity. It indicated that interventions targeted either at specific combinations of common conditions or at specific problems for patients with multiple conditions may be the most effective method.

Managing patients with multimorbidity

Siemens HbA1c test kit approved

The Siemens Healthcare Diagnostics DCA HbA1c test kit, already used to monitor diabetes patients’ HbA1c levels, has achieved the CE mark as an aid to diagnose diabetes and identify patients at risk for developing the disease. The kit is expected to be available across the Middle East in March next year. Available for use on the company’s DCA systems, including the DCA Vantage Analyzer, the test kit provides clinicians with a streamlined solution that delivers fast, actionable results for the diagnosis and management of diabetes in environments ranging from physicians’ offices to hospitals and clinics.

The benefits of using hemoglobin A1c (HbA1c) testing to measure average blood glucose levels in the management and treatment of patients with confirmed diabetes is well established. More recently, the medical community has recognised the clinical utility of HbA1c testing in the disease’s diagnosis. Notably, in 2009, several major diabetes associations, including the International Diabetes Federation (IDF), American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), were part of an International Expert Committee that accepted the HbA1c test for diabetes diagnosis based on several advantages when compared with the traditional method of measuring blood glucose levels.

Convenience was cited as a significant advantage of HbA1c testing since it can be conducted at any time and requires no preparation by the patient, unlike fasting plasma glucose (FPG) measurements, where fasting must occur at least eight hours prior to testing. Also, HbA1c testing only requires a single measurement as opposed to blood glucose testing that involves serial blood draws over several hours.

With the Siemens DCA HbA1c test, only a small (1 μL) whole blood finger stick sample is needed, enabling clinicians to identify at-risk patients within minutes, review test results and discuss early intervention and disease management options during the same office visit. By reducing the need for followup visits, in-office testing of HbA1c with the Siemens DCA HbA1c kit not only helps consolidate operations, but also contributes to improved patient care through a simple-to-use tool.

 Date of upload: 20th Nov 2012


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