Benchmark Cambridge Trial In Quest For Ambulatory Artificial Pancreas

I had reported earlier that once perfected and approved by regulators, safe and robust ambulatory artificial pancreas ‒ or to use the scientific term ‘closed loop insulin delivery system’ ‒ has the potential to greatly improve the health and lives of people with type 1 diabetes. The idea itself is not new but the old generation closed loop insulin delivery systems were cumbersome and unsuitable for long term or outpatient use.

Artificial pancreas concept

The newer systems link a continuous glucose monitor and a subcutaneous insulin infusion pump via a control algorithm, which retrieves continuous glucose monitoring data in real time (for example, every five minutes) and uses a mathematical formula to compute insulin delivery rates that are then transmitted to the insulin pump.

However, artificial pancreas that can be worn by diabetics on their person as they go about their daily lives is still in development, with the first in-clinic studies now being reported. Preliminary results have been promising ‒ the most notable improvement is in overnight control of type 1 diabetes, with improvements in safety and a reduction in nocturnal hypoglycemia being reported.

These improvements result from the fine adjustment of insulin delivery provided by closed loop control overnight being superior to a generally fixed basal rate and less likely to cause hypoglycemia. The first application of closed loop control is therefore likely to be in glucose regulation overnight, a step that has the potential to improve dramatically the safety of insulin delivery during crucial, generally unsupervised, periods.

Now a University of Cambridge research tem led by Roman Hovorka has demonstrated the safety and efficacy of overnight closed loop insulin delivery with conventional insulin pump therapy in adults with type 1 diabetes.

Artificial Pancreas Best Hope For Diabetics In Near Term

The trial group consisted of 24 adults (10 men and 14 women) aged 18-65, who had used insulin pump therapy for at least three months and the research team used two protocols ‒ a medium sized meal (60 g carbohydrate) and a large size meal (100 g carbohydrate + alcohol) ‒ to see whether artificial pancreas were effective in overcoming nocturnal hypoglycemia.

As in previous studies carried out by Boris Kovatchev and others in the U.S. and France, the Cambridge closed loop system significantly increased the time that plasma glucose was in the target range (70-144 mg/dl), reduced incidence of hypoglycemia, and better overnight control.

But what makes the Cambridge study important is that the randomized crossover trial design is virtually unique in the field of closed loop control. Because this design is the gold standard for clinical research, the results set a benchmark for future studies.

The only other randomized controlled trial of closed loop control was recently presented by the University of Virginia research team led by Kovatchev at the 4th International Conference on Advanced Technologies and Treatments for Diabetes. This study recruited 24 adults and adolescents with type 1 diabetes in the United States and in France and achieved results similar to those reported by Hovorka and colleagues ‒ more time within the target range of 70-180 mg/dl and a threefold reduction in hypoglycemia.

Dr Roman Hovorka

Moreover, the control algorithm used by Hovorka and colleagues belongs to an advanced class of closed loop control technologies known as “model predictive control”. Algorithm designs for artificial pancreas have generally used either “proportional-integral-derivative control” or “model predictive control”.

Proportional-integral-derivative control algorithms are reactive, responding to changes in glucose levels with adjustment in insulin delivery. Model predictive control algorithms are built over a model of the human metabolic system and are therefore proactive, delivering insulin in anticipation of changes in glucose concentrations.

This compensates partially for the time delays inherent in subcutaneous glucose control (the time delay in insulin action, which can amount to 60 minutes or more). For this reason, model predictive control has become the approach of choice more recently.

The algorithm developed by Hovorka and colleagues has certain distinct features, such as real time adaptation of the underlying model to changing patient parameters implemented as a selection from several predefined models. However, this potential advantage remains to be evaluated.

Most importantly, this is one of the first studies to test realistic meal scenarios and challenge the participants with a large dinner that included alcohol. As such, the study is a clear advance in the quest for an artificial pancreas that can be used by a diabetic while performing normal daily activity.

However, as the authors admit, one limitation is the exclusivelymanual control of the artificial pancreas used relied on study personnel to transmit data manually from the continuous glucose monitor (CGM) to the computer running the closed loop control, and to transmit insulin injection recommendations from the computer to the insulin pump because of technological and regulatory barriers

In fully automated systems ‒ which is what researchers and medical device makers are hoping to make a reality for diabetics ‒ these processes are handled by data transmission and pump control devices, respectively. However, Cambridge method limited the investigation to testing only the control algorithm, not the artificial pancreas as a whole. The testing of other key components, such as sensor-pump communication and error mitigation, would require much more effort and thorough system validation.

Studies using fully automated systems have already been reported by the Artificial Pancreas Project and offer hope for the future of ambulatory systems i.e. devices that be worn by diabetics on their person in their daily lives.

Lastly, despite the sophistication of the control algorithm and the significant reduction in nocturnal hypoglycemia, four episodes of severe hypoglycemia (<70 mg/dl) occurred, three of which the authors thought were attributable to the preceding prandial insulin dose and could not be prevented by the artificial pancreas suspending insulin delivery.

This finding reinforces the recently proposed idea that a dedicated hypoglycemia safety system ‒ a separate algorithm responsible solely for the assessment and mitigation of the risk of hypoglycemia ‒ may need to accompany closed loop control. Such safety systems already exist, and have proved useful.

Based on ‘Boris Kovatchev: Closed Loop Control For Type 1 Diabetes (BMJ 2011; 342:d1911)

Related Post: Killer Apps That Are Revolutionizing Diabetes Care

Dental Health Key to Diabetes Control

Did you know there is a "closed loop" between your dental health, gum disease/health, and dental care and the worsening or improvement of your ability to successfully control your blood sugar levels? And did you know: all dentists are not equally prepared to assist diabetics with their dental health, periodontal care, implant dentistry or restoration after years of inadequate care, if needed?

Along with eyes, feet, skin, hearing and heart complications that can arise when someone has diabetes, the American Diabetes Association also lists oral health factors into the equation as well. Indeed, having poor gum health, under the gum line low-level infections, loose teeth or other dental problems can be a secret enemy fighting your efforts to manage your diabetes.

"Research shows that there is an increased prevalence of gum disease among those with diabetes," warns the American Diabetes Association, which includes the dentist as a key member of the healthcare team when someone is living with diabetes.

Connections Between Treatment of Diabetes and Gum Disease
It’s very important for people who have diabetes symptoms to work closely with their dental treatment team to keep their teeth and gums in great shape. Unfortunately, however, not all dentists understand the connections between treatment of diabetes and gum disease, let alone knowing how to lower blood sugar.

Putting the problem in perspective, Mayo clinic experts list how oral health ties into a person's overall health. Like all infections, serious gum disease may be a factor in causing blood sugar to rise and may make diabetes harder to control.

"Diabetes reduces the body's resistance to infection - putting the gums at risk. In addition, people who have inadequate blood sugar control may develop more frequent and severe infections of the gums and the bone that holds teeth in place, and they may lose more teeth than do people who have good blood sugar control," experts warn.

Research also suggests that the relationship between serious gum disease and diabetes is two-way. Not only are people with diabetes more susceptible to serious gum disease, but serious gum disease may have the potential to affect blood glucose control and contribute to the progression of diabetes.

People with diabetes are at higher risk for oral health problems, such as gingivitis (an early stage of gum disease) and periodontitis (serious gum disease) because they are generally more susceptible to bacterial infection, and have a decreased ability to fight bacteria that invade the gums.

Gum Disease (Periodontitis)

The American Dental Association lists systemic diseases, including diabetes, as a factor that can increase the risk of periodontal disease. Periodontitis involves the inflammation and infection of bones and ligaments that support the teeth.

Dentists should encourage diabetics to make sure they have periodontal charting or probing done. That process measures the space of the gums around a tooth. Two to 3 millimeters of space is in the normal range. The space deepens to 5-10 mm in someone with gum disease, and by 8-9 mm, teeth are getting mobile.

Many people have a misconception a tooth can just be replaced, but nothing functions as well as your own teeth. When someone has gum disease, it's important to have cleanings more often. The process can include deep cleaning or surgery to treat gum disease.

According to the American Dental Association, plaque, a sticky film of bacteria, covers the teeth. After someone eats or drinks something that contains starch or sugar, the bacteria release acids that attack tooth enamel, and over time, the attacks can cause enamel to break down, which can lead to cavities.

Dry Mouth & Thrush
In addition to gum disease and tooth decay, other health conditions have connections to diabetes. For example, someone with diabetes might be prone to xerostomia (dry mouth), which also is a side effect with many medications, and candidiasis (thrush), an oral infection. Burning mouth syndrome is another condition that might affect someone who has diabetes.

When diabetes isn't properly controlled, high glucose levels in saliva can create an environment favorable to these bacteria. The ADA recommends brushing twice a day and flossing daily to help remove plaque that could cause tooth decay.

Saliva contains enzymes and proteins that help control the bacteria in the mouth to help prevent oral infections, dental decay and gum disease. Yet for those with diabetes, higher sugar levels in the blood and saliva encourage bacterial growth.

Dental researchers say there also may be a link between xerostomia and the medications prescribed to treat diabetics. According to recent studies, three-fourths of those who suffer from diabetes also have high blood pressure, and most drugs used to treat hypertension can cause the salivary glands to produce less saliva. Dryness can also be intensified by the use of other drugs, such as antidepressants and antihistamines. For diabetics it is a vicious cycle, so it is important to use products specially formulated to treat gum disease and dry mouth.

Plaque & Tartar
Plaque that isn't removed can harden into tartar. When tartar builds above the gum line, it becomes more difficult to brush well and to clean between the teeth. This can ultimately lead to chronic inflammation and infection. Diabetes isn't caused by gum disease, but gum disease can make it worse and vice versa, say dental hygienists.

If members of the dental team don’t achieve the progress they expect with a patient, they might send him to have a full workup done to see what might be affecting how the dental treatment is going. When someone is having trouble controlling blood sugars, taking care of their dental situation results in improvements a lot of times.

Indeed, just removing plaque every six months can help a lot. Bacteria in the mouth is a concern because if it gets into you bloodstream through your mouth, it can go systemic. It's important to let your dentist know if you have been diagnosed with diabetes.

Nutritional Status
Good oral health also plays a role in a person's nutritional status, which has a significant impact on overall health. A diet high in carbohydrates, which break down into sugar, could affect a person's likelihood of developing cavities. Tooth loss can also affect a person's ability to eat.

Giving up cigarettes is equally important because tobacco smoke dries out the mouth, besides being linked to a number of other health risks, including cancers. Use of other tobacco products also tightens the blood vessels. You need blood flow into your mouth.

To prevent dental problems associated with diabetes, first and foremost, control your blood glucose level. Then, take good care of your teeth and gums, along with regular checkups every six months. To control thrush, a fungal infection, maintain good diabetic control, avoid smoking and, if you wear them, remove and clean dentures daily. Good blood glucose control can also help prevent or relieve dry mouth caused by diabetes.

Remember, whatever has kept you from getting the optimum, complete dental care you need in the past should not concern you now. Today's methods can actually be virtually pain free; you can be assured of respectful, compassionate care in a relaxed environment, never any criticism for having put off treatment. And every dental problem has a solution.

Bottom Line

Managing diabetes includes everything from nutrition to exercise to medication to dental health.

Sources: American Diabetes Association, American Dental Association, Mayo Clinic, Colgate