Key Artificial Pancreas Advances Are in the Works

BETHESDA, MD. — A fully “closed-loop” insulin pump delivery system is still several steps away, but steady progress is being made toward the creation of a functional artificial pancreas that provides far better glucose control for type 1 diabetic patients than is currently available.

That was the consensus from a meeting sponsored by the National Institutes of Health and the Juvenile Diabetes Research Foundation in which scientists, clinicians, and industry representatives came together to address the current state of the art and to discuss ways of overcoming technical obstacles.

Over the last 2 decades, external insulin pump therapy has become a standard treatment option for patients with type 1 diabetes. Current pumps are “open loop,” meaning that they require input from the user, both in setting the background (basal) infusion rate and for delivering premeal boluses based on the blood glucose level and anticipated carbohydrate consumption. Recent advances have incorporated a continuous glucose monitor into the system along with algorithms that estimate the bolus dose, but the technology still requires user input—and therefore is subject to some degree of error.

The main problem isn't in delivering the insulin. Rather, it's overcoming the numerous technical barriers to developing a real-time sensor that can respond to the current glucose level, as well as its rate and direction of change. Moreover, algorithms linking the sensor with the delivery system must also account for all the other physiologic factors that contribute to glucose homeostasis, such as incretins, free fatty acids, and counterregulatory hormones.

“There are three elements to a closed-loop system: the delivery device, the sensing device, and linking algorithms. Each element is very complex, and difficult to develop. Each must really be developed independently before you can put together a complete closed-loop system,” explained Dr. Christopher D. Saudek, professor of medicine at the Johns Hopkins University and director of the Johns Hopkins Diabetes Center, Baltimore.

But Dr. Saudek, who has been researching open-loop implantable pumps for the last 25 years, still sees mechanical insulin delivery as more immediately promising than a biological approach such as islet or stem cell transplantation. “Either would be a cure if it worked reliably and well. But the biological approach still requires enormous basic science breakthroughs before it will help people. The mechanical approach is applied research. It's a matter of refining techniques we have that work.”

The preference for mechanical “cure” certainly applies to children and adolescents, for whom the need for lifelong immune suppression following transplantation is undesirable, said Dr. William V. Tamborlane, professor of pediatrics and chief of pediatric endocrinology at Yale University, New Haven, Conn.

Maintaining good diabetes control is particularly difficult in adolescents, and not just because they tend to be rebellious and noncompliant. Teenagers experience wide swings in glucose because their unique physiology makes them more insulin resistant while paradoxically more vulnerable to hypoglycemia, especially at night. “The development of a closed-loop artificial pancreas is the most likely candidate to revolutionize the treatment of childhood type 1 diabetes in the foreseeable future,” Dr. Tamborlane said.

He reviewed preliminary results of short-term (30–35 hours), closed-loop control in seven adolescents with type 1 diabetes, using Medtronic Minimed's external glucose sensor and infusion pump (information about both available at www.minimed.com

However, despite multiple premeal infusion adjustments, peak postmeal blood glucose levels often exceeded 200 mg/dL, particularly after breakfast.

Currently under investigation is “semi-automatic” or “hybrid” strategy, where the patient manually administers a partial, priming dose of insulin prior to eating, with the remaining insulin regulated by the system. Although not closed loop, this would be a great improvement over currently available technology, Dr. Tamborlane noted.

The same would be true of an imperfect completely closed loop: “Now, when my patients forget to bolus, their blood glucose goes up to 400 [mg/dL]. At least with a closed loop, it would only go to 250. … Maybe we don't need to aim for perfect,” he said.

Similar postmeal problems were seen among 22 young adults with type 1 diabetes in whom a system developed by Roche Diagnostics (www.roche-diagnostics.com

This system utilized an empirical glucose-control algorithm based on a calculation of the current glucose concentration and its gradient, the remaining effect of already-infused insulin, the amount of carbohydrate intake, and patient-specific factors such as basal insulin requirement and insulin-to-carbohydrate ratio. As with the adolescents, overnight values approached the target of 120 mg/dL, with only half the variability that occurred among the patients without the controller. But blood glucose values remained highly variable throughout meal times, again particularly after breakfast.

“Our data suggest that a semi-closed loop system using the subcutaneous route for glucose measurement and insulin application is possible. Although the time delay of insulin action means that a 'feed-forward' insulin dose is necessary, during nighttime the feedback part of the algorithm is able to achieve good control,” Dr. Freckmann said.

Indeed, such time delays will always occur with sensors that monitor glucose in the interstitial fluid, according to Dr. Jeffrey I. Joseph, director of the Artificial Pancreas Center at Thomas Jefferson University, Philadelphia.

Minimed Medtronic has been developing a glucose sensor that measures changes in the oxygen concentration within the superior vena cava, where it is implanted for the long term. Using the vascular sensor and a peritoneal implantable insulin delivery device, French researchers have demonstrated the feasibility of a closed-loop system.

Although the physiological delay with this system is tiny, here the problem is longevity. From a practical standpoint, any implantable device would need to work for at least 7 years to be viable. Currently the Minimed system must be replaced every 12–16 months, Dr. Joseph noted.

Since 1996, he has been working with another major insulin pump manufacturer, Animas (www.animascorp.com

At least two other companies are forging ahead with continuous glucose sensors. Abbott's Navigator, currently under review by the Food and Drug Administration, would be used to make therapeutic decisions, although calibration by the user would still be required (www.abbottdiabetescare.comwww.dexcom.com

BETHESDA, MD. — A fully “closed-loop” insulin pump delivery system is still several steps away, but steady progress is being made toward the creation of a functional artificial pancreas that provides far better glucose control for type 1 diabetic patients than is currently available.

That was the consensus from a meeting sponsored by the National Institutes of Health and the Juvenile Diabetes Research Foundation in which scientists, clinicians, and industry representatives came together to address the current state of the art and to discuss ways of overcoming technical obstacles.

Over the last 2 decades, external insulin pump therapy has become a standard treatment option for patients with type 1 diabetes. Current pumps are “open loop,” meaning that they require input from the user, both in setting the background (basal) infusion rate and for delivering premeal boluses based on the blood glucose level and anticipated carbohydrate consumption. Recent advances have incorporated a continuous glucose monitor into the system along with algorithms that estimate the bolus dose, but the technology still requires user input—and therefore is subject to some degree of error.

The main problem isn't in delivering the insulin. Rather, it's overcoming the numerous technical barriers to developing a real-time sensor that can respond to the current glucose level, as well as its rate and direction of change. Moreover, algorithms linking the sensor with the delivery system must also account for all the other physiologic factors that contribute to glucose homeostasis, such as incretins, free fatty acids, and counterregulatory hormones.

“There are three elements to a closed-loop system: the delivery device, the sensing device, and linking algorithms. Each element is very complex, and difficult to develop. Each must really be developed independently before you can put together a complete closed-loop system,” explained Dr. Christopher D. Saudek, professor of medicine at the Johns Hopkins University and director of the Johns Hopkins Diabetes Center, Baltimore.

But Dr. Saudek, who has been researching open-loop implantable pumps for the last 25 years, still sees mechanical insulin delivery as more immediately promising than a biological approach such as islet or stem cell transplantation. “Either would be a cure if it worked reliably and well. But the biological approach still requires enormous basic science breakthroughs before it will help people. The mechanical approach is applied research. It's a matter of refining techniques we have that work.”

The preference for mechanical “cure” certainly applies to children and adolescents, for whom the need for lifelong immune suppression following transplantation is undesirable, said Dr. William V. Tamborlane, professor of pediatrics and chief of pediatric endocrinology at Yale University, New Haven, Conn.

Maintaining good diabetes control is particularly difficult in adolescents, and not just because they tend to be rebellious and noncompliant. Teenagers experience wide swings in glucose because their unique physiology makes them more insulin resistant while paradoxically more vulnerable to hypoglycemia, especially at night. “The development of a closed-loop artificial pancreas is the most likely candidate to revolutionize the treatment of childhood type 1 diabetes in the foreseeable future,” Dr. Tamborlane said.

He reviewed preliminary results of short-term (30–35 hours), closed-loop control in seven adolescents with type 1 diabetes, using Medtronic Minimed's external glucose sensor and infusion pump (information about both available at www.minimed.com

However, despite multiple premeal infusion adjustments, peak postmeal blood glucose levels often exceeded 200 mg/dL, particularly after breakfast.

Currently under investigation is “semi-automatic” or “hybrid” strategy, where the patient manually administers a partial, priming dose of insulin prior to eating, with the remaining insulin regulated by the system. Although not closed loop, this would be a great improvement over currently available technology, Dr. Tamborlane noted.

The same would be true of an imperfect completely closed loop: “Now, when my patients forget to bolus, their blood glucose goes up to 400 [mg/dL]. At least with a closed loop, it would only go to 250. … Maybe we don't need to aim for perfect,” he said.

Similar postmeal problems were seen among 22 young adults with type 1 diabetes in whom a system developed by Roche Diagnostics (www.roche-diagnostics.com

This system utilized an empirical glucose-control algorithm based on a calculation of the current glucose concentration and its gradient, the remaining effect of already-infused insulin, the amount of carbohydrate intake, and patient-specific factors such as basal insulin requirement and insulin-to-carbohydrate ratio. As with the adolescents, overnight values approached the target of 120 mg/dL, with only half the variability that occurred among the patients without the controller. But blood glucose values remained highly variable throughout meal times, again particularly after breakfast.

“Our data suggest that a semi-closed loop system using the subcutaneous route for glucose measurement and insulin application is possible. Although the time delay of insulin action means that a 'feed-forward' insulin dose is necessary, during nighttime the feedback part of the algorithm is able to achieve good control,” Dr. Freckmann said.

Indeed, such time delays will always occur with sensors that monitor glucose in the interstitial fluid, according to Dr. Jeffrey I. Joseph, director of the Artificial Pancreas Center at Thomas Jefferson University, Philadelphia.

Minimed Medtronic has been developing a glucose sensor that measures changes in the oxygen concentration within the superior vena cava, where it is implanted for the long term. Using the vascular sensor and a peritoneal implantable insulin delivery device, French researchers have demonstrated the feasibility of a closed-loop system.

Although the physiological delay with this system is tiny, here the problem is longevity. From a practical standpoint, any implantable device would need to work for at least 7 years to be viable. Currently the Minimed system must be replaced every 12–16 months, Dr. Joseph noted.

Since 1996, he has been working with another major insulin pump manufacturer, Animas (www.animascorp.com

At least two other companies are forging ahead with continuous glucose sensors. Abbott's Navigator, currently under review by the Food and Drug Administration, would be used to make therapeutic decisions, although calibration by the user would still be required (www.abbottdiabetescare.comwww.dexcom.com

BETHESDA, MD. — A fully “closed-loop” insulin pump delivery system is still several steps away, but steady progress is being made toward the creation of a functional artificial pancreas that provides far better glucose control for type 1 diabetic patients than is currently available.

That was the consensus from a meeting sponsored by the National Institutes of Health and the Juvenile Diabetes Research Foundation in which scientists, clinicians, and industry representatives came together to address the current state of the art and to discuss ways of overcoming technical obstacles.

Over the last 2 decades, external insulin pump therapy has become a standard treatment option for patients with type 1 diabetes. Current pumps are “open loop,” meaning that they require input from the user, both in setting the background (basal) infusion rate and for delivering premeal boluses based on the blood glucose level and anticipated carbohydrate consumption. Recent advances have incorporated a continuous glucose monitor into the system along with algorithms that estimate the bolus dose, but the technology still requires user input—and therefore is subject to some degree of error.

The main problem isn't in delivering the insulin. Rather, it's overcoming the numerous technical barriers to developing a real-time sensor that can respond to the current glucose level, as well as its rate and direction of change. Moreover, algorithms linking the sensor with the delivery system must also account for all the other physiologic factors that contribute to glucose homeostasis, such as incretins, free fatty acids, and counterregulatory hormones.

“There are three elements to a closed-loop system: the delivery device, the sensing device, and linking algorithms. Each element is very complex, and difficult to develop. Each must really be developed independently before you can put together a complete closed-loop system,” explained Dr. Christopher D. Saudek, professor of medicine at the Johns Hopkins University and director of the Johns Hopkins Diabetes Center, Baltimore.

But Dr. Saudek, who has been researching open-loop implantable pumps for the last 25 years, still sees mechanical insulin delivery as more immediately promising than a biological approach such as islet or stem cell transplantation. “Either would be a cure if it worked reliably and well. But the biological approach still requires enormous basic science breakthroughs before it will help people. The mechanical approach is applied research. It's a matter of refining techniques we have that work.”

The preference for mechanical “cure” certainly applies to children and adolescents, for whom the need for lifelong immune suppression following transplantation is undesirable, said Dr. William V. Tamborlane, professor of pediatrics and chief of pediatric endocrinology at Yale University, New Haven, Conn.

Maintaining good diabetes control is particularly difficult in adolescents, and not just because they tend to be rebellious and noncompliant. Teenagers experience wide swings in glucose because their unique physiology makes them more insulin resistant while paradoxically more vulnerable to hypoglycemia, especially at night. “The development of a closed-loop artificial pancreas is the most likely candidate to revolutionize the treatment of childhood type 1 diabetes in the foreseeable future,” Dr. Tamborlane said.

He reviewed preliminary results of short-term (30–35 hours), closed-loop control in seven adolescents with type 1 diabetes, using Medtronic Minimed's external glucose sensor and infusion pump (information about both available at www.minimed.com

However, despite multiple premeal infusion adjustments, peak postmeal blood glucose levels often exceeded 200 mg/dL, particularly after breakfast.

Currently under investigation is “semi-automatic” or “hybrid” strategy, where the patient manually administers a partial, priming dose of insulin prior to eating, with the remaining insulin regulated by the system. Although not closed loop, this would be a great improvement over currently available technology, Dr. Tamborlane noted.

The same would be true of an imperfect completely closed loop: “Now, when my patients forget to bolus, their blood glucose goes up to 400 [mg/dL]. At least with a closed loop, it would only go to 250. … Maybe we don't need to aim for perfect,” he said.

Similar postmeal problems were seen among 22 young adults with type 1 diabetes in whom a system developed by Roche Diagnostics (www.roche-diagnostics.com

This system utilized an empirical glucose-control algorithm based on a calculation of the current glucose concentration and its gradient, the remaining effect of already-infused insulin, the amount of carbohydrate intake, and patient-specific factors such as basal insulin requirement and insulin-to-carbohydrate ratio. As with the adolescents, overnight values approached the target of 120 mg/dL, with only half the variability that occurred among the patients without the controller. But blood glucose values remained highly variable throughout meal times, again particularly after breakfast.

“Our data suggest that a semi-closed loop system using the subcutaneous route for glucose measurement and insulin application is possible. Although the time delay of insulin action means that a 'feed-forward' insulin dose is necessary, during nighttime the feedback part of the algorithm is able to achieve good control,” Dr. Freckmann said.

Indeed, such time delays will always occur with sensors that monitor glucose in the interstitial fluid, according to Dr. Jeffrey I. Joseph, director of the Artificial Pancreas Center at Thomas Jefferson University, Philadelphia.

Minimed Medtronic has been developing a glucose sensor that measures changes in the oxygen concentration within the superior vena cava, where it is implanted for the long term. Using the vascular sensor and a peritoneal implantable insulin delivery device, French researchers have demonstrated the feasibility of a closed-loop system.

Although the physiological delay with this system is tiny, here the problem is longevity. From a practical standpoint, any implantable device would need to work for at least 7 years to be viable. Currently the Minimed system must be replaced every 12–16 months, Dr. Joseph noted.

Since 1996, he has been working with another major insulin pump manufacturer, Animas (www.animascorp.com

At least two other companies are forging ahead with continuous glucose sensors. Abbott's Navigator, currently under review by the Food and Drug Administration, would be used to make therapeutic decisions, although calibration by the user would still be required (www.abbottdiabetescare.comwww.dexcom.com