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The artificial pancreas is a technology in development to help diabetic persons automatically control their blood glucose level by providing the substitute endocrine functionality of a healthy pancreas.
There are several important exocrine (digestive) and endocrine (hormonal) functions of the pancreas, but it is the lack of insulin production which is the motivation to develop a substitute. While the current state of insulin replacement therapy is appreciated for its life-saving capability, the task of manually managing the blood sugar level with insulin alone is arduous and inadequate.
The goal of the artificial pancreas is twofold:
Different approaches under consideration include:
Additional recommended knowledge
Background in endocrine physiology
The pancreas produces three hormones that are important to glycemic control:
Upon digestion of carbohydrates, glucose levels in the blood will begin to rise. As the blood and glucose flow into the pancreas, insulin and amylin are cosecreted by the pancreatic beta cells directly into the bloodstream in response to elevated blood glucose levels. Insulin causes blood glucose to be removed from the bloodstream and stored in the liver and muscle cells. Notice as the blood sugar goes higher, additional insulin will bring the blood sugar back down in a classic negative feedback loop. As insulin is released from the beta cells, amylin is also released into the bloodstream. Amylin slows gastric emptying, and also inhibits the release of glucagon from the pancreatic alpha cells. The effect of amylin is to spread out the blood glucose peak after eating, reducing the quantity of insulin needed. As the blood sugar level comes back toward normal, the beta cells will stop spurting insulin and amylin. As the glucose level approaches a low mark, the pancreatic alpha cells will release glucagon directly into the bloodstream. Glucagon causes the liver to release stored glucose back into the bloodstream. Notice that increased glucagon will increase blood glucose levels in a positive feedback loop. Together, the three endocrine hormones work as a system to control the blood glucose level between high and low boundaries.
When the beta cell produces insulin from proinsulin, a connecting peptide (or C-peptide) is also manufactured and released into the bloodstream. Absence of C-peptide in the blood indicates that insulin has not been released from the pancreas, and this fact confirms the diagnosis of diabetes type 1. C-peptide was believed to be only a by-product of natural insulin production, however recent studies suggest that C-peptide exerts beneficial therapeutic effects on diabetic nociceptive neuropathy.
Ideally, to replicate the natural function of the pancreas as closely as possible, an artificial pancreas might someday replace all of the beneficial endocrine functions lost, including the delivery of insulin, amylin, glucagon, and C-peptide.
Background in insulin therapy
In insulin-dependent persons, blood glucose levels have been roughly controlled using insulin alone. The number of grams of carbohydrate is estimated by measuring foods, and is then used to determine the amount of insulin necessary to cover the meal. A simple open-loop model is used: an insulin to carbohydrate ratio (adjusted based on past success) is multiplied by the grams of carbohydrates to calculate the units of insulin needed. That quantity of insulin is then adjusted based on a pre-meal blood glucose measurement (insulin added for a high blood sugar and insulin removed for a low blood sugar). Insulin is injected or infused under the skin, and enters the bloodstream in approximately 15 minutes. After the insulin has acted in the bloodstream, the blood glucose level can be tested again and then adjusted with injection of more insulin, or eating more carbohydrates, until balance is restored.
There are notable differences with insulin replacement compared to the function of pancreatic insulin delivery:
An insulin pump to infuse a rapid-acting insulin is the first step in simulating the function of the pancreas. The pump can accurately deliver small increments of insulin compared to an injection, and its electronic controls permit shaping a bolus over time to match the insulin profile required for a given situation. However, the pump is still controlled manually by the pump user to bolus on command based on a snap shot of the recent blood glucose level and an estimate of the grams of carbohydrate consumed. This predictive approach is said to be open-loop. Once a bolus has been calculated and delivered, the pump continues to deliver its basal rate insulin in the manner that has been programmed into the pump controls based on the predicted insulin requirements of its user.
While insulin replacement is appreciated as a life saving therapy, its practical use in controlling blood glucose levels sufficiently to avoid the long term complications associated with hyperglycemia is not ideal.
Approaches to an Artificial Pancreas
A biological approach to the artificial pancreas is to implant bioengineered tissue containing islet cells, which would secrete the amount on insulin, amylin, and glucagon needed in response to sensed glucose.
When islet cells have been transplanted via the Edmonton protocol, insulin production (and glycemic control) was restored, but at the expense of immunosuppression. Encapsulation of the islet cells in a protective coating has been developed to block the immune response to transplanted cells, which relieves the burden of immunosuppression and benefits the longevity of the transplant.
One concept of the bio-artificial pancreas uses encapsulated islet cells to build an islet sheet which can be surgically implanted to function as an artificial pancreas.
This islet sheet design consists of:
Islet sheet research is pressing forward with large animal studies at the present, with plans for human clinical trials within a few years.
Gene therapy approach
Medical equipment approach
Development of Continuous Blood Glucose Monitoring
Technology for continuous blood glucose monitoring supports the mission of the artificial pancreas by:
These capabilities suggest that a stream of real-time data can be used to "close the loop" and control the insulin pump directly.
Some issues with the present performance of continuous sensing technology suggest that additional study is needed for application to the artificial pancreas:
As the state of the art for blood glucose monitoring continues to advance, so does the promise of the artificial pancreas.
Feedback of real-time blood glucose data to an insulin pump for basal control
The first step in controlling an insulin pump based on continuous blood glucose data is to automatically control the basal rate of the insulin pump. When a bolus has not recently been performed, the pump can manage the blood glucose level by adjusting the basal rate as needed:
When controlling the basal rate alone, the closed loop can still correct a meal bolus error that was too large or small for the food consumed by:
First clinical tests: implantable insulin pumps and continuous glucose sensors
In France, a human clinical trial of an artificial pancreas is underway. The system is fully automated by combining Medtronic MiniMed's long-term glucose sensor and its implantable insulin pump. A summary of the project shows promise as well as some present limitations:
Insulin and amylin combination
Pramlintide is a relatively new treatment for diabetes. The treatment involves:
Pramlintide can be infused using an insulin pump. At the present time, the mixing of pramlintide and insulin in the same cartridge is not an approved practice, so two infusion pumps are used simultaneously. Since insulin and amylin are co-secreted by the pancreatic beta cells in response to raising blood glucose levels, using pramlintide and insulin together more closely duplicates the function of the pancreas.
Symlin has potential to support the artificial pancreas project because:
Feedback of real-time blood glucose data to an insulin pump for bolus control
The ability of the electronic controls of the infusion pump, particularily in the bolus shaping capability, suggests that the control algorithm may replicate the function of the healthy pancreas in a more copycat fashion. At present, the insulin bolus is a predictive dose based on what is about to be eaten, and then infused completely. Even with the benefit of the closed-loop control of the basal insulin, the standard bolus is still a "guess and then fix it later" approach. Compare to the pancreatic physiology, where insulin and amylin are released from the beta cells in pulses almost directly to the liver in response to the immediate blood glucose level. The natural release from the beta cells is a closed loop response to sensed glucose, and the shape of the insulin delivery is adaptable and appropriate to the food eaten and the body's present metabolic capability.
As technology for continuous blood glucose monitoring improves, the integrated components will support a typical application of control theory by employing the proportional, integral, and derivative control algorithm. This will make it feasible to infuse an adaptive bolus that changes its shape and integral dose based on the measured performance of the bolus in progress, depending on:
The adaptive bolus could start with an assumption of a typical proportions and a bolus shape like the combination bolus. This could include:
The benefits of an automatic bolus delivery might include:
The purpose of glucagon is to raise blood sugar, primarily by promoting release of stored glucose in the liver. Human glucagon has been synthesized by recombinant DNA technology and is available in a dry powder form in the glucagon rescue kit. This is useful for rescue of unconscious diabetics from a severe state of hypoglycemia.
In healthy pancreatic function, glucagon production is initially suppressed by beta cell production of insulin and amylin when blood sugar is high, and then is later produced by low or falling blood sugar. The natural pancreatic function uses glucagon at the end of an insulin cycle to release glucose from the liver, with two advantages:
If an artificial pancreas was to simulate the natural endocrine pancreas to the maximum extent, then insulin and amylin would be used at the beginning of an insulin cycle and glucagon would be used at the end of the insulin cycle. While the copycat function of using glucagon seems desirable, the trade-off in cost and complexity relative to a gain, if any, beyond an artificial pancreas without glucagon is not known.
Initiatives around the globe
In the United States in 2006, the Juvenile Diabetes Research Foundation (JDRF) launched a multi-year initiative to help accelerate the availability of an artificial pancreas to people with diabetes. The overall goal of the Artificial Pancreas Project is to accelerate the development, regulatory approval, and acceptance of continuous glucose monitoring and artificial pancreas technology in the shortest possible timeframe. The long term goal is for broad patient access and a thriving competitive market for these devices and products.
JDRF's role in quickening the development and availability of the Artificial Pancreas consists of funding research in order to look over the outcomes of patients using the Artificial Pancreas, keeping close contact with the Food and Drug Administration so that the standards of the patient are met, advocating for health care coverage of technologies such as the Artificial Pancreas and working to ensure clinical acceptance of technologies such as the Artificial Pancreas.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Artificial_pancreas". A list of authors is available in Wikipedia.|