Artificial Pancreas - Background in Insulin Therapy

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 the measurement is used to determine the amount of insulin necessary to cover the meal. The calculation is based on a simple open-loop model: an insulin to carbohydrate ratio (adjusted based on past success) is multiplied by the grams of carbohydrate to calculate the units of insulin needed. That quantity of insulin is then adjusted based on a pre-meal blood glucose measurement (insulin bolus increased for a high blood sugar or insulin bolus delayed and reduced 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. Assuming the design requirement is to truly mimic normal pancreatic delivery of insulin to the liver in order to achieve proper hepatic stimulation, and to cause normal insulin induced functions, until another system is available to deliver portal vein concentrations of insulin, an intravenous infusion device will be needed.

There are notable differences with insulin replacement compared to the function of pancreatic insulin delivery:

1. the insulin dose is predicted based on measured food (where accuracy of measured carbohydrate is difficult) whereas pancreatic insulin is released in proportional response to actual blood glucose levels;
2. pancreatic insulin is released into to the portal vein, where it flows almost directly to the liver, which is the major organ for storing glycogen (50% of insulin produced is used by the liver);
3. pancreatic insulin is pulsatile which helps maintain the insulin sensitivity of hepatic tissues;
4. injected insulin is delivered subcutaneously (under the skin) but not directly to the bloodstream, so there is a delay before injected insulin begins to reduce blood glucose (although this can be compensated by injecting insulin 15 minutes before eating);
5. insulin which is not delivered intravenously cannot achieve normal momentary concentrations in the portal vein which connects the pancreas to the liver;
6. replacement insulin therapy does not include amylin (although Symlin is now available for use), which can reduce the insulin need by 50%;
7. replacement insulin is dosed as a best compromise between aggressive use for lowering the blood sugar when eating but also conservative use to avoid a post-prandial low blood sugar due to excess insulin, whereas pancreatic function releases insulin aggressively and later includes automatic release of glucagon at the end of an insulin cycle to manage the blood sugar level and avoid hypoglycemia.

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. The insulin pump is controlled by the pump user to bolus manually based on a recent blood glucose measurement 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. Also, it is generally agreed that even with very tight glucose control, there are a significant number of patients who go on to develop all of the life impacting complications of diabetes. Thus, the goal of the Artificial Pancreas should be to normalize carbohydrate and lipid metabolism at a minimum.