WHY THE IMPLANTABLE INSULIN PUMP WORKS SO WELL

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1 WHY THE IMPLANTABLE INSULIN PUMP WORKS SO WELL H ave you ever wondered why it is so very difficult to manage your diabetes? There is no lack of motivation - we know how important good control is, and we are acutely aware of the likely long-term consequences of poor control. We also know that, with a little luck, it is actually possible for some of us to generate pretty good numbers by being extraordinarily disciplined most or all of the time. Even if we are disciplined, however, our blood glucose numbers do sometimes unexpectedly fly up or down due to an unexpected change of schedule or a momentary lapse of memory, attention or discipline or even some unknown factor. Driving those numbers back where we want them to be is a demanding task. KEY POINTS Achieving and maintaining near-normal s is extraordinarily difficult for people who have type 1 diabetes. The reason has less to do with motivation than with the fact that insulin is being delivered in a non-physiologic way that prevents the liver from doing an optimal job of stabilizing as it does in non-diabetic people. Non-diabetics enjoy a Positive Portal Peripheral Insulin Gradient - The liver receives all of the insulin produced by the pancreas and keeps and uses the majority of it. Type 1 diabetics live with a Negative Portal Peripheral Insulin Gradient with the liver getting only a small percentage of the insulin supplied by injections or external pumps. This reversal of the natural Positive Portal Peripheral Insulin Gradient prevents the liver from adequately performing it s crucial role in regulation. The Implantable Insulin Pump reestablishes a Positive Portal Peripheral Insulin Gradient for the type 1 diabetic. Even though we are motivated and deeply concerned about the longterm consequences of less than perfect control - most of us do not manage to achieve the goals we know are so important. It has always been this way. The sad truth is that most type 1 diabetics, throughout the ninety years of the insulin era, have not managed to tightly control their s. We believe that there is a reason for this, and it is not because diabetics don t care or don t try. The reason is that insulin is being delivered to the wrong place in the body, and this alone makes it extraordinarily difficult to control blood sugars in a real-life setting while using a reasonable amount of effort and diligence. Insulin is meant to be delivered directly to the liver. The liver, in normal physiology, plays the role of master coordinator of levels in the body. In untreated type 1 diabetes it is the liver that produces the glucose that leads to massively excessive levels. In order to play its natural role, the liver must be first in line for insulin, and it must use far more of it than any other tissue in the body. The liver does not get the insulin it needs when insulin is injected under the skin, and all efforts aimed at refining this method of insulin delivery will not solve the basic problem. Understanding what is meant by saying that insulin is being delivered to the wrong place will make a lot of sense if we first master a basic concept of normal physiology: The Positive Portal Peripheral Insulin Gradient. The Positive Portal Peripheral Insulin Gradient: Normally, the blood entering the liver from the portal vein contains a great deal more insulin than the blood delivered to the peripheral tissues. This is the normal physiological state that is enjoyed by all non-diabetic individuals. The liver receives its blood supply from two sources. The hepatic artery delivers blood rich in oxygen directly to the liver and is responsible for 25% of the total volume of blood received by the liver. The portal vein delivers blood that has been collected from the capillaries throughout the general area of the intestines, and this blood is poor in oxygen but rich in whatever has been consumed (food, drugs, alcohol and anything else that

2 enters the digestive system). Importantly, the portal blood also contains, among other things, the hormones produced by the pancreas. Type 1 diabetics, treated with subcutaneous insulin either by injections or continuous infusion pumps do not enjoy this normal state. In fact they experience a Negative Portal Peripheral Insulin Gradient where the liver is receiving less insulin from the portal vein than it needs and the peripheral tissues are getting more insulin than they need. The opposite of what is expected. This abnormal Negative Portal Peripheral Insulin Gradient is reversed back to the normal Positive Portal Peripheral Insulin Gradient by the Implantable Insulin Pump. One might argue that it is a bit of a leap to suggest that insulin dumped into the peritoneal space actually finds its way to the portal vein of the liver. In fact, this was one of the early controversies surrounding the Implantable Insulin Pump. Numerous experiments over the years indicated that a considerable amount of the insulin delivered to the peritoneum did make it to the liver. Then in 1990 a paper was published 1 that proved that virtually all of the insulin delivered to the peritoneum (as it is by the Implantable Insulin Pump) was delivered to the liver via the portal vein. We now have solid experimental proof that the insulin delivered by the Implantable Insulin Pump does arrive at the liver first and does establish a Positive Portal Peripheral Insulin Gradient for the type 1 diabetic lucky enough to have one of these devices. The following table shows how insulin from the Implantable Insulin Pump very closely mimics the normal process while insulin from subcutaneous injection or constant infusion does not. The Implantable Insulin Pump does not exactly match the normal process, but it is far closer to normal than is subcutaneous insulin. 1 Selam J-L, Bergman RN, Raccah D, Jean-Didier N, Lozano J and Charles MA: Determination of Portal Insulin Absorption from Peritoneum via a Novel Nonisotopic method. Diabetes 39: , 1990

3 The Implantable Insulin Pump delivering insulin intraperitoneally closely, but not exactly, matches the normal delivery of insulin while subcutaneous insulin delivery produces an abnormal portal peripheral insulin gradient. Normal Insulin Delivery Insulin is released from the Pancreas All of the insulin passes directly into the Portal Vein All of the insulin enters the liver The liver extracts and keeps over 50% and as much as 80% of the insulin for its own use The insulin not kept by the liver leaves the liver via the hepatic vein and is routed to the heart and on to the peripheral circulation A POSITIVE PORTAL PERIPHERAL Result: The liver is fully enabled to operate in its role of regulating Insulin Delivered by the Implantable Insulin Pump Insulin is delivered into the peritoneal space All of the insulin is collected by the peritoneal vascular and lymphatic systems All of the insulin is deposited into the Portal Vein All of the insulin enters the liver The liver extracts and keeps over 50% and as much as 80% of the insulin for its own use The insulin not kept by the liver leaves the liver via the hepatic vein and is routed to the heart and on to the peripheral circulation A POSITIVE PORTAL PERIPHERAL Result: The liver is fully enabled to operate in its role of regulating Insulin Delivered by Subcutaneous Injection or Continuous Subcutaneous Infusion Insulin is injected or continuously infused under the skin A localized insulin depot forms under the skin at the injection site Insulin is collected by the capillaries at inconsistent rates Insulin collected by the capillaries is routed to the venous system Insulin is routed to the heart Insulin is routed to the lungs Insulin is routed back to the heart Insulin is routed to the arterial circulation throughout the body All of the peripheral tissues of the body are bathed in insulin A diluted portion of the insulin makes its way to the liver via the hepatic artery (the liver gets about 25% of its blood supply from the Hepatic Artery and 75% from the Portal Vein. Additional diluted insulin makes its way to the liver after passing through the tissues in the peritoneum A NEGATIVE PORTAL PERIPHERAL Result: The liver is not fully enabled to operate in its role of regulating

4 The following diagram is another way of showing the differences in insulin distribution between a normal, non-diabetic person and a type 1 diabetic treated either with subcutaneous insulin or the Implantable Insulin Pump. In the chart below the large green circles with upward pointing white triangles represent a relatively high concentration of insulin and the smaller green circles with downward pointing triangles represent relatively low insulin concentrations. In the left, Normal panel we can see that insulin is more concentrated in the liver than in the rest of the body: a state not replicated by subcutaneous delivery of insulin but actually reversed! However, the normal insulin concentration state is more closely replicated by Implantable Insulin Pump delivery of insulin center panel. Positive Portal Peripheral Insulin Gradient Negative Portal Peripheral Insulin Gradient There are numerous methods for replacing insulin in the treatment of type 1 diabetes. Unfortunately, most of these options do not achieve the goal of preferential delivery of insulin to the liver and some of those that do have, at least at the present, unattractive consequences. The following chart summarizes these options and contrasts them with the Implantable Insulin Pump and normal physiology.

5 Insulin Replacement Strategies and Physiological Results Insulin Replacement By: Peripheral (Systemic) Portal (liver) Peripheral Assessment Insulin Levels insulin levels Hyperinsulinemia? Non-diabetic : no replacement Low High No This is the goal needed Subcutaneous Injections Continuous Subcutaneous Insulin Infusion (CSII) The External Insulin Pump Continuous Subcutaneous Insulin Infusion (CSII) AND High Low Yes Not good enough Continuous Glucose Sensor PLUS a Control Algorithm (prototype systems have been tested; final system is in development) Implantable Insulin Pump with Peritoneal Delivery Low High No Yes but we need modern pumps Percutaneous Port 2 (example: Diaport) Low High No No unacceptable format Intravenous Insulin Infusion (IV) Intramuscular Insulin Injection (IM) Inhaled Insulin Nasal or Lung (in trials) Pancreas Transplant 3 Endocrine Systemic Drainage. Requires immunosuppressant therapy High Low Yes No - Wrong drainage and Pancreas Transplant Endocrine Portal Drainage. Requires immunosuppressant therapy Islet or Beta Cell Transplant Portal Vein site. Requires immunosuppressant therapy Low High No No Good delivery but cost of is too high Low High No No Good delivery but cost of is too high For the present, if a type 1 diabetic wishes to attain a Positive Portal Peripheral Insulin Gradient and avoid peripheral hyperinsulinemia the only reasonable solution is the Implantable Insulin Pump that is unless it disappears. In that case, for those with extreme insulin resistance or extremely brittle diabetes the choice of the percutaneous port may be an option if this device is approved for widespread use. To Be Continued 2 This device is essentially a mechanical access port grafted into the abdominal wall and attached to a large diameter catheter that penetrates into the peritoneal space. An external insulin pump catheter may then be threaded through this port and catheter into the peritoneum. 3 In pancreas transplantation there is a choice of where the endocrine secretions of the pancreas will be delivered. The two dominant choices are delivery to the systemic circulation or delivery to the portal circulation. The primary concern of the transplant surgeons is graft survival and studies have shown that the portal delivery choice does not impair survival.