DOCTOR'S VIEW ARCHIVEMedical Author: Ruchi Mathur, M.D.
Medical Editor: William C. Shiel, Jr., MD, FACP, FACR
I am lucky to have so many wonderful patients who try so very hard to maintain the best blood sugar control possible. For many of them, this involves insulin pump therapy or multiple injections of insulin a day - in addition to testing their blood sugars often. I often get asked is there is anything on the horizon that will make life easier for them. I tell them they may have to "squint" a bit to see it - but off to the distance, there just may be.
The symptoms of diabetes were described more than 2000 years ago. Aretaeus of Cappadocia (circa 150 A.D) noted that "...it consists of a moist and cold wasting of the flesh and limbs into the urine. The patient never ceases making water. The disease is chronic in character, though the patient does not survive long when it is completely established for the maramus produced is rapid and death is speedy." Ancient Hindu texts also described a diabetic syndrome, characterized by "honeyed urine." These astute observations characterized the clinical syndrome associated with what is now called type 1 diabetes (formerly known as insulin dependent diabetes). Type 1 diabetes usually manifests in childhood or young adulthood. Until the latter half of the 20th century, type 1 diabetes was a fatal disease.
From the time of these ancient observations, there was little in the way of treatment for patients with type 1 diabetes. This primarily was because the cause of the disease was not recognized. In the 1700's, it was found that there were high amounts of sugar in the urine of patients with diabetes. Consequently, the disease was initially thought to be a problem with the kidneys. In the early 1800s, the link between diet and the amount of sugar seen in the urine was established. It was observed that if patients with diabetes ate carbohydrates, their urine contained more sugar than if they ate protein. Over the next century, physicians began reporting autopsy finding that showed abnormal changes in the pancreas of patients who had died of type 1 diabetes. It wasn't until the early 20th century that scientists realized the pancreas produced a substance that regulated blood sugar. In 1921, Banting and Best identified that substance as insulin. They were awarded a Nobel prize for their discovery.
Even with the realization that type 1 diabetes was caused by a deficiency of insulin, patients continued to die. In the first half of this century, insulin was in short supply. At that time, the insulin used was being derived from animal sources, particularly cows and pigs. Not only was there a problem with the supply of insulin meeting the demand, but beef and pork insulin also had specific problems. Being from animals, these types of insulin caused immune reactions in people. Patients would become intolerant or resistant to animal insulin. With the acceleration of scientific research in the latter half of this century, beef and pork insulin were replaced by human insulin. In 1977, the gene for human insulin was cloned, and through modern technology, manufactured human insulin was made available. Up until very recently, insulin has been used only in injection form; drawn up by a needle and syringe and injected just under the skin (subcutaneously).
This century has seen remarkable progress in the treatment of type 1 diabetes. Patients now have the opportunity to live longer, healthier lives than at any other time in history. The last few years have focused on fine-tuning insulin therapy to meet individual requirements and on minimizing the possible long term consequences of diabetes. It is well established that poor blood sugar control contributes to the development of diabetes-related complications such as blindness, kidney failure, nerve damage, and heart disease. Recent advances have focused on manufacturing insulin with specific profiles that can be used individually or in combination to fit a specific patient's needs. In addition, new methods of delivery have been developed to allow for more patient convenience and less discomfort.
At present, injectable insulin is commonly available. Insulin now comes in a variety of preparations that differ in time of onset and length of action. Because of these differences, combinations of insulin are often used to allow for a more tailored regimen of blood sugar control. The table below lists the most common types of insulin currently in use in the United States, and their specific properties.
|Name of Insulin||Onset of Action||Peak Effect after Injection|
|Humalog/Novolog/Very Short Acting||5-15 minutes||30-60 minutes|
|Regular/Short Acting||30 minutes||2-5 hours|
|NPH/Intermediate Acting||1-2.5 hours||8-14 hours|
|Lente/Intermediate Acting||1-2.5 hours||8-12 hours|
|Ultra Lente/Long Acting||4-6 hours||10-18 hours|
|Combinations - 70/30, 50/50, 75/25||30 minutes||7-12 hours|
For example, a patient may take an injection of Lente in the morning and evening to provide a baseline of insulin throughout a 24-hour period. In addition, the same patient may take an injection of Humalog just before meals to cover the increase in carbohydrate load after eating.
Not only is the variety of insulin preparations available growing, so are the methods for administering insulin. In the past, insulin was available only in an injectable form. This involved carrying syringes (which a few decades age were made of glass and required sterilization), needles, vials of insulin, and alcohol swabs. Needless to say, patients often found it difficult to take multiple shots a day, and as a result, good blood sugar control was often compromised. Many pharmaceutical companies are now offering discreet and convenient methods of insulin delivery. Novo Nordisk and Lily and Aventis have an insulin pen delivery system. This system is similar to an ink cartridge in a fountain pen. A small pen-sized device holds an insulin cartridge (usually containing 300 units). Cartridges are available in the most widely used insulin formulations, such as those listed in the table above. The amount of insulin to be injected is dialed in by turning the bottom of the pen until the required number of units is seen in the dose-viewing window. The tip of the pen consists of a needle that is replaced with each injection. A release mechanism allows the needle to penetrate just under the skin and deliver the required amount of insulin. The cartridges and needles are disposed of when finished, and new ones are simply inserted. These insulin delivery devices are discreet and less cumbersome than traditional methods.
The most recently available advance in insulin delivery is the insulin pump. In the United States, MiniMed and Disetronic and Deltronic market the insulin pump. An insulin pump is composed of a pump reservoir similar to that of an insulin cartridge, a battery-operated pump, and a computer chip that allows the user to control the exact amount of insulin being delivered. Currently, pumps on the market are about the size of a beeper. The pump is attached to a thin plastic tube (an infusion set) that has a soft cannula (or needle) at the end through which insulin passes. This cannula is inserted under the skin, usually on the abdomen. The cannula is changed every 3 days. The tubing can be disconnected from the pump while showering or swimming. The pump is used for continuous insulin delivery, 24 hours a day. The amount of insulin is programmed and is administered at a constant rate (basal rate).
Often, the amount of insulin needed over the course of 24 hours varies depending on factors like exercise, activity level, and sleep. The insulin pump allows for the user to program many different basal rates to allow for this variation in lifestyle. In addition, the user can program the pump to deliver a "bolus" during meals to cover the excess demands of carbohydrate ingestion. Over 50,000 people worldwide are using an insulin pump. This number is growing dramatically as these devices become smaller and more user friendly. Insulin pumps allow for tight blood sugar control and lifestyle flexibility while minimizing the effects of low blood sugar (hypoglycemia).
At present, the pump is the closest device on the market to an artificial pancreas. Naturally, the next step would be a pump that can also sense blood sugar levels and adjust the insulin delivery accordingly. At present, the newer pumps allow for communication with hand held meters through an infra red system, This allows the glucose reading from the finger stick to be transferred to the pump. The pump can then perform a calculation to determine if a bolus of insulin is needed, and if so, how much. The user can then use the advice at his/.her discretion. Ideally the next step is to take that blood glucose reading directly from a device connected to the pump avoiding the finger stick. Much effort is being concentrated on this area of research and possibly, even within the next year, a prototype device will be available for trial.
Another promising route of insulin administration is through inhalation. Inhaled insulin is currently being tested but has not been approved by the United States Food and Drug Administration (FDA). Many devices are available that allow for other medications to be used in this manner, the best example of which is asthma therapy. Insulin is not absorbed through the bronchial tubes (airways), and must reach the air sacks at the end of the bronchial tubes (alveoli) to be absorbed. Once at the alveoli, insulin can be absorbed and enter the bloodstream. Currently, powdered inhalers and nebulizers are being studied to determine which delivery system is the most reliable. The safety of inhaled insulin still needs to be established before a product for consumer use can be made available. One of the closest to market is Exubera, marketed by Pfizer.
Other routes for the delivery of insulin have also been tried. Intranasal insulin delivery was thought to be promising. However, this method was associated with poor absorption and nasal irritation. Transdermal insulin (skin patch delivery) has also yielded disappointing results to date. Insulin in pill form is also not yet effective since the digestive enzymes in the gut break it down.
Ultimately, the goal in the management of type 1 diabetes is to provide insulin therapy in a manner that mimics the natural pancreas. Perhaps the closest therapy available at this time is a transplant of the pancreas. Several approaches to pancreatic transplantation are currently being studied, including the whole pancreas and isolated islet cells (these groups of cells contain beta cells that are responsible for insulin production). Data available from 1995 indicates that almost 8,000 patients underwent pancreatic transplantation. Most patients undergo pancreatic transplantation at the time of kidney transplantation for diabetic kidney disease.
Transplantation is not without risk. Both the surgery itself and the immunosuppression that must occur afterwards pose significant risks to the patient. For these reasons, the kidney and pancreas are usually transplanted at the same time. At present, there is disagreement about whole pancreas transplantation in patients not currently requiring kidney transplantation. The issue of whether the benefits outweigh the risks in these patients is under debate. There is also a chance that diabetes will occur in the transplanted pancreas. Selectively transplanting islet cells is an interesting alternative to whole pancreas transplantation. However, the concern over rejection remains. Attempts to disguise the islet cells in tissues that the body won't reject (for example, by surrounding the islet cells by the patient's own cells and then implanting them) are underway. In addition, researchers are exploring artificial barriers that can surround the islet cells, provide protection against rejection, and still allow insulin to enter the bloodstream.
The next few years promise to be an exciting time in diabetes care. The options for insulin therapy continue to grow and methods for insulin delivery continue to become more refined. While research continues to expand in this area, one thing remains constant. Achieving the best blood sugar control possible remains the ultimate goal. We now know, beyond a doubt, that good blood sugar control minimizes the long-term complications of diabetes, including blindness, nerve damage, and kidney damage. While insulin therapy is a necessity for patients with type 1 diabetes, it can also give patients the opportunity for healthy and productive lives.