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Treatments:

Overview Introduction

At the present time, there is as much innovation and excitement in diabetes

research as there is in any other field of medicine. Every major drug company

maintains a very active presence in the field, and there are a number of smaller

companies whose total effort is directed towards new therapies for diabetes. Add

to this a large and growing number of academic labs devoted to diabetes

research, and it comes as no surprise that there are several areas of

investigation that look extremely promising.

Drug Therapy

Drug therapy is still the cornerstone of diabetes management, and there are many

new drugs in testing. Many of these are variations on old themes, such as new

forms of insulin that have longer periods of action. There is also a significant

amount of effort devoted to improving the delivery of insulin; new oral,

inhaled, and transdermal (skin patch) preparations may one day make insulin

injections an unpleasant memory. Novel oral medications, such as sulfonylureas,

biguanides, alpha-glucosidase inhibitors, and thiazolidinediones (TZDs), are

also in various stages of testing and are likely to be the first new drugs that

become publicly available.

Recent insights into how insulin is released from the insulin-producing

pancreatic beta cells have led to the development of several new drugs that

enhance this process. Some of these, like repaglinide, are already available,

while many others are still in development. The success of insulin sensitizers

like the biguanides and TZDs have led to the discovery of new types of insulin

sensitizers that work in slightly different ways. The discovery that TZDs work

by activating a protein called PPAR gamma (peroxisome proliferator-activated

receptor gamma), for example, has spurred several companies to develop drugs

that activate PPAR gamma in different ways.

In addition to insulin sensitizers, which are only useful in people who still

retain the ability to secret their own insulin (i.e., type 2 diabetics), there

is considerable excitement about new drugs that mimic the actions of insulin

directly. These so-called insulin mimetics can be given orally and hold promise

for patients with all forms of diabetes.

Other hormones besides insulin play an important role in the way that the human

body deals with glucose, and there are several new therapies directed at

manipulating these hormones. Glucagon, for example, is a hormone that is made by

the pancreas and acts as a natural antidote to the actions of insulin--it causes

cells to release sugar into the bloodstream. By blocking either glucagon release

or the ability of glucagon to trigger cells to release sugar, blood glucose

levels can be lowered. Drugs that inhibit the action of two other hormones that

increase blood sugar levels, glucocorticoid and growth hormone, should have a

similar effect.

GLP-1 is a hormone that increases the release of insulin from the pancreas.

Several oral or injectable forms of GLP-1 are being studied, as are drugs that

inhibit the natural breakdown of GLP-1.

Because type 1 diabetes is an autoimmune disease, a disease in which parts of

the body are mistakenly attacked by its own immune response, there is a great

deal of interest in strategies that dampen the immune response. Drugs that use

these strategies are called immune modulators. Immune modulators include novel

drugs to suppress the immune system, vaccines (compounds that help eliminate the

parts of the immune system that attack beta cells), and drugs designed to attack

cytokines, compounds that contribute to the immune response. The hope with these

therapies is that they could prevent progression of early type 1 diabetes, and

ultimately might block the appearance of the disease in individuals who are

likely to get diabetes. While very exciting, the application of these

technologies to diabetes in people is still a long way off.

Finally, there is a tremendous effort being made to identify drugs that prevent

the dreaded complications of diabetes, rather than managing elevated blood sugar

levels directly. Drugs currently being tested include aldose reductase

inhibitors for nerve damage (neuropathy), angiogenesis inhibitors for

retinopathy (eye disease), and AGE (advanced glycation end product) inhibitors

for several diabetic complications. While these therapies do not address the

underlying defects in diabetes, they may greatly reduce the problems associated

with the disease.

Islet Cell Transplantation

Islet cells of the pancreas include the insulin-secreting beta cells. While

whole pancreas transplantation continues to be used in certain circumstances,

the shortage of suitable organs and the risks of lifelong immunosuppression

(which leaves the patient vulnerable to serious infections) have prevented this

procedure from being widely used. Attempts at pure islet cell transplantation in

the past have been disappointing; one recent high profile study, however, has

renewed excitement in this procedure. Several procedures for isolating,

culturing, and implanting islet cells have been worked out, but improvements are

still needed.

Perhaps the most exciting technology that has surfaced recently is the use of

stem cells derived from pancreatic ducts. Stem cells are immature cells that can

be renewed indefinitely, and can be induced to form mature pancreatic beta cells

in the laboratory. They would thus provide an unlimited source of beta cells for

transplantation. There have been recent successes with this technology in

reversing the diabetes of mice with a form of type 1 diabetes, and although

experiments with humans are a bit in the future, it seems likely that this line

of inquiry will yield the most tangible benefits in the long run.

Gene Therapy

The holy grail of medical research for many years has been a safe and effective

form of gene therapy in which the defective genes that cause diabetes are

replaced by healthy copies. There is very active gene therapy research in many

areas of medicine, including diabetes. Progress has been limited however, by

several factors, not least of which is the fact that we do not yet know most of

the genes that cause diabetes. Even if these genes were identified (as they will

be in the next few years) many researchers have serious doubts about our ability

to successfully replace defective copies with new ones in a safe way. Recent

setbacks in gene therapy research in other diseases have made national news, and

it seems doubtful that major advances will be made in this area in the immediate

future. The promise of gene therapy for diabetes, however, is that it corrects

the fundamental problem causing the disease, and would therefore provide a true

cure. This scenario is so seductive that one can be sure that there will be

significant efforts made in this arena despite the current pessimistic climate.

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