Targeting A Cure For Type 1 Diabetes – A Sneak Peek

by lisa rotenstein, ben kozak, adam brown, michael dougan, and kelly close

This Learning Curve covers a very exciting topic – curing type 1 diabetes; it is an introduction to our new book "Targeting a Cure for Type 1 Diabetes," which you can download for free at www.diatribe.org/cure.

“Targeting a Cure for Type 1 Diabetes is a valuable and thought-­provoking overview of research efforts underway to cure type 1 diabetes. Education about the progress being made – and the hurdles to be faced – is crucial if we’re to achieve our ultimate goal of ridding type 1 diabetes from the lives of our loves ones. I thank the diaTribe team for their ongoing efforts to inform and enlighten all those who care about type 1 diabetes.”

–Jeffrey Brewer (President and CEO, Juvenile Diabetes Research Foundation, New York, NY)

foreword

Since we founded diaTribe in 2006, its focus has always been on providing helpful, practical information to people with diabetes. Our new book, “Targeting a Cure For Type 1 Diabetes” aims to continue that focus by providing a detailed update on progress toward curing type 1 diabetes. We hope that you will enjoy and learn from it whether you are a person living with type 1 diabetes, a parent or caregiver, a researcher or clinician, or anyone else looking for clear information on an issue that inspires strong opinions and stirring hopes. In writing this book, we have assumed that our readers are interested in details, but not that they have deep experience in science or medicine. Though no one knows exactly when a cure will come or what it will look like, we hope that this book will give you a better idea of the possibilities and the promises of the search for it. We are not blind optimists. We know the hurdles are high. But we also know that the gains made have been substantial, and we believe that a cure will arrive in our children’s lifetimes.

features of the full report

The full book covers a lot of ground and contains considerably more detail than is presented below, befitting the scope of research to cure type 1 diabetes. We realize that you may have time to read only parts of the report, so in addition to further detail we’ve added several features to make the document as accessible as possible.

The book uses icons at the top of nearly every section to provide key information about each therapy, with the goal of helping you find the information that is most interesting to you. The icons indicate the stages of diabetes most likely to benefit from a given therapy, as well as indicating how long we think development of the therapy will take, and how optimistic we are about the area research. We have “Kelly’s Take” sections throughout the book in which Kelly draws conclusions and provides her own opinions on the promise of each cure-targeted therapy. These sections are written to be as accessible as possible and to provide quick important “take home” points; these sections are used alongside summary boxes that present key bullet points using more of the scientific terminology introduced in the longer text. The book concludes with a section entitled “Targeting a Cure: The Takeaways.” This section is written to provide a concise summary of the entire report, giving the reader a sense of the scope of the material discussed, and emphasizing the more relevant aspects. Finally, throughout the text, key words are presented in boldface and appear with definitions in a glossary section.

where are we today?

The discovery of insulin in 1922 was one of modern medicine’s greatest breakthroughs, and has saved millions of lives. With insulin’s discovery, people with diabetes could hope to live long, productive lives as long as they continued to receive injections of this "miracle" drug.  Today, nearly 90 years later, insulin remains the most important drug for people with type 1 diabetes and many with type 2 diabetes, but as the t-shirt that some of you may have says – insulin is not a cure.

Some inroads into the search for a cure have been made in recent years. Our understanding of what causes type 1 diabetes has improved. We have successfully reversed diabetes in some animal models of the disease. We have devised methods to keep transplanted islets alive for longer periods of time. Blood glucose monitors, insulin pumps, continuous glucose monitors, Symlin, and other therapies and technologies have enabled better daily management of glucose levels. These advances could eventually lead to preventing, reversing, or overcoming diabetes.  But for now, the cure for human type 1 diabetes remains painfully elusive. In “Targeting a Cure for Type 1 Diabetes: How Long Will We Have to Wait?”, we present what we believe are the four most promising categories of therapies that target a cure: immune therapeutics, islet transplantation, regeneration of beta cells, and the artificial pancreas. While all have the same goal, each has its unique advantages and disadvantages, which are introduced below.

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what happens in type 1 diabetes

To understand what a treatment would need to do to "cure" type 1 diabetes, we must first understand the changes that occur in the body that lead to this condition. Type 1 diabetes is caused by the destruction of beta cells, cells housed in structure within the pancreas called islets that are responsible for producing insulin. This drastically reduces the production of insulin.

As many readers will know, insulin is a hormone that allows glucose produced from the carbohydrates we eat to enter the cells of our body that use glucose for nutrition. The beta cells in a healthy person secrete enough insulin to admit the right amount of glucose into cells, but that process breaks down in people with type 1 diabetes because of insulin deficiency.

In people with type 1 diabetes, the destruction of insulin-producing beta cells is caused by the immune system, the part of the body normally charged with protecting us from bacteria and viruses. The immune system is thought to destroy beta cells in type 1 diabetes, because the beta cells have been misidentified as “foreign” invaders. Why the immune system misidentifies beta cells as “foreign” (akin to thinking the cells are infected with a virus) is not yet known, but is an active area of research. The general theory is that some kind of environmental trigger (a toxin or infection) may inappropriately initiate an immune response in certain genetically susceptible people.

what does "targeting a cure" mean?

To "cure" type 1 diabetes, a therapy would either have to replace the beta cells that have been destroyed and prevent further beta cell loss, or closely mimic the normal insulin producing function of beta cells in a way that does not require constant management.

Another way to think of a "cure" is that it would either prevent diabetes from ever happening, halt it in its very early stages, replace lost beta cells, or make up for lost beta cell function without placing additional burdens on the person with diabetes.

Four approaches known as immune therapeutics, islet transplantation, regeneration of beta cells, and the artificial pancreas could potentially achieve these goals.  Figure 1 illustrates how each of these approaches may be used to “cure” type 1 diabetes at different stages of disease.

Figure 1. Cure targeted strategies and therapies for type 1 diabetes broken down by stage of disease. (Adapted from JDRF).

1. immune therapeutics

The goal of immune therapeutics is to modify or modulate the immune system in a way that prevents the destruction of beta cells. This type of approach addresses diabetes at a cellular level, attempting to “cure” the root cause of the disease: the immune system’s components are not functioning the way they should. Several approaches to immune therapy are being developed. These include diabetes vaccines, as well as drugs that target specific components on the immune response in an attempt to shut down ongoing beta cell destruction, and reinitiate the normal mechanisms that prevent the immune system from destroying healthy parts of the body.

Both of these approaches are discussed in detail in the full report, which surveys several specific therapies and presents much of the current state of basic research and clinical trials. Unfortunately, recent developments in immune therapy have not been encouraging as several recent trials have failed to show adequate efficacy, both for vaccines and for immune modulating drugs. Nevertheless, research in this field continues and several clinical trials are still ongoing.

2. islet transplantation

Islets, found in the pancreas, contain a number of different cells which produce hormones involved in controlling blood glucose levels, most notably beta cells. Islet transplantation replenishes lost beta cells through an infusion of islets from another source, which using today’s technology involves using islets from a deceased donor. Deceased donor islets are not available in large numbers, substantially restricting the number of transplants that can be performed each year.

Islet transplantation is a potential cure in that the transplanted "new" islets will work in place of destroyed ones. In fact, estimates suggest that over two-thirds of people who receive islet transplantations no longer require insulin injections one-year after the procedure. The procedure works well and lowers insulin dose requirements or removes the need for injectable insulin entirely. Unfortunately, this treatment is not long lasting, and five years after transplant, only 10% of people are able to remain independent of injectable insulin.

The biggest risk of islet transplantation is the accompanying immune suppressive therapy, which is necessary to prevent rejection of the transplanted islets just as it is necessary after transplantation of any other organ from an unrelated donor. Immune suppressive drugs have many side effects, including damage to the kidneys, and an increased risk of infection.

Many companies and academic researchers are trying to develop new methods to generate beta cells for transplant (in order to circumvent the limitations of small numbers of deceased donor organs), and to prevent rejection of transplanted beta cells without the need for immune suppression. These areas of research are discussed in detail in the full report, but include developing beta cells from human stem cells, harvesting islets from pigs, and producing mechanical barriers to prevent contact between the transplanted cells and the immune system.

3. beta cell regeneration and survival therapies

In light of the challenges of islet transplantation, the discovery of ways to stimulate new beta cells to grow within the pancreas of people with diabetes, and protect their health and survival would represent a major leap forward.

If successfully developed, drugs that stimulated beta cell regeneration could be used for any person with type 1 diabetes as a means to restore beta cells and regain independence from insulin therapy. They may also halt the progression of type 1 diabetes in people in the early stages of disease, by (ideally) stimulating an increase in beta cell numbers beyond that necessary to compensate for loss due to immune destruction.

Animal research has provided scientists with useful targets for development of regeneration therapies, which are discussed in the full report. In addition, considerable attention has been turned to the use of incretins (a group of drugs that includes two classes approved for the treatment of type 2 diabetes). Basic research in animals indicates that incretins can help beta cells survive longer and regenerate more readily, giving them the potential to ameliorate type 1 diabetes.

4. the artificial pancreas

The artificial pancreas (AP), though not a cure for diabetes in the traditional sense, is an extraordinarily promising technology in our view. The AP is an automated device that tries to reproduce the function of a normal pancreas by delivering the right amount of insulin (and maybe other hormones) to maintain normal glucose control. In the AP, a continuous glucose monitor (CGM), an insulin pump, and a control algorithm work together to do the pancreas’s job. A truly “closed loop” AP would require no intervention from the patient, while an “open loop” would require some intervention. We see the AP as a bridge to the cure for diabetes but, using technology similar to that currently developed, not a true cure by itself.

One of the biggest problems facing the development and use of an AP is that varied sleep patterns, exercise, diet, and stress can all influence blood glucose, and can be very difficult for current technology to handle, often leading to under or over pumping of insulin. Increasingly sophisticated algorithms, more accurate CGMs, and faster insulins are all being developed to address these problems. In addition to technological hurdles, regulatory caution has slowed the implementation of some new technologies in the US, and may prove to be a significant stumbling block in the path to developing a workable AP.

Although the technical and regulatory issues have yet to be solved, an AP system operating in even a very broad target range while presenting a low risk of hypoglycemia could yield enormous A1c benefits. Our book details all the issues surrounding AP development and what they mean for its future.

conclusion

While movement is slower than anyone would like to see, the progress toward finding a cure for type 1 diabetes is exciting and we believe ultimately hopeful. Though development may take many years, we believe that each of the broad categories discussed in this report has significant promise, and that one or several may one day be an option for curing people with type 1 diabetes.

If you are interested in learning more about these areas, together with our perspective on their chances for success and when they will come to fruition, please download our free book ‘Targeting A Cure for Type 1 Diabetes”. We hope you will find it helpful.

Please visit www.diatribe.org/cure to download the book.