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Type 1 Diabetes

In this short guide, we are going to look at Type 1 Diabetes and how stem cells can help with its treatment. You will find information on the symptoms and long term effects of type 1 diabetes ass well as the treatments available. We will also look at if stem cells can help and this will include information on embryonic stem cells, induced pluripotent stem cells, spermatogonial stem cells, adult stem cells as well as information on clinical studies into the treatment of type 1 diabetes. This guide is for informational purposes only and should never replace the advice of your doctor.

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About Diabetes

Diabetes mellitus includes a range of diseases that result in high blood sugar (glucose) or hyperglycemia. There are four broad clinical types of diabetes and in this guide we are going to look at type 1 and type 2 diabetes. While both of these differ in their causes and major populations affected, they do share the same propensity for causing chronic damage to multiple organ systems as the disease progresses.

The cause of type 1 diabetes still remains a mystery. It is known that certain susceptibility genes, (e.g., major histocompatibility complex genes contributing to the immune response), combined with some kind of trigger (environmental or infectious) promote the autoimmune attack on beta cells in the pancreas. When this happens, the body's own immune system destroys the beta cells which are vital for producing insulin. Insulin is a hormone that is essential for regulating carbohydrate, fat and protein metabolism and uptake of glucose by the cells. The attack on the beta cells is so vigorous that the body is left with very little or no insulin at all. The high levels of glucose circulating the bloodstream inevitably wreak havoc on the blood vessels, eyes, kidneys, brain, nerves and heart. Type 1 diabetes is also called childhood or juvenile-onset diabetes because it most commonly affects children and young adults under 30. In reality, the autoimmune attack on beta cells can happen at any age.

When it comes to type 2 diabetes, there is no single risk factor to blame which makes finding a cause quite difficult. Instead a complex interplay of genetics, environment and lifestyle collide to impact a person's risk of developing this disease. Although it is not currently possible to predict type 2 diabetes based on genetics, a genetic component is indisputable. The risk of inheriting diabetes climbs to nearly 40% when both parents have it, and multiple genes are known to incrementally contribute to a person's overall risk. The best known implicated environmental factors are obesity, nutrition and exercise; hence the conventional description that type 2 diabetes occurs in sedentary and overweight individuals later in life. The role that obesity plays cannot be understated; approximately 80% of all type 2 diabetics are obese. Certain ethnic populations (African American, Latino, Native American, Asian American and Pacific Islanders), and health conditions (hypertension, polycystic ovaries or a history of gestational diabetes) are also known risk factors.

In susceptible individuals, the coincidence of risk factors leading to disease is twofold; the body gradually becomes resistant to insulin and the beta cells lose their ability to secrete it. The risk of developing type 2 diabetes most often increases with age, but it is becoming more common in children and young adults who are obese.

Diabetes is the fourth leading cause of death in the world and it is rising. The burden of health on the population is staggering and shows no signs of stopping. For the past twenty years, the global prevalence has skyrocketed from 30 million in 1985 to 366 million in 2011. Men and women are equally at risk. If this trend remains unchecked, it is estimated to reach 552 million people by 2030.

Symptoms and Long Term Effects

The onset of symptoms in type 1 diabetes can be sudden. Individuals may experience increased thirst, frequent urination, constant hunger, weight loss, blurred vision and extreme tiredness. If the condition is not diagnosed and treated in time with insulin, a person with diabetes could lapse into a life-threatening coma. People with type 2 diabetes may experience a similar, but often less pronounced range of symptoms.

The long-term effects of living with diabetes are considerable. The risk of death is at least double for those with diabetes as compared with non-diabetics. Fifty percent of people with diabetes eventually die from cardiovascular disease which is mostly attributed to heart disease or stroke. Ten to twenty percent of people end up with kidney failure. Diabetes is also the leading cause of amputation of the lower limbs as a result of poor blood flow. Diabetic retinopathy is a type of adult blindness and this happens when there is an accumulation of damage to the blood vessels in the retina. After many years of diabetes, around two percent of people experience blindness and ten percent experience severe visual impairments. Nerve damage, or neuropathy, is also seen in up to fifty percent of diabetics who commonly experience symptoms of tingling, pain, numbness or weakness in the hands and feet.

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Treatment of Type 1 Diabetes

Type 1 Diabetes cannot be prevented or managed through changes in lifestyle such as exercising and eating healthier foods. These are the things that can be done to prevent and control type 2 diabetes. The vast majority of people with type 1 diabetes manage the disease by testing their blood sugar and injecting themselves with insulin multiple times every day. This may sound pretty straightforward, but intensive management is needed to effectively design regimens that balance blood sugar levels, which can fluctuate for many reasons. Reason for fluctuation in blood sugar levels include food intake, exercise, hormonal changes, growth periods, infections and even emotions. Despite even the best efforts to tailor the insulin dose, diabetics will invariably experience periods when blood glucose is lower or higher than it should be. When blood glucose is too low a person can experience cognitive impairment or coma. At the other end of the spectrum, blood glucose that is too high can lead to debilitating complications. As a result, people with diabetes often live 15 years less than those without the disease.

In an effort to more tightly control blood glucose levels, researchers have started to explore the possibilities of using cell-based therapies that would replace lost beta cells. The first efforts focused on whole pancreas transplants, which have been performed now for over fifty years. Although they have been shown to lead to insulin independence for several years, pancreas transplants to treat type 1 diabetes are not widespread. There are a number of reasons for this including the fact that it is a major surgery and the accompanying risk of death is one to three percent. The complications that ensure include cardiac death and systemic infections. In addition to this, patients have to take powerful drugs to suppress their immune systems to prevent their body rejecting the transplanted pancreas and these drugs have to be taken for life. This leaves them susceptible to infections and a range of other diseases. Many doctors also feel that the immunosuppressant therapy could be a greater health threat than the diabetes ad will only recommend a pancreas transplant if the patient also needs a kidney transplant which could require life-long immunosuppressant drugs anyway.

The complications arising from whole pancreatic transplants opened the door to the idea of transplanting only pancreatic islets, the precious patches of tissue in the pancreas that actually contain the beta cells. For this procedure, doctors use special enzymes to separate the islets from two or more pancreases of deceased donors and then a few teaspoons of islets are injected into the patient's liver. The liver is chosen because of the easy access via the portal vein, and the islets successfully graft here. Once implanted, the beta cells in the replacement islets begin to make and release insulin. This procedure is easier and far less invasive than whole pancreas transplants.

The problem with this is that patients still have to take immunosuppresant therapy to prevent their bodies from rejecting the foreign cells and to prevent their immune systems from attacking and destroying the replacement beta cells as they did the originals. The traditional, steroid-based anti-rejection drugs, in addition to leaving patients susceptible to other diseases, also have a negative effect on insulin-producing cells and eventually may exhaust the cells' ability to produce insulin.

Long-lived islet graft survival rates are still not satisfactory even with improvements such as the Edmonton protocol for transplanting islets. Transplanting islet cells from living donors is not practical because this procedure would put the donor at risk for type 1 diabetes. Islet cell transplants from animal sources, such as pigs, might provoke serious immune responses or even causes diseases in the transplant recipient. An unlimited source of islet cells would really help towards making type 1 diabetics remain insulin injection free.

Can Stem Cells Help ?

Type 1 diabetes results in the loss of the beta cells in the pancreatic islets. This is the loss of a single cells type and there is proof that just a few teaspoonfuls of islet cells can restore insulin production. This means that this disease is a perfect candidate for a regenerative stem cell therapy. Stem cells have the potential to grow into any of the body's more than 200 cell types. Finding the stem cells that can be coaxed into becoming insulin-producing beta cells or restoring the secretion of insulin has been something that researchers have been working on for a number of years.

In theory, stem cells offer a lot of advantages when compared to the current transplant therapies. Donor availability wouldn't be an issue and the stem cells could produce and unlimited source of new beta cells. These attributes have fueled the search for the best type of stem cells and the signals required to promote their differentiation into beta cells, either directly in the patient or in the laboratory first before being transplanted. The key to success for this is being able to scale up the production of stem cells to meet the demand of transplant therapies.

High on the list of candidate stem cells being studies to treat type 1 diabetes are embryonic stem cells, induced pluripotent (iPS) stem cells, spermatogonial stem cells and adult stem cells.

Embryonic Stem Cells

Embryonic stem cells are pluripotent. This means that they have the potential to turn into any cell type in the body. It is of no surprise, then, that scientists have been able to come up with methods for turning both mouse and human embryonic stem cells into insulin producing beta cells. What is most promising about this work is that the newly formed beta cells are able to keep blood sugar under control after being transplanted into mouse models of diabetes. Translating these results into clinical trials however is not as easy as it might seem. Researchers first have to devise strategies to separate the newly formed beta cells from any undifferentiated embryonic cells that retain the potential to form teratomas. This is a type of tumor. In addition to this challenge, the ethical concerns about using embryonic stem cells continues to hamper their use in therapies.

Induced Pluripotent Stem Cells (iPSC)

Induced pluripotent stem cells off the advantages of embryonic stem cells without the controversy. These cells can be reprogrammed from normal adult skin cells, and can also become all the different cell types found in the body. In 2010, researchers first provided proof of principle for the clinical applications of induced pluripotent stem cells. They were able to differentiate induced pluripotent stem cells in the laboratory into insulin secreting beta-like cell which when transplanted could normalize blood sugar levels in diabetic mouse models.

In a bid to get one step closer to using these stem cells in a clinical setting, researchers are looking at ways to reprogram the starting skin cell population that are safer than the original retroviral technique as this can carry the risk of tumor formation.

Spermatogonial Stem Cells

Back in 2010 researchers showed that sperm stem cells could be reprogrammed to become embryonic-like cells that could, in turn, make beta-like cells. This approach is very interesting because the reprogramming agents are growth factors rather than viral genes. It is also interesting because the beta-like cells could lower high blood sugar in mouse models of diabetes. Spermatogonial stem cells, although male-centric, could potentially be a vast source of pluripotent cells.

Adult Stem Cells

The pancreas seems to be an obvious place to search for stem cells that make beta cells. Studies in rodents have identified a number of different routes by which such beta cells could be made. These include differentiation from non-beta cells in the pancreas, slow replication of mature beta cells or from early stem-cell like progenitors. Although these cell types are not easy to isolate from the pancreas, researchers are continuing their investigations. The priorities are to identify the cells in people with type 1 diabetes along with the factors that will coax them into becoming insulin producing beta cells.

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The fact that the liver and pancreas are derived from the same embryonic tissue, called endoderm, has prompted researchers to question whether the liver could also be a source of stem cells that could be reprogrammed to make beta cells. The liver has a tremendous capacity for regenerating itself and by removing a small portion of it from a diabetic patient would not put them at any moral risk, and the beta cells grown from the liver would be patient-specific. The key to getting this to work is to find out which factors can encourage the growth of beta cells and how they can be grown in large quantities in the laboratory. While the results are encouraging, there are as yet no protocols that can expand the reprogrammed liver cells in the numbers required for transplant therapies.

When researchers refer to bone marrow stem cells, they usually mean either hematopoietic stem cells or mesenchymal stem cells. Hematopoietic stem cells have the advantage of being tried and true in terms of bone marrow transplantation procedures and they have also been proven to support beta cell regeneration in damaged pancreas tissue. In addition to this, both hematopoietic and mesenchymal stem cells harvested from the bone marrow are able to inhibit the autoimmune response that brings about the destruction of beta cells. This is really important because newly formed beta cells, regardless of how they are made, will need to be protected from the same autoimmune responses that destroyed the pancreatic beta cells in the first place.

Clinical Studies

The majority of the clinical trials being carried out at present evaluating stem cell therapies to treat type 1 diabetes are exploring the use of hematopoietic stem cells from bone marrow or mesenchymal stem cells from bone marrow or other tissues. For the most part, the stem cell transplants are autologous, meaning from the patient, and the therapy includes the administering of drugs that first destroy the patient's immune system. It is hoped that this approach will reprogram the immune system so that it will not attack the newly transplanted stem cells. This will give the new stem cells a chance to restore normal insulin production.

A nine year clinical trial sponsored by the University of Sao Paolo, Brazil, Northwestern University and Genzyme is due to finish shortly. The goal of this Phase I/II study is to test the safety and efficacy of autologous hematopoietic stem cell transplantation for early onset type 1 diabetes mellitus. In this trial, peripheral blood hematopoietic stem cells from the bone marrow were harvested from patients who were aged between 12 and 25. After the patients received high doses of chemotherapy to destroy their immune systems, the stem cells were administered intravenously. Patients were monitored for five years with the hope that the treatment would offset the amount of exogenous insulin required to manage blood sugar levels. Other trials that are evaluating hematopoietic stem cells are in various stages of completion.

Clinical trials transplanting mesenchymal stem cells into type 1 diabetes patients take advantage of two assets that these stem cells possess. Firstly, they have the regenerative potential to repair beta cells, and secondly they can modulate the immune system by inhibiting the responses that lead to the autoimmune attack on pancreatic beta cells. In the trials that are underway, the most common source of mesenchymal stem cells is bone marrow, but some studies are also looking at mesenchymal stem cells from cord blood or menstrual blood. If successful, these trials will not only prove the safety and efficacy of mesenchymal stem cells but they could also replace the need for immunsuppressive drugs in future transplant therapies. The results of a large Phase II clinical trial by Osiris Therapeutics (Genzyme) are eagerly awaited. In this trial, 60 patients were given Prochymal, which is a special human mesenchymal stem cell preparation.

Scientists are also looking a trials where mesenchymal stem cells are to be co-transplanted with pancreatic islets, which have already demonstrated clinical benefits in patients with type 1 diabetes. The rational for adding the mesenchymal stem cells is to improve the engraftment of the islet cells and to protect them from being damaged by the immune system. The hope of these trials is that this approach will promote beta cell function, thereby reducing or eliminating the requirement for exogenous insulin.

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