Type1: Diabetes and Autoimmunity

The JDRF is celebrating its 40th anniversary this year. A lot has changed in the past four decades. One change has to do with the organization’s name. JDRF stands for Juvenile Diabetes Research Foundation. Years ago we called what we now know as type 1 diabetes, Juvenile Onset Diabetes Mellitus (JODM). We called it that because we knew (or thought we knew) it was the kind of diabetes that occurred in children. We now know that type 1 diabetes occurs in people of all age groups. There was a lot we didn’t know 40 years ago, one of which was that type 1 diabetes is an autoimmune disease.

Many people still use the broad term “diabetes mellitus” to cover all types of diabetes. The word diabetes means, “to go through” or siphon, meaning it drains patients of more fluids than they take in. The word mellitus is the Latin word for honey, or sweet. The name, diabetes mellitus, really describes the symptoms rather than the condition. Two symptoms are frequent urination, and if your blood glucose is high enough, a lot of sweet, sticky urine. Why so many use this broad term is because the symptoms of diabetes mellitus are for the most part the same for the different types of diabetes. Dig a little deeper, however, and you’ll find the causes are much different. This means the types of diabetes are much different, as are the treatments, and hopefully the future treatments, cures, and preventative therapies.

JDRF’s main goal is a cure, but until that time, they (and people affected by type 1 diabetes) are happy that over the past 40 years, there has been a lot of research and discoveries to improve the lives of people with type 1 diabetes.

The JDRF asked scientists to weigh in on the research highlights over the past four decades. Their responses included:

  1. The β-cell (beta cell) is the focus of all forms of diabetes. Lost β-cells need to be replaced or, if possible, regrown.
  2. Controlling blood glucose prevents complications.
  3. Common pathways lead to multiple complications.
  4. Type 1 diabetes is different than other forms of diabetes due to autoimmunity. The autoimmune response must be stopped at every stage of the disease.

The focus of this article is the autoimmune response and clinical studies available testing investigational agents that may stop the autoimmune response.

The immune system

Your immune system is not located in one place of your body, but rather is a network of cells, tissues, and organs, that protect your body from “invaders, strangers, or foreigners,” which are usually microbes. Microbes are disease producing agents such as bacteria, parasites, fungi, and viruses that can cause infections. Your body is an ideal environment for many of these microbes. It is the job of your immune system to keep them out, or if they enter, to seek them out and destroy them.

A healthy immune system is able to tell the difference between your cells (termed “self”) from an invader’s cells (“nonself”). Both have markers, distinguishing them as self and nonself. When a healthy immune system recognizes the nonself markers, it launches an attack on them in an attempt to keep you healthy.

Terms and concepts

An antigen is anything that can provoke an immune attack. Microbes, and tissues or cells from another person except an identical twin, are considered antigens. (This is why transplants can be rejected.)

Antibodies fight (kill and destroy) the invader and allow your body to remember and recognize previous invaders to help your body destroy them in the future.

A lymphocyte is a type of white blood cell that originates in your bone marrow.

Lymphocytes produce antibodies in response to an antigen.

T lymphocytes travel to your thymus gland and mature there. They are called T cells.

T cells destroy the antigen that’s been presented to it by the immune system, and later suppress the immune response so as to not overact.

  • T cells that destroy are called T effector cells or “killer cells.”
  • T cells that later suppress the immune system so as to not over stimulate the immune response are called T regulatory cells.

T cell receptors (TCRs) are receptors on the surface of the T cell. (Note that a protein called CD3 is a part of the T cell receptor complex found on all mature T cells.)

The autoimmune response occurs when something goes wrong in your immune system. Your immune system starts to attack your own cells – self rather than nonself.

Autoimmune diseases are caused by the autoimmune response. The location where the attack occurs determines the type of autoimmune disease. When this attack occurs on the β-cells of your pancreas, it causes type 1 diabetes.

Type 1 diabetes and autoimmunity

In type 1 diabetes, your T effector cells start to attack your β-cells – the insulin producing cells located in the islet cells of your pancreas. It is not fully understood how long it takes before a patient loses enough β-cells for blood glucose to be high enough to be diagnosed with type 1 diabetes, but it’s not an overnight process, and the rate is different for each person.

When there are no longer enough β-cells to keep blood glucose within normal levels, symptoms of high blood glucose will appear. The classic symptoms of high blood glucose levels are:

  • Extreme hunger
  • Extreme thirst
  • Frequent urination
  • Weight loss (irrespective of caloric intake)

Other symptoms include feeling tired, abdominal pain, tingling of your fingers and or toes, wounds that don’t heal, and with severely high blood glucose levels, even coma or death.

The above symptoms will most likely take you to a doctor (or hospital), who checks your blood glucose level, finds it above the normal level, gives you a diagnosis of diabetes, and starts you on insulin. Note, not all doctors diagnose type 1 diabetes at first.  Some may treat you with blood glucose lowering medications that work well in people with type 2 diabetes but don’t work as well for people who have type 1 diabetes.  People with type 1 diabetes need insulin! If you happen to be one of those people who have type 1 diabetes but are not diagnosed as such, despite taking those medicines, your blood glucose levels may not go down, and you will most likely not feel any better. In fact, your blood glucose levels will likely continue to rise, and your symptoms will only get worse until you start taking insulin. And, it does take time to determine the right dose for you.

There is no way to differentiate type 1 or type 2 diabetes from a blood glucose test, the test that only tells you the level of your blood glucose. There are blood tests to check if you have type 1 diabetes, however, only endocrinologists or diabetologists usually order these. These blood tests have to do with your immune system and measure the presence of certain antibodies. If you test positive for any one of these, you have type 1 autoimmune diabetes.

Type 1 diabetes antibody tests include:

  1. Insulin antibody test, which checks and measures to see if your body has produced antibodies against insulin.
  2. Islet cell antibody test, which checks and measures to see if your body has produced antibodies against your pancreatic islet cells where your β-cells reside.
  3. Glutamic acid decarboxylase (GAD) antibody test, which checks and measures the amount of GAD in your body. GAD is an enzyme in the brain and a protein in the pancreas that plays several roles in the body.

If you have type 1 diabetes, you will need to take insulin…for life. All people, whether they have diabetes or not, need insulin to manage blood glucose levels. People who don’t have diabetes have functioning β-cells that produce enough insulin to manage their blood glucose. People who have type 2 diabetes may be able to manage their blood glucose levels with healthy eating, being more active, and maybe taking medications (including insulin) to do so. When you have type 1 diabetes, because of the damage to your β-cells, the only way for you to get enough insulin to manage your blood glucose is to take insulin, either by injection with a syringe, pen, or pump. Yes, it’s important that you eat healthy, and are active too, but if you have type 1 diabetes, you will also need to take insulin.

Insulin has gotten a bad rap, but in actuality, it’s a lifesaver. Some of the bad rap is real, such as the inconvenience, and challenge of balancing your blood glucose levels, but some has also come from misunderstandings. There have been many advances in exogenous insulins and the way insulin is administered over the past forty years. There is also a lot of ongoing research regarding types of insulin, administration devices, and routes for taking insulin.

Honeymoon period

Early on, many people newly diagnosed experience what is called the honeymoon period or a time of partial remission. This is the time shortly after you are diagnosed with type 1 diabetes. You have lost enough β-cells (50 – 90%) that caused your blood glucose to rise to diabetic levels, and you’ve already started taking insulin. During this time, your remaining β-cells continue to put out enough or almost enough insulin to manage your blood glucose with very small amounts of insulin, or none at all. There’s not a lot of blood glucose fluctuation (swings from highs to lows and lows to highs) during this time. Things seem fairly smooth. However, in time (which varies for everyone, but usually within a year), the autoimmune response, which caused the loss of the β-cells thus far, will continue to destroy more β-cells. When this happens, you will need to take more insulin to manage your blood glucose, and for many, a life long roller coaster of the highs and lows begins.

Many experts think it’s important for people in the honeymoon period to continue to take small amounts of insulin during this time for several reasons. One is psychological: they have just been told they have type 1 diabetes, have to take insulin for life, and make a lifestyle change. They have started to learn how to administer insulin and make food and activity changes. This in itself is a challenge. Then to be told they don’t have to take insulin now, but will have to do so again soon, is a lot to handle. It may also lead to them thinking that they don’t have diabetes, and maybe even forget what has been taught. Then when the honeymoon period comes to an end, they have to start all over again. Another reason to take insulin during the honeymoon period is biological: there is the hope that taking insulin during this time may protect the remaining β-cells from further damage. Research is showing the importance of preserving as much β-cell function as possible.

β-cells and C-peptide levels

The best and simplest way we have at this time to measure β-cell is with a blood test called C-peptide. This indirectly tests β-cell function because C-peptide and insulin are made in equal amounts by the β-cells. C-peptide shows how much insulin is being produced.

Preserving β-cell function may permit one to use less insulin to reach blood glucose goals and therefore produce less glucose variability (the ups and downs). Preserving β-cell function can be likened to the honeymoon period, where it is much easier to manage blood glucose levels. This may decrease the complications from glucose variability and improve quality of life. Also, having some β-cell function may be helpful when new treatments are approved.  There is also new research suggesting that C-peptide itself may be of benefit in preventing the complications of type 1 diabetes.

Clinical Studies: What you need to know about them

There are several clinical studies at this time looking at the prevention, treatment, and cure for type 1 diabetes. These trials are run by pharmaceutical companies to see if new drugs are safe and effective. In other words, to see if a drug works.

In the United States, the Food and Drug Administration (FDA) is the body of government that reviews this information and ultimately decides if an experimental drug can be approved for use. To get a drug approval, clinical studies must be done to meet certain formal requirements and standards. Many people are involved in gathering the information necessary to ask the FDA for their review: doctors, nurses, other health care providers, and study subjects who are people with the disease being studied. These studies follow strict international standards and codes of ethics called “Good Clinical Practices.” Learn more at www.fda.org

There are usually three kinds of studies in humans that are necessary to ask the FDA for approval. These are:

Phase 1: Researchers test an experimental drug or treatment in a small group of people for the first time to study its safety, determine a safe dose range, and identify side effects. These are sometimes called “first in human” studies.

Phase 2: The experimental drug or treatment is given to a larger group of people to see if there is an effect on the target disease and to further study safety. These are sometimes called “dose exploration” studies.

Phase 3: The experimental drug or treatment is given to large groups of people to confirm it is safe and has the desired effect on the target disease. These are sometimes called “dose confirmation” or pivotal studies.

Clinical Studies available for people with autoimmune type 1 diabetes

JDRF has partnered with several biotechnology and pharmaceutical companies to speed the discovery, development, and availability of therapeutics and devices to better treat and cure type 1 diabetes and its complications.

Monoclonal antibody (mAb)

As an example, two monoclonal antibodies (mAb) that target the T cell are being evaluated in type 1 diabetes. A mAb is an antibody that is produced and engineered to attach to a specific target, in this case CD3 on T cells. These mAbs are called anti-CD3s. They are thought to change the immune response (immune modulation), by down-regulating T effector cells (stopping the attack on your β-cells) and up-regulating T regulatory cells (protecting your β-cells from further attack).

One study with an anti-CD3 mAb (otelixizumab, pronounced oh’ te lix iz’ oo mab) has thus far shown that a 6 day treatment can suppress the rise in insulin requirements of recent-onset type 1 diabetic patients over 48 months, depending on their age and initial residual β-cell function. (1). Another study with an anti-CD3 mAb (teplizumab, pronounced tep liz’ oo mab) showed similar results (2[lxv1] ).

The DEFEND-2 (Durable-response therapy Evaluation For Early or New-onset type 1 Diabetes) clinical study is evaluating the investigational agent otelixizumab. Otelixizumab is now being tested to see if it can reduce the destruction of β-cells and preserve β-cell function in people 12 to 45 years old, who have recently been diagnosed (within the last 90 days), and who test positive for an autoantibody blood test. Patients receive one course of an infusion of otelixizumab or placebo, which consists of a 30 minute outpatient IV infusion per day for 8 consecutive days. After the infusion, there are periodic follow-up visits for 2 years. This study will measure C-peptide levels, A1C, incidence of abnormal glucose levels, and average daily insulin used. Learn more at www.defendagainstdiabetes.com

The Protégé Encore clinical study is evaluating the investigational agent teplizumab. Teplizumab is now being tested to see if it can reduce the destruction of β-cells and preserve β-cell function in people 8 to 35 years old, who have recently been diagnosed (within the last 12 weeks), and who test positive for an autoantibody blood test. Patients receive 2 courses of an infusion of teplizumab or placebo, which consists of an outpatient IV infusion per day for 14 consecutive days at start of the study, and another 14 days of infusions after 6 months. There are periodic follow up visits for 2 years. This study will evaluate A1C and total daily insulin usage. Learn more at http://www.protegediabetes.com/

Glutamic acid decarboxylase (GAD)

Glutamic acid decarboxylase, is an enzyme in the brain and a protein in the pancreas that plays several roles in the body. As an enzyme, it converts the excitatory amino acid glutamate into the inhibitory neurotransmitter GABA, which nerve cells use to communicate. But it also has a less helpful role, as an autoantigen in autoimmune diabetes.

Most people with type 1 diabetes have antibodies to GAD. Some people who don’t have type 1 diabetes also have antibodies to GAD, which predicts a higher chance of developing type 1 diabetes. When given as a treatment, GAD seems to intervene in the autoimmune response that causes type 1 diabetes. A study using the investigational agent Diamyd GAD in children and adolescents with newly diagnosed type 1 diabetes demonstrated β-cell protection. (3)

Diamyd GAD is now being tested to see if it can reduce the destruction of β-cells and preserve β-cell function in people 10 to 20 years old, who have recently been diagnosed (within the last 90 days), and who test positive for a GAD antibody blood test. Patients will receive a subcutaneous injection of Diamyd GAD or placebo on days 1, 30, 90, and 270 (month 9) – a total of 4 injections – with follow up visits at these times. This study will primarily measure C-peptide levels.

One must wonder if 40 years ago, the JDRF knew what it knows now, would it be called the JDRF or something else? Maybe the Autoimmune Diabetes Research Foundation – ADRF. But for now, JDRF will do. Better to keep putting money into research than the cost of changing a name.

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1. Keymeulen B, et al. Four-year Metabolic Outcome of a Randomised Controlled CD3-antibody Trial in Recent-onset Type 1 Diabetic Patients Depends on Their Age and Baseline Residual Beta Cell Mass. Diabetologia. April 2010; 53(4); 614-623.

2. Herold KC, et al. Treatment of patients with new onset Type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years. Clin Immunol. 2009 Aug;132(2):166-73. Epub 2009 May 14.

3. Ludvigsson J, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008 Oct 30;359(18):1909-20. Epub 2008 Oct 8.