What Type of Diabetes Do I Have?

When you were diagnosed, you were probably told you had either Type 1 or Type 2 diabetes. Clear-cut and tidy. Since diabetes typically occurs in two types, you have to fit into one of them. Many people fit clearly into one of these categories, but others do not. And those who clearly fit one type when diagnosed may find these clear lines begin to smudge over time. Are there really only two types? Are you really the type you were told you were? Could you have more than one type of diabetes? Is your original diagnosis still correct after all these years?

A Short History Of Types

Described and treated since ancient times, diabetes has certain characteristics that have long been recognized. Before the discovery of insulin, people found to have sugar in their urine under the age of 20 usually died in their youth, while those diagnosed when over the age of 40 could live for many years with this condition.
Beginning in the mid 1920s, those who got diabetes when young (juvenile onset) were put on insulin, and those who got it when older (adult onset) often were not. However, the mechanisms that led to this difference in treatment were unknown. The only marker that differentiated the two types at that time was the presence in the urine of moderate or large levels of ketones when blood sugars were high. When significant ketones were present because the person could no longer make Tenough insulin, injected insulin was needed to control the glucose and they were called insulin-dependent.

Differences In The Three Major Types Of Diabetes
	Type 1	Type 1.5/LADA	Type 2
Avg. age at start	12	35	60
Typical age at start	3-40*	20-70*	35-80*
% of all diabetes	10% (25%**)	15%	75%
Insulin problem	absence	deficiency	resistance
Antibodies	ICA, IA2, GAD65, IAA	mostly GAD65	none
Early treatment	insulin is vital, diet & exercise changes helpful	pills or insulin vital, diet & exercise changes helpful	pills helpful, diet & increased activity essential
Late treatment	insulin, diet, exercise (occasionally pills)	insulin, pills, diet, exercise	insulin, pills, diet, exercise
* may occur at any age if all antibody positive cases are included, ie Type 1 and Type 1.5

Type 1 Diabetes

In the early 1980s a breakthrough showed that early onset diabetes, now called Type 1 was actually an autoimmune disease in which the body destroyed its own beta cells. Antibodies produced by the immune system signaled a clear cause that distinguished it from adult onset diabetes.
Type 1 or insulin-dependent diabetes mellitus (IDDM) appears primarily in childhood or adolescence with excessive thirst and urination, loss of weight, and extremely high glucose levels. Other than the recent weight loss, a relatively normal weight is typical when Type 1 diabetes starts. Type 1 occurs in 7 to 22% of all people who have diabetes (See Type 1.5 below). Treatment for this type revolves around replacing the missing insulin delivery with an insulin pump or injections t match diet and exercise.
Many interventions are being attempted to stop the progressive loss of beta cells that is seen in Type 1 diabetes. Antibodies can often be detected a couple of years before glucose levels rise sufficiently for a diagnosis, and some children with antibodies do not develop Type 1 diabetes. When antibodies are present, there is a 68% probability of developing Type 1 diabetes, and the presence of multiple autoantibodies has the highest predictive value for Type 1 diabetes.¹

Type 1.5 or LADA

The older term of “juvenile onset” is no longer used because so many people develop Type 1 as adults. Unfortunately, many Type 1 adults do not immediately require insulin for treatment and are often mistakenly told they have Type 2 diabetes. One in every seven to ten people diagnosed as having Type 2 diabetes actually have antibodies that indicate they have the slower form of Type 1 diabetes found in adults called Type 1.5 or LADA (latent autoimmune diabetes in adults). Here, the diabetes develops more slowly because adults often have fewer antibodies destroying the beta cells. They can often be treated with oral medications at first because insulin production may continue for a few years. Early treatment with insulin, however, is an advantage in that it “rests’ the beta cells and prolongs insulin production. With retention of internal insulin production, glucose levels are easier to control for more years.
Those with Type 1.5 diabetes number about 2 million people in the U.S., about double the million or so people with Type 1 diabetes. The only difference from Type 1 is that there are typically only one or two antibodies present in the blood, rather than three or more. The most common antibody found in Type 1.5 diabetes is the GAD-65 or glutamic acid decarboxylase antibody (See Table 24.1).
Type 1.5 differs from Type 2 in that insulin resistance is often not involved. Compared with Type 2 diabetes, Type 1.5 starts about 15 years earlier (average age 46 rather than 61), excess weight and insulin resistance are usually not involved, and there is often a family history of other autoimmune disease.² Type 1.5 should be suspected when an adult does not show other classic signs of Type 2 diabetes, such as high triglyceride levels, low HDL levels, abdominal obesity, or a family history of high blood pressure or gout. When glucose levels are controlled, they usually do not have the high risk for cholesterol, blood pressure, or cardiac and vascular problems typically found in true Type 2 diabetes. Correct diagnosis of I is important because insulin treatment will be required much sooner in Type 1.5 than Type 2 diabetes. In the UKPDS study, 94% of those with Type 1.5 diabetes required insulin six years after being diagnosed compared to only 16% of those with Type 2 diabetes and no antibodies.³ If Type 1.5 is suspected, a GAD-65 antibody test should be done. When GAD-65 or islet cell antibodies are present, the decline in insulin production is faster and the person requires insulin earlier than in Type 2.
With the increase in weight seen in the general population, people with Type 1 and 1.5 can develop Type 2 diabetes with its classic signs of insulin resistance. In fact, the rising obesity rates in children now make it difficult for clinicians to differentiate Type 1 and Type 2 diabetes in the very young. There is also an increasing tendency for antibodies to appear in obese teens originally diagnosed as having Type 2.
Basically Type 1s can develop characteristics of Type 2 diabetes when they become older and gain weight, and Type 2s can develop characteristics of Type 1 diabetes as insulin production is gradually lost over time or in the young when inflammatory and other processes generate antibodies against their beta cells.

Type 2 Diabetes

In contrast to Type 1 where the immune system destroys beta cells, Type 2 diabetes develops from a gradual decline in the beta cells’ ability to over-produce insulin. Type 2 is a progressive disease in which insulin production has been increased for several years as the body attempts to keep up with the insulin resistance associated with abdominal obesity or an apple shape. Insulin production gradually degrades as the beta cells become exhausted.
Type 2 is often part of a metabolic syndrome that includes various signs of insulin resistance: high blood pressure, high total cholesterol (over 200), high triglycerides (also over 200), low levels of HDL or protective cholesterol (under 40 mg/dl), gout, and abdominal obesity.
Treatment for Type 2 diabetes revolves around varied combinations of diet, exercise, medications, and/or insulin injections. Type 2 diabetes can be prevented if a person remains diligent about staying physically active and maintaining normal weight. In the Diabetes Prevention Program conducted by the NIH, the diagnosis of diabetes was reduced by 58% in the group that did these two things.4 Two classes of diabetes medications, GLP-1 agonists and glitizones, have been shown to slow the loss of beta cells in Type 2 diabetes. When started early, these medications appear to preserve insulin production, delay loss of glucose control, and delay the need for insulin for at least several years.
At least 90% of people with diabetes have Type 2 and 30 to 40% of them currently use insulin. About 30% of Americans have insulin resistance and about 30% of these will eventually develop Type 2 diabetes at some time in their lives.
Of all the people with diabetes, roughly 10% will have classic Type 1, 75% will have Type 2 (insulin resistant), and another 15% will have Type 1.5.

Other Types of Diabetes

Other forms of insulin resistant diabetes also can be seen in gestational diabetes, polycystic ovary disease, acanthosis nigricans, and maturity-onset diabetes of the young or MODY. Insulin resistant diabetes can also be unmasked by medications like prednisone. In rare cases, a type similar to Type1 diabetes but without antibodies may be seen following trauma to the pancreas, following pancreatic surgery, or after exposure to toxins like Agent Orange. This type is insulin dependent because no insulin can be produced once the pancreas is removed or severely damaged.

Does Your Diabetes Type Ever Change?

Even ignoring the high numbers of people with Type 1.5 who are initially misdiagnosed as Type 2, the lines between Type 1 and Type 2 diabetes often get blurred over time. Due to aging and weight gain in those with Type 1, the progressive nature of beta cell failure in Type 2, and the mixture of obesity and antibodies in young people, those with one type of diabetes often tend to take on characteristics of the other.
With less exercise and more weight around the middle, some Type 1s become not only insulin deficient but also insulin resistant. They can develop the cardiac risks associated with the Metabolic Syndrome and benefit from medications that lower cholesterol and blood pressure. More insulin is required to control glucose levels, while certain Type 2 medications, like Glucophage (metformin) and GLP-1 agonists, may benefit their control.
On the other hand, as Type 2 diabetes progresses, insulin production may diminish to a point where it can no longer maintain normal glucose levels. Insulin will be required to keep glucose levels under control. Some people with Type 2 eventually become totally dependent on insulin and can go into ketoacidosis in stressful situations. In fact, ketoacidosis is about twice as common in Type 2 diabetes as it is in Type 1.

Lab Tests Used for Diagnosis
A variety of lab tests and clinical signs help to provide the information needed to correctly determine which type of diabetes a person has.

• Ketones: Ketones are a byproduct produced when the body uses large amounts of fat as fuel. This occurs when carbohydrate is no longer available as fuel due to a lack of insulin. When a urine or blood test shows moderate or large amounts of ketones, the person definitely has Type 1 or insulin-dependent diabetes. (One rare exception is young, black males who may have ketones present at diagnosis but regain insulin production.) If insulin is injected before ketones are tested, the opportunity to find large amounts of ketones may have passed. Ketones can be tested at home in blood with certain meters, or in the urine with Ketostix or Ketodiastix anytime glucose levels are high.
• Antibodies:  Type 1 diabetes is an autoimmune disease, so 80 to 90% of the time when Type 1 exists, the person is producing antibodies characteristic of Type 1, such as the islet cell, insulin, and GAD-65 antibodies. A blood test shows if these antibodies are present. Free testing is available in the TrialNet Study (http://www.diabetestrialnet.org/PathwayToPrevention/).
• High triglyceride and low HDL:  Cholesterol problems characterized by high triglycerides and low HDL are typical of insulin resistance. These markers for the Metabolic Syndrome are commonly found in Type 2 diabetes. A routine cholesterol or lipid profile test is used to measure these.
• Uric Acid:  The high uric acid level often found in people with gout is a component of insulin resistance. A high uric acid level with a high glucose level is highly likely to be Type 2 diabetes.
• C-peptide: If other tests fail to indicate the type of diabetes, a C-peptide test can reveal how much insulin a person is producing. C-peptide is half of the precursor molecule to insulin that is split off when insulin is produced by the body. If C-peptide is normal or high, Type 2 diabetes is more likely. If the level is significantly low, Type 1 diabetes is likely. If the level is near normal but low, the person might have early Type 1, Type 1.5, or long-term Type 2 with negligible insulin production. This test should be done when the glucose level is at least 200 mg/dL (11.1 mmol/L).

  Some people develop diabetes as adults in the same way as type 2 diabetes. However, their condition is in fact a late-onset form of type 1 diabetes.
People with this form of diabetes have GAD antibodies. Testing for these can help diagnose the type of diabetes an adult has.

Contents of this article:

1. What are GAD antibodies?
2. What is LADA?
3. Symptoms of diabetes
4. Type 1 diabetes and GAD antibodies
5. Treatment of type 1 diabetes

What are GAD antibodies?

GAD antibodies stop insulin being produced in the pancreas by marking out cells for attack.

GADA is short for GAD autoantibodies. Antibodies in this case means autoantibodies.
GAD antibodies result in the immune system stopping insulin being produced, leading to diabetes.

Normal role of GAD

GAD is short for glutamic acid decarboxylase. This is an enzyme that is needed to make a neurotransmitter. Neurotransmitters are involved in nerve messaging.
The neurotransmitter is gamma-aminobutyric acid (GABA), an amino acid that has the effect of reducing nerve transmission.
GAD inhibits nerve messages. It relaxes muscles, for example. Lack of GAD is involved in a disease known as stiff-person syndrome.
GAD is found in the brain and the pancreas, the organ in the belly that produces insulin.

When GAD produces antibodies

Unfortunately, GAD can also act as an autoantigen. This means that it triggers the immune system to produce antibodies against its own cells.
In this case, these GAD autoantibodies mark out cells in the pancreas for attack.
These pancreas cells produce insulin. Diabetes is the result of the immune system attacking these cells as if they were foreign material that must be destroyed.
Autoimmunity is the cause of type 1 diabetes, and other diabetes-related autoantibodies are also involved aside from GAD autoantibodies.
Finding GAD antibodies is a way to diagnose type 1 diabetes when doctors are not sure. This may be when people show signs in later life that start to resemble type 1 diabetes, whereas type 1 usually develops at younger ages.

What is LADA?

LADA stands for latent autoimmune diabetes in adults. It can be considered slow-developing type 1 diabetes. It usually appears after the age of 30.
LADA is a condition in people later in adulthood who develop what might appear at first to be type 2 diabetes. In fact, the condition is more similar to type 1 diabetes. It has been called "type 1.5 diabetes."
Adults with diabetes who are positive for the GAD autoantibodies are more likely to need insulin treatment. A need for insulin at the time of diagnosis defines type 1 diabetes. It is usually diagnosed in late childhood.
LADA usually requires insulin treatment within 6 to 12 months of a GADA-positive test.

Symptoms of diabetes

High thirst may be one symptom of diabetes.

Classic diabetes symptoms include:

• Needing to urinate often
• High thirst
• Unusual hunger
• Lack of energy
• Blurry vision

These symptoms are caused by high levels of sugar in the blood. They are often what lead to a diagnosis of diabetes. The symptoms are reduced by treatment.
Some other symptoms, such as tingling or numbness in the feet or hands, can signal advanced disease caused by diabetes.
Some symptoms are more typical of type 1 diabetes than type 2 diabetes, such as unusual weight loss.

Type 1 diabetes and GAD antibodies

Most people with diabetes have type 2 diabetes, which usually develops in adult life.
Type 1 diabetes is less common and usually has an onset in children and young adults. If the diagnosis of type 1 or 2 diabetes is unclear, a test for GAD antibodies can help.

How is a GAD antibody test done?

A test for GAD antibodies is done by scientists working in a lab. The sample they test is from the blood. The sample may also be used for other diabetes tests done at the same time.
Taking the blood sample involves a needle through the skin, usually in the arm, to reach a vein and draw blood. The small wound may be mildly painful afterward.

What do GAD antibody results mean?

The GAD antibody test comes back with a measurement of the level of GADA in the blood:

• If the result is equal to or below 0.02 nanomoles per liter, this diagnoses type 1 diabetes
• Higher concentrations above 0.03 nanomoles per liter signal nervous disorders

Other tests for diabetes

Testing for GAD antibodies is not routine for people suspected of having diabetes.
It is used when there is doubt about whether the condition is type 1 or type 2 diabetes. Other antibodies are also tested during this lab diagnosis:

• Islet cell cytoplasmic autoantibodies (ICA) - these antibodies also result in insulin-producing cells being attacked
• Insulinoma-associated-2 autoantibodies
• Insulin autoantibodies - insulin itself can trigger an attack by the immune system

Standard tests for diabetes are usually enough to make a diagnosis of type 1 or type 2 diabetes. Both kinds involve measurement of blood sugar levels.
The decision to diagnose type 1 or 2 is usually made based on features such as age of onset, severity of symptoms, and need for insulin.
Blood sugar levels are tested in the blood sample. This can measure the concentration indicated at the time of the sample. The A1C test indicates the average blood sugar level over the previous 3 months.

What other conditions result in high GAD antibodies?

Injecting insulin works to control blood sugar levels.

Autoimmunity against the neurotransmitter targeted by GAD antibodies results in a nerve disorder known as stiff-person syndrome.
This condition is uncommon but happens more often in people with other autoimmunity disorders, including type 1 diabetes.
Symptoms of stiff-person syndrome include:

• Muscle stiffness
• Muscle spasms

The symptoms progress slowly. They affect the trunk mostly, but also the limbs.
The level of GAD antibodies is typically higher in people who have stiff-person syndrome than in people who have type 1 diabetes.

Treatment of type 1 diabetes

Type 1 diabetes caused by autoimmunity needs to be treated by providing the insulin that cannot be produced by the body.
Treatment is not targeted at the autoimmune aspect caused by GAD autoantibodies. Instead, it treats the problem caused by it.
Insulin treatment controls blood sugar levels. This prevents complications caused by high blood sugar, which causes damage to blood vessels.
People with type 1 diabetes, including people with LADA, must manage their condition with daily blood tests and insulin injections.
Insulin may also be needed to treat type 2 diabetes in its later stages. Type 2 diabetes does not involve the attack of insulin-producing cells led by GAD antibodies, however.

Written by Markus MacGill

 To be screened, you must fulfill at least one of the two conditions below:

• 1 to 45 years of age and have a brother, sister, child, or parent with type 1 diabetes
• 1 to 20 years of age and have a cousin, aunt, uncle, niece, nephew, half sibling, or grandparent with type 1 diabetes

About this Study

The Natural History Study of the Development of Type 1 Diabetes will study people at increased risk for type 1 diabetes to learn more about how type 1 diabetes occurs.
TrialNet is screening close blood relatives of people with type 1 diabetes because relatives of people with type 1 diabetes have a 10 to 15 times greater risk for developing the disease than people with no family history.

Screening

The study is divided into two parts: Screening and Monitoring. During screening, you will be tested for diabetes-related autoantibodies in the blood. Autoantibodies are proteins that are made by the body’s immune system. If these proteins are present, it could mean that cells in the pancreas which produce insulin are damaged. Certain kinds of autoantibodies can be found in the blood years before type 1 diabetes occurs.
If the screening blood tests show that you have autoantibodies, we will ask you to participate in the monitoring part of the study.

Procedures

We will ask you to provide information about yourself and your family history of diabetes. We will take up to 1 tablespoon of blood at each visit to test for diabetes related autoantibodies. A member of the TrialNet research team will contact you if you have one or more autoantibodies present in the blood (you are positive). You will then be asked to return for a repeat blood test to confirm the presence of autoantibodies.
If we do not find autoantibodies in your blood (you are negative), you will receive results by letter. Testing negative for autoantibodies does not mean you will never get diabetes, but the chances are much lower than if you tested positive. It is still possible that you could develop autoantibodies in the future. For this reason, we will offer to test you each year until you turn 18. We may ask some people who are negative for antibodies to be in the monitoring part of the study so that we can compare their results with people who are positive.

Monitoring

Annual Monitoring for those with Autoantibodies at Screening
Individuals with one autoantibody will have an Oral Glucose Tolerance Test (OGTT) and HbA1c at the first monitoring visit to determine their monitoring plan. If these results confirm you are at a lower 5-year risk for diabetes, you will have Annual Monitoring.
Annual monitoring visits include testing for autoantibodies and HbA1c. If your HbA1c increases or you develop two or more autoantibodies you will be asked to come for Semi-Annual Monitoring so that you can be followed more closely for possible progression towards type 1 diabetes.
Semi-Annual Monitoring for those with Autoantibodies at Screening
Individuals in this group have a higher 5-year risk of diabetes. They will be asked to come in for Semi-Annual Monitoring. This includes individuals found to have two or more autoantibodies during Screening. It also includes individuals that have one autoantibody as well as other test results that indicate a higher 5-year risk for diabetes.
Semi-annual Monitoring visits include blood tests for autoantibodies, HbA1c, as well as an (OGTT).

These tests are described here:

• Oral Glucose Tolerance Test (OGTT)
  After an overnight fast (not eating during the night), you will have an OGTT. This test is done to measure the level of glucose (sugar) in the blood after you drink a sweet liquid that contains glucose over a 5-minute period. We will measure your height and weight. To make taking the blood easier, we will place an intravenous needle and plastic tube (IV) in a vein in your arm. Blood samples will be drawn through the IV before you drink the liquid and then at several times after you have finished drinking it. The entire test will take about 21/2 hours.
  
  
• Autoantibody Test
  This test looks to see if you have diabetes-related autoantibodies in your blood. Autoantibodies are proteins that are made by the body's immune system. They are a sign that the cells in the pancreas that produce insulin could be damaged. These proteins can be found in the blood years before a person develops type 1 diabetes.
  
  
• HbA1c Test
  This blood test measures a person’s average blood glucose level for last 2-3 months before the test.

A Caucasian woman, 55 years of age, was referred to a general practitioner (GP) after an optometry assessment revealed possible signs of diabetes. Her blood glucose, measured at a community pharmacy, was found to be 28.5 mmol/L. The patient was generally healthy and not on any regular medications. She had a hereditary solitary kidney but 
renal function had always been normal. On specific questioning, she reported a short history of polyuria and polydipsia. There was also history of intermittent epigastric and right upper quadrant abdominal pain over several years and, more recently, these pains were associated with meal times and so she had decreased her food intake. There was no unintended weight loss. An abdominal ultrasound, performed 2 months prior to investigate these symptoms, had revealed no biliary pathology. Routine blood tests collected at that time revealed a fasting glucose level of 6.3 mmol/L. An oral glucose tolerance test had not been performed. There was no family history of diabetes.
At presentation, examination findings were normal. Blood pressure was 120/80 mmHg and heart rate was 80 beats per minute. Abdominal examination was unremarkable. She weighed 57 kg and was 158 cm tall (body mass index of 22.8 kg/m²). Clinically, there were no signs of dehydration. Neurological examination revealed decreased vibration sensation only in her first metatarsophalangeal joints bilaterally. Urinary ketones were negative, but glucose was moderately positive on urine dipstick analysis. Random blood glucose was 26.3 mmol/L, but blood ketones were not available.
A diagnosis of diabetes mellitus was considered and the patient was sent for urgent investigations including fasting blood glucose, electrolytes, liver, kidney and thyroid function tests, and a coeliac disease screen in case gluten intolerance was causing her abdominal pains with meals. The patient was asked to return within the next 24 hours for results of the initial tests. Fasting glucose was 15.6 mmol/L and HbA1c was 10.3% (89 mmol/mol). Thyroxine (T4) was mildly elevated at 20.9 pmol/L but thyroxine stimulating hormone (TSH) was within the normal range. Albumin:creatinine ratio, measured on a spot urine sample, was 14.5 mg/mmol, which is indicative of microalbuminuria. There were no previous assays to use as a comparison. The coeliac disease screen was negative.
On the basis of these initial results, the patient was advised to commence insulin treatment. She was reluctant to accept this, despite attempts to explain the importance of glycaemic control, the need to avert diabetic ketoacidosis and the likelihood of substantial symptom relief from the control of her hyperglycaemia. The patient decided to adopt a strict ‘raw’ diet and observe its effect on her blood glucose levels. Given the rapid onset of hyperglycaemia in this case, further testing for autoimmune pathology was indicated. Within the week, the results returned with strongly positive glutamic acid decarboxylase (GAD) antibodies, insulinoma antigen-2 (IA2) antibodies and islet cell antibodies, confirming a diagnosis of type 1 diabetes mellitus.
Despite this, the patient could not accept the need for insulin treatment. Against medical advice, she managed to keep her blood glucose levels remarkably well controlled initially with a low-carbohydrate diet. Despite being advised that dietary modifications alone would be unsustainable to manage her blood glucose levels while ensuring adequate nourishment, she resolved to continue a low-carbohydrate diet for a further week. A postprandial serum assay revealed reduced serum C-peptide levels, confirming depletion of endogenous insulin.
Further education regarding the absolute insulin depletion in type I diabetes was still met with refusal to consume a more feasible, balanced diet and commence insulin therapy.
The patient returned 1 week later complaining of worsening visual acuity, particularly with long distance sight, intense hunger and a concern about the effects it would have on her driving. At this stage she began to accept her condition and the medical and nutritional management required, permitting the necessary treatment and allied health professionals to be involved in her care. She remains defiant, however, over the need to use insulin.

Discussion

Type 1 diabetes mellitus results from a T-cell-mediated destruction of pancreatic beta islet cells, resulting in rapid progression to absolute insulin deficiency. Of patients newly diagnosed with type 1 diabetes, 80% are positive for GAD or IA2 antibodies,¹ whereas 20% are antibody negative at the time of diagnosis.² The risk of developing diabetes over a 10-year period, on the basis of positive GAD and IA2 antibody tests, is three times greater with a family history of type 1 diabetes in a first-degree relative.² This patient had no family history of type 1 diabetes or of any autoimmune disease.
The incidence of anti-islet cell autoantibodies is 31% in type 1 diabetes, 6% in non-type 1 diabetes and 8–9% in unaffected first-degree relatives of people with type 1 diabetes. This is in contrast to type 1a diabetes, also called latent autoimmune diabetes of adulthood (LADA), where there is a more insidious progression of hyperglycaemia due to insulin resistance.² The development of GAD antibodies in adulthood is associated with type 1 diabetes, but also occurs in adults developing type 1a diabetes.³ Interestingly, the BABY-DIAB study,⁴ TEEN-DIAB study⁵ and the Diabetes Autoimmunity Study in the Young (DAISY)⁶ have shown that in children these anti-islet cell antibodies can first appear in early life and are predictive of the development of type 1 diabetes later in life. These antibodies are also present in 1% of individuals without diabetes, although usually at low titre.⁷
This case highlights an important diagnostic point, that types 1 or 1a diabetes should be considered in adult patients who present with particularly rapid-onset hyperglycaemia. In this case, there was no evidence of other associated autoimmune conditions. Coeliac disease is known to occur in up to 10% of patients with type 1 diabetes,⁸ and there is a strong association between type 1 diabetes and autoimmune thyroiditis.⁹ Although there have been numerous immunological markers identified in types 1 and 1a diabetes,¹⁰ the commercially used assays that are acceptably sensitive and specific for the condition are the anti-GAD and anti-IA2 antibodies.² Early detection of autoimmune diabetes mellitus in adults ensures appropriate treatment of the condition and early establishment of euglycaemia,¹¹ which supports a legacy effect of blood glucose control,¹² and reduction in the risk of complications such as diabetic nephropathy and retinopathy.
Although it is possible to predict the development of type 1 diabetes through human leukocyte antigen (HLA) genetic predisposition and the appearance of islet cell autoantibodies,^13,14 none of the treatments trialled to date have been able to arrest the progressive loss of insulin secretion resulting from destruction of beta islet cells.¹⁵ Further research has enabled identification of another major islet autoantigen, zinc transporter-8 (ZnT8), which is associated with beta islet cell secretory granules. Antibodies against ZnT8 are found in about 70% of patients with type 1 diabetes and may predict the development of the disorder, thereby providing an opportunity to treat patients before the onset of autoimmune beta cell destruction.¹⁶
It is also pertinent to consider the psychological effects of such a diagnosis in adulthood. Significant changes across all areas of life are generally required and the condition has the potential to affect work and family life. As with other chronic disease diagnoses, patients would be expected to experience the usual stages of bereavement, and GPs play a pivotal role in supporting these patients to overcome the grief of the diagnosis. Beyond accurate and timely diagnosis of the condition, education and instilling confidence in the adult patient newly diagnosed with type 1 diabetes is critical to the patient’s ability to self-manage. Indeed, there is a need not only for counselling and support from the GP, but also the consideration of additional counselling from allied health professionals such as psychologists for optimal support and patient outcomes.

Islet cell autoantibodies and what they tell us

Islet autoantibodies are markers that appear when insulin producing beta cells in pancreas are damaged. They can be detected a long time before beta cells are completely destroyed.
We use autoantibodies to estimate an individual’s risk of developing type 1diabetes.  This information can be used to select people who are potentially eligible to take part in clinical trials testing potential treatments that might delay or prevent type 1 diabetes. Islet autoantibody testing can also to help clinicians classify the type of diabetes and decide on the best treatment in  people in whom this is not clear. 
The first islet autoantibodies to be discovered were those that bound to the islet cells of human pancreas.
A very early finding of our research group was that the immune system started producing autoantibodies a very long time before someone developed diabetes.  This suggests that, even if autoantibodies are present, there is a big ‘window of opportunity’ to delay or prevent type 1 diabetes if effective treatment to slow the underlying autoimmune process becomes available  (Lancet 1981) This finding has provided the rationale for all the subsequent research aiming to prevent the condition.
The test for ICA has been very useful for identifying those people who are likely to progress to diabetes, but has now been largely superseded by tests for autoantibodies to specific proteins found in the islet.
  The islet autoantibodies that we currently measure bind to:

• Glutamic acid decarboxylase65 (GAD)
• Protein tyrosine phosphatase islet antigen-2 (IA2)
• Insulin.
• Zinc transporter 8 (ZnT8)

We have developed sensitive radiobinding tests to measure these autoantibodies in blood samples.  Some people who will never develop diabetes may have detectable levels of antibodies to one of these islet proteins. The risk of developing diabetes is greatly increased when two or more antibodies are present (Diabetes 1997). We therefore estimate risk based on the combined results of testing for 3 or 4 antibodies. Counting the number of antibodies detected has proved to be a highly accurate method of predicting who is likely to develop type 1 diabetes in the future (Diabetes Care 1999).
Islet autoantibodies often appear in a particular sequence, with insulin or GAD autoantibodies developing first, sometimes as early as 6 months of age, to be followed by IA2 and ZnT8 autoantibodies. This spreading of autoimmunity to different islet proteins indicates that the process leading to destruction of the insulin producing cells is progressing. Further, progression is also marked by the development of antibodies that recognize different regions of the target islet proteins  IA2: Working with researchers in Milan, we found that IA2 autoantibodies bind to two main regions of the molecule. We also discovered that people who produced antibodies to more than one of these binding regions were likely to develop diabetes far sooner than those who produced antibodies to a single binding region  (Journal of Immunology 2002). We also showed that relatives who have antibodies to IA2β, a protein similar to IA2, are at particularly high risk of developing diabetes (Diabetologia 2008) 
 ZnT8A are the most recently identified islet autoantibodies. To determine how what these novel markers added to diabetes prediction, we measured ZnT8A in ENDIT participants. We found that although adding ZnT8A measurement to all the other antibodies did not improve prediction in the majority of relatives, ZnT8A were useful additional risk markers in relatives at low genetic risk of diabetes and older individuals (J Clin Endocrinol Metab 2012)

Developing methods for measuring islet autoantibodies

Insulin autoantibodies (IAA): To improve antibody testing, we developed a microassay that allows us and other scientists to measure insulin autoantibodies (IAA) very accurately using very small volumes of serum or plasma.  Insulin autoantibodies are very important, as they are often the first autoantibody that can be detected in early childhood.  Previously, assays required relatively large volumes of serum, which made them unsuitable for screening young children and large populations.  Our microassay is now being used throughout the world (Journal of Autoimmunity, 1997), but we have gone on to refine the assay and make changes that further improve the sensitivity (Journal Immunol Methods, 2006) and specificity of the test (Journal  Immunol Methods, 2010). Recently we have also confirmed that assessing IAA affinity with a simple test can further improve our ability to predict diabetes (Clin Exp Immunol, 2012). By continually improving our assays, and assisting other researchers to do the same, we hope to further improve the prediction of diabetes and the standardisation of assays between laboratories. 
Antibodies to IA2: During our investigation into assay methods, as part of the autoantibody harmonization program, we discovered that two common assay reagents could reduce binding of autoantibodies to IA2 (Journal Immunol Methods, 2009). This finding has implications for assay stability, but also focused our attention on the importance of the amino acid cysteine to IA2 autoantibody binding (Diabetes, 2012).

Autoantibodies and diabetes susceptibility genes

 We are interested in the relationship between the autoantibodies that a person develops and their diabetes susceptibility genes.  It has been known for a long time that people with HLA DRB1*04 alleles have increased levels of IA2 autoantibodies at diagnosis of type 1 diabetes. We found that patients with HLA DRB1*09 alleles were also more likely to develop IA-2 autoantibodies, while IA-2 autoantibodies in patients carrying HLA DQB1*02 alleles were less likely to bind to the JM domain. We also found that that IA2 autoantibody development was increased in patients carrying the neutral risk HLA DRB1*07 allele (Diabetologia, 2008) This suggests a dissociation between diabetes risk alleles and the autoantibody response once immune regulation had broken down.

 Autoantibodies and gender

 Girls and boys have a similar risk of developing type 1 diabetes, but men are more likely to develop the condition than women. To understand why, we looked at autoantibodies by gender in the ENDIT screening cohort of first degree relatives of patients with type 1 diabetes. We found that adolescent and young adult males were more likely to have ICA than adolescent or young adult females (Diabetologia, 2002). We also found that, at diagnosis of type 1 diabetes, boys in late adolescence were more likely to have insulin autoantibodies (Diabetologia, 2003). This indicates that boys may be more susceptible to developing islet autoimmunity during adolescence.

 Changes in autoantibodies over time

 We are interested the relationship between islet autoimmunity and the increasing incidence of childhood type 1 diabetes.  We recently found that the frequency of IA-2 and ZnT8 autoantibodies increased during the period between 1985 and 2002 when the incidence of the condition was rising rapidly. The levels of IA-2, ZnT8 and IA-2β autoantibodies also showed an increase over this period (Diabetes, 2012). These results suggest that there is more inter- and intra-molecular spreading of the autoimmune response in patients who were diagnosed more recently.

 Coeliac disease related autoantibodies

 Coeliac disease or gluten intolerance is an autoimmune condition that has similar susceptibility genes to type 1 diabetes, and has a high prevalence in people with type 1 diabetes. We investigated coeliac disease related autoimmunity in patients with type 1 diabetes and their relatives by measuring autoantibodies to tissue transglutaminase (TGA) (Diabetes Care, 2001). We found that these antibodies were more common in the relatives compared with healthy schoolchildren. This shows that relatives of people with type 1 diabetes are an increased risk of coeliac disease, as well as the patients themselves.
In the relatives, there was no association between coeliac antibodies and islet autoimmunity. This suggested that gluten was not an environmental trigger of islet autoimmunity as previously proposed.
We also found that 1% of 5470 seven year old children drawn from the general population already had coeliac disease related autoimmunity, suggesting that the process leading to coeliac disease starts in early childhood (BMJ, 2004). Children with coeliac disease related autoantibodies were shorter and lighter than other children, indicating that undiagnosed coeliac disease has an impact on childhood growth. Our laboratory is currently measuring TGA as reference laboratory for the TEDDY study.

Antibody workshops and standardization

Our group plays a major role in international endeavours to improve the performance of islet antibody assays throughout the world. We jointly co-ordinated the international Diabetes Antibody Standardization Programme (DASP) with the US Centre for Disease Control (CDC) in Atlanta.  This programme was designed to ensure that antibody testing in many laboratories around the world will give equivalent results. DASP has now been replaced by a similar programme, the Islet Autoantibody Standardization Program (IASP) and we will continue in our efforts to ensure assays are equivalent no matter which laboratory they are performed in.  Any laboratory wishing to join the IASP standardisation programme should contact Alistair Williams.
To improve agreement between antibody measurements performed in different laboratories we have also taken part in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored islet autoantibody harmonization programme. This has resulted in a standardized protocol for GAD and IA-2 autoantibody measurement, which has greatly improved agreement in results between American and European laboratories. (J Clin Endocrinol Metab, 2010). Efforts to harmonize insulin and ZnT8 antibody measurement are ongoing.

 Current research

 Recently, we have identified a specific amino acid in IA2 and IA2β which is very important to autoantibody binding and helps us to distinguish between the two major autoantibody binding regions in the protein tyrosine phosphatase (PTP) domain. We are currently investigating how autoantibody responses to this and other autoantibody binding regions alter over time and whether the pattern of binding is associated with a different risk profile. This has included the expression and purification of native and novel insulins to characterise autoantibody binding to different regions of the insulin molecule. We also aim to develop a new assay for insulin autoantibodies that does not require the use of radioactivity, to facilitate large scale screening programmes. We continue to investigate the relationship between the autoantibody response, diabetes susceptibility and beta cell destruction.
 We also collaborate on national and international research projects with other laboratories and provide autoantibody results in our role as an antibody reference laboratory.