Latent autoimmune diabetes
Encyclopedia
Latent Autoimmune Diabetes of Adults (LADA), also known as, Diabetes Type 1.5, is a term coined by Tuomi et al. in 1993 (Diabetes 42:359-362) to describe slow-onset Type 1 autoimmune diabetes in adults. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (Diabetes Care, Volume 30, Supplement 1, January 2007) does not recognize the term LADA; rather, the Expert Committee includes LADA in the definition of Type 1 autoimmune diabetes (“Type 1 diabetes results from a cellular-mediated autoimmune destruction
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 of the beta-cells of the pancreas. In Type 1 diabetes, the rate of beta-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults).”) The National Institutes of Health (NIDDK) defines LADA as “a condition in which Type 1 diabetes develops in adults.” LADA is a genetically-linked, hereditary autoimmune disorder that results in the body mistaking the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...

 as foreign and responding by attacking and destroying the insulin-producing beta
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...

 islet cells of the pancreas. Simply stated, autoimmune disorders, including LADA, are an "allergy to self.”

Adults with LADA are frequently initially misdiagnosed as having Type 2 diabetes, based on age, not etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....

. In a recent survey conducted by Australia’s Type 1 Diabetes Network, one third of all Australians with type 1 diabetes reported being initially misdiagnosed as having the more common type 2 diabetes.

Other names for LADA

LADA may be diagnosed using any of the following terms:
  • latent autoimmune diabetes of adulthood
  • late-onset autoimmune diabetes of adulthood
  • latent autoimmune diabetes of aging
  • slow onset type 1 diabetes, or
  • type 1.5 (type one-and-a-half) diabetes

Diagnosing latent autoimmune diabetes

It is estimated that 20% of persons diagnosed as having non-obesity-related type 2 diabetes may actually have LADA. Islet cell, insulin, and GAD antibodies testing should be performed on all adults who are not obese that appear to present with type 2 diabetes. Not all people having LADA are thin or skinny, however—there are plus-sized
Overweight
Overweight is generally defined as having more body fat than is optimally healthy. Being overweight is a common condition, especially where food supplies are plentiful and lifestyles are sedentary...

 individuals carrying LADA but not getting accurately diagnosed because of their weight. These individuals are more often denied insulin by their health care physicians, considering people who were diagnosed with or have type 2 diabetes
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

 are given those treatments by diabetes specialists or their physicians extremely often. Moreover, it is now becoming evident that autoimmune diabetes may be highly underdiagnosed in many individuals who have diabetes, and that the body mass index
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...

 levels may have rather limited use in connections with latent autoimmune diabetes. Also, many physicians or diabetes specialists don't recognize LADA or probably don't know the condition actually exists, and so LADA is misdiagnosed as or mistaken for Type 2 diabetes highly often.

Diagnostic tests include:

C-peptide (also known as insulin C-peptide, connecting peptide)

This test measures residual beta cell function by determining the level of insulin secretion (C-peptide
C-peptide
C-peptide is a protein that is produced in the body along with insulin. First preproinsulin is secreted with an A-chain, C-peptide, a B-chain, and a signal sequence. The signal sequence is cut off, leaving proinsulin...

). Persons with LADA typically have low, although sometimes moderate, levels of C-peptide as the disease progresses. Patients with insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

 or type 2 diabetes are more likely to, but will not always, have high levels of C-peptide due to an over production of insulin.

Diabetes mellitus autoantibody panel

Glutamic acid decarboxylase (GAD) autoantibodies, radioimmunoassay (RIA) and insulin antibodies, radioimmunoassay, RIA.

Glutamic acid decarboxylase antibodies are commonly found in diabetes mellitus type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...

.

Islet Cell Antibodies (ICA) tests

Islet Cell IgG Cytoplasmic Autoantibodies, IFA; Islet Cell Complement Fixing Autoantibodies, Indirect Fluorescent Antibody (IFA); Islet Cell Autoantibodies Evaluation; Islet Cell Complement Fixing Autoantibodies - Aids in a differential diagnosis
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...

 between LADA and type 2 diabetes. Persons with LADA often test positive for ICA, whereas type 2 diabetics only seldom do.

Glutamic Acid Decarboxylase (GAD) Antibodies tests

Microplate ELISA: Anti-GAD, Anti-IA2, Anti-GAD/IA2 Pool - In addition to being useful in making an early diagnosis for type 1 diabetes mellitus, GAD antibodies tests are used for differential diagnosis between LADA and type 2 diabetes and may also be used for differential diagnosis of gestational diabetes, risk prediction in immediate family members for type 1, as well as a tool to monitor prognosis of the clinical progression of type 1 diabetes.

Insulin Antibodies (IAA) tests

RIA: Anti-GAD, Anti-IA2, Anti-Insulin; Insulin Antibodies - These tests are also used in early diagnosis for type 1 diabetes mellitus, and for differential diagnosis between LADA and type 2 diabetes, as well as for differential diagnosis of gestational diabetes, risk prediction in immediate family members for type 1, and to monitor prognosis of the clinical progression of type 1 diabetes. Persons with LADA may test positive for insulin antibodies; persons with type 2, however, rarely do.

Other characteristics of LADA that may aid in differential diagnosis include:
  • Onset usually at 25 years of age or older

  • Initially mimics non-obese type 2 diabetes (patients are usually thin or of normal weight, although some may be overweight to minimally obese
    Overweight
    Overweight is generally defined as having more body fat than is optimally healthy. Being overweight is a common condition, especially where food supplies are plentiful and lifestyles are sedentary...

    )

  • Oftentimes, but not always, a lack of family history for T2DM
    Diabetes mellitus type 2
    Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

     (family history for type 2 diabetes is sometimes involved regarding a latent autoimmune diabetic adult)

  • Persons with LADA are insulin resistant
    Insulin resistance
    Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

     like, but at prevalence levels less than, Type 2
    Diabetes mellitus type 2
    Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...


  • Human leukocyte antigen (HLA) genes associated with type 1 diabetes are seen in LADA but not in type 2 diabetes

  • Although some people having type 2 diabetes may inject insulin, this only rarely happens; in contrast, people with LADA require insulin injections around three to 12 years after so called type 2 diabetes diagnoses

Prevalence

It is estimated that approximately 20% of all persons diagnosed with type 2 diabetes might actually have LADA. This number accounts for an estimated 5%-10% of the total diabetes population in the U.S. or, as many as 3.5 million persons with LADA.

Treatment

LADA often does not require insulin at the time of diagnosis and may even be managed with changes in lifestyle in its early stages such as exercise, eating right
Diabetic diet
There is much controversy regarding what diet to recommend to sufferers of diabetes mellitus. The diet most often recommended is high in dietary fiber, especially soluble fiber, but low in fat . Recommendations of the fraction of total calories to be obtained from carbohydrate intake range from 1/6...

, and, if optional, weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...

. However, some clinicians believe that insulin should be started at onset or as soon as possible, rather than using sulfonylureas or other diabetes pills for initial treatment. Moreover, it is not clear whether early insulin therapy is of benefit to the remaining beta islet cells.

Initially, a person with LADA may respond to oral diabetes medications, eating right
Diabetic diet
There is much controversy regarding what diet to recommend to sufferers of diabetes mellitus. The diet most often recommended is high in dietary fiber, especially soluble fiber, but low in fat . Recommendations of the fraction of total calories to be obtained from carbohydrate intake range from 1/6...

 and lifestyle changes, although beta cells continue to be destroyed and LADA patients should be closely monitored. Some studies have demonstrated that the use of sulfonylureas and the insulin-sensitizing drug metformin, may increase the risk of severe metabolic disorder
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...

 in persons with LADA. When blood glucose can no longer be managed through lifestyle and medications, daily insulin injections will be required.

80% of persons initially diagnosed with type 2 but test positive for GAD (an indication of LADA) progress to insulin dependency within 6 years (some sources say between 3–12 years after diagnosis). Those who test positive for both GAD and IA2, however, will progress more rapidly to insulin dependence.

Living with any chronic illness is stressful, and patients with diabetes, let alone LADA, may be more prone to depression and eating disorders as a result. Counseling, therapy, and participation in support groups can play an important and positive role in the lives of persons with LADA.

Part of diabetes therapy should include patient education about diet
Diabetic diet
There is much controversy regarding what diet to recommend to sufferers of diabetes mellitus. The diet most often recommended is high in dietary fiber, especially soluble fiber, but low in fat . Recommendations of the fraction of total calories to be obtained from carbohydrate intake range from 1/6...

, exercise, stress management, and handling their diabetes on "sick" days. Patients need to understand how to manage their diabetes, as well as how to recognize, treat, and prevent hypoglycemia (low blood sugar) and hyperglycemia (high blood sugar) and how to give injections of insulin and glucagon. Blood glucose levels should be checked not less than 3-4 times per day when a patient is insulin dependent and, often, at least once during the night.

Hypoglycemia

Hypoglycemia
Diabetic hypoglycemia
Diabetic hypoglycemia is a low blood glucose level occurring in a person with diabetes mellitus. It is one of the most common types of hypoglycemia seen in emergency departments and hospitals...

 (low blood sugar) presents an immediate and life-threatening danger. Any reading 70 mg/dL (3.9 mmol/L) or below, for a person with diabetes, classifies as "low."

If the blood glucose falls too low a person can become disoriented and unable to swallow. Without being able to ingest a fast-acting sugar they may lose consciousness. If left untreated, hypoglycemia can lead to seizures, diabetic coma and death. Onset of hypoglycemia is often, albeit not always, rapid, and may be attributed to many things including too much insulin (insulin shock), not eating enough, heavy exercise, excitement, certain medications, or a combination of factors.

Because of the potential danger associated with hypoglycemia, persons using insulin should carry a glucagon kit, fast-acting food sugars, and medical identification with them at all times. At least one family member or friend should be instructed on glucagon administration as the patient is likely to be unable to inject themselves.

Hyperglycemia

Hyperglycemia (high blood glucose levels) occurs when too much food is eaten for insulin that was taken, not enough insulin, stress, dehydration, or illness are present. Hyperglycemia, if untreated, can lead to a deadly state called diabetic ketoacidosis
Diabetic ketoacidosis
Diabetic ketoacidosis is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances...

 (DKA). If insufficient insulin is present the body cannot use blood glucose as energy, and a combination of things happen, one of which is the body turning to fat stores for energy. Burning of fat causes a ketonic state that may result in an excess of ketones. Persons with high blood glucose levels should use a test strip to check their urine for ketones anytime their glucose levels are 240 mg/dL (13.3 mmol/L) or higher. Patients should call their doctor if ketones measure in the moderate-to-high range as DKA may require hospitalization.

A person in DKA requires immediate medical attention and should not attempt to simply administer more insulin independent of a physician's recommendation. Doing so (self-treating) could lead to serious health risks, even death. DKA can lead to heart failure, cerebral edema, coma, and death.

Long-term complications

The long-term complications of LADA are the same as for those with type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...

 (formerly juvenile diabetes) and with type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

. According to one major study, the Diabetes Control and Complications Trial
Diabetes control and complications trial
The Diabetes Control and Complications Trial , was a landmark medical study conducted by the United States National Institute of Diabetes and Digestive and Kidney Diseases . It significantly changed the management principles of Diabetes mellitus from the 1990s onwards...

 (DCCT), the risk of long-term problems are directly related to how well the blood glucose levels are managed. The American Diabetes Association
American Diabetes Association
The American Diabetes Association is a United States-based association working to fight the consequences of diabetes, and to help those affected by diabetes...

 recommends LADA patients strive for a HbA1c test of 7.0 or lower.

Uncontrolled diabetes of all types results in high blood glucose levels (hyperglycemia) which over time may cause diabetic neuropathy, diabetic retinopathy, eye trouble, kidney failure, heart disease, high blood pressure
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

, stroke, peripheral arterial disease (PAD), chronic infections and wounds that may not heal, erectile and other urological dysfunction, gastroparesis (delayed emptying of stomach contents), gangrene
Gangrene
Gangrene is a serious and potentially life-threatening condition that arises when a considerable mass of body tissue dies . This may occur after an injury or infection, or in people suffering from any chronic health problem affecting blood circulation. The primary cause of gangrene is reduced blood...

, blindness
Blindness
Blindness is the condition of lacking visual perception due to physiological or neurological factors.Various scales have been developed to describe the extent of vision loss and define blindness...

, amputation, lactic acidosis, diabetic ketoacidosis (DKA).

Prognosis

According to one study—"Similar as in prediabetic relatives of type 1 diabetic patients the risk for beta cell failure in adult 'type 2 diabetic' patients increases with the number of antibodies positive."

Eventually, the latent autoimmune diabetic adult will become dependent upon injecting insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

 in order to maintain glucose control. They will require daily injection of insulin and need to be diligent in following their diabetes care plan provided by their physician.

Diabetes, including latent autoimmune diabetes of adults, is a chronic illness that can have devastating complications. However, it is possible for most persons with diabetes to actively participate in their daily health care needs and dramatically reduce the risk of diabetes complications.

Patient education, motivation, and state of mental health all play an important role in how well a person with LADA will be able to manage their disease.

Comparison between LADA, type 1 diabetes and type 2 diabetes

LADA is slow-onset Type 1 autoimmune diabetes in adulthood (NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases ).
  • Onset: Type 1 diabetes onsets rapidly and at a younger age than does LADA.

  • Family history: There is often a family history of autoimmune conditions (for example, rheumatoid arthritis
    Rheumatoid arthritis
    Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

    , thyroid disease
    Thyroid disease
    -Hyper- and hypofunction:Imbalance in production of thyroid hormones arises from dysfunction of the thyroid gland itself, the pituitary gland, which produces thyroid-stimulating hormone , or the hypothalamus, which regulates the pituitary gland via thyrotropin-releasing hormone . Concentrations of...

    s, etc.). Furthermore, there is controversy about whether or not people with LADA have a family history of T2DM
    Diabetes mellitus type 2
    Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...

    .

  • Antibodies: Persons with type 1 diabetes and LADA usually test positive for certain (same) antibodies (GAD, ICA, IA-2) that are not present in type 2 diabetes. Moreover, there are also TCF7L2
    TCF7L2
    Transcription factor 7-like 2 also known as TCF7L2 or TCF4 is a protein acting as a transcription factor. In humans this protein is encoded by the TCF7L2 gene...

     genes associated with Type 2 diabetes involved in latent autoimmune diabetes of adults.

  • GAD antibodies: Persons with LADA usually test positive for GAD antibodies, whereas in type 1 diabetes these antibodies are more commonly seen in adults rather than in children.

  • Lifestyle and excess weight: People with LADA typically have a normal BMI or may be underweight due to weight loss prior to diagnosis. But some people with LADA may be overweight to mildly obese. LADA (Type 1 diabetes) is an autoimmune disease that cannot be prevented.

  • Prognosis: About 80% of all persons initially diagnosed with type 2, who also have GAD antibodies, will become insulin dependent within 3 to 12 years (according to differing LADA sources). Those with both GAD and IA2 antibodies, however, will become insulin dependent sooner. LADA occurs slowly, but progresses towards insulin dependency.

  • Treatment: Although LADA may appear to initially respond to similar treatment (lifestyle and medications, sometimes weight loss
    Weight loss
    Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...

    if needed) as type 2 diabetes, it will not halt or slow the progression of beta cell destruction, and people with LADA will eventually become insulin dependent.

External links

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