Latent autoimmune diabetes of adults

Latent autoimmune diabetes of adults (LADA), often also late-onset autoimmune diabetes of adulthood or aging, slow onset type 1 diabetes or diabetes type 1.5 is a form of diabetes mellitus type 1 that occurs in adults, often with a slower course of onset. Adults with LADA may initially be diagnosed as having type 2 diabetes based on their age, particularly if they have risk factors for type 2 diabetes such as a strong family history or are obese.

The diagnosis is based on the finding of high blood sugar together with the clinical impression that islet failure rather than insulin resistance is the main cause; detection of a low C-peptide and raised antibodies against the islets of Langerhans support the diagnosis. It cannot be treated with the usual oral treatments for type 2 diabetes, and insulin treatment is usually necessary, as well as long-term monitoring for complications. The concept of LADA was first introduced in 1993.

Signs and symptoms
The symptoms of latent autoimmune diabetes in adults are similar to those of other forms of diabetes: polydipsia (excessive thirst and drinking), polyuria (excessive urination) and often blurry vision.

Compared to childhood type 1 diabetes, the symptoms develop comparitavely slowly.

Diagnosis
It is estimated that more than 50% of persons diagnosed as having non-obesity-related type 2 diabetes may actually have LADA. Glutamic acid decarboxylase autoantibody (GADA), islet cell autoantibody (ICA), insulinoma-associated (IA-2) autoantibody, and zinc transporter autoantibody (ZnT8) testing should be performed on all adults who are not obese who are diagnosed with diabetes. Not all people having LADA are thin, however—there are overweight individuals with LADA but who are misdiagnosed because of their weight. 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 levels may have rather limited use in connections with latent autoimmune diabetes. Also, many physicians or diabetes specialists don't recognize LADA or don't know that Type 1 diabetes may occur in adults, and so LADA is misdiagnosed as or mistaken for Type 2 diabetes very often.

C-peptide
This test measures residual beta cell function by determining the level of insulin secretion (C-peptide). Persons with LADA typically have low, although sometimes moderate, levels of C-peptide as the disease progresses. Patients with insulin resistance 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.

Autoantibody panel
Glutamic acid decarboxylase autoantibodies (GADA), islet cell autoantibodies (ICA), insulinoma-associated (IA-2) autoantibodies, and zinc transporter autoantibodies (ZnT8). Glutamic acid decarboxylase antibodies are commonly found in diabetes mellitus type 1.

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 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 autoantibodies (GAD, ICA, IA-2, ZnT8); autoantibodies are not present in persons with type 2 diabetes.

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)


 * Often, but not always, a lack of family history for T2DM (family history for type 2 diabetes is sometimes involved regarding a latent autoimmune diabetic adult)


 * Persons with LADA are insulin resistant like, but at prevalence levels less than, Type 2


 * 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 diagnosis

Classification
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus does not recognize the term LADA; rather, it includes LADA in the definition of Type 1 autoimmune diabetes: "Type 1 diabetes results from a cellular-mediated autoimmune destruction 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".

Prevalence
It is estimated that between 6-50% of all persons, depending on population, 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 appropriately, and, if indicated, weight loss. 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 appropriately 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 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, 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.

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 (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 (formerly juvenile diabetes) and with type 2. According to one major study, the Diabetes Control and Complications Trial (DCCT), the risk of long-term problems are directly related to how well the blood glucose levels are managed. The American Diabetes Association 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, 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, 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 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 diabetic 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
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, Hashimoto's Disease (autoimmune hypothyroidism) and Celiac Disease, etc.).
 * Autoantibodies: Persons with type 1 diabetes and LADA usually test positive for certain (same) autoantibodies (GAD, ICA, IA-2, ZnT8 ) that are not present in type 2 diabetes. Studies have reported an association of Type 1 diabetes/LADA with high risk genes, HLA-DR3, HLA-DR4.
 * GAD autoantibodies: 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 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 misdiagnosed with type 2, who have GAD autoantibodies, 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 more slowly than classic rapid-onset Type 1 diabetes, but progresses towards insulin dependency.
 * Treatment: The treatment for Type 1 diabetes/LADA is exogenous insulin, to control glucose levels, prevent further destruction of residual beta cells, reduce the possibility of diabetic complications, and prevent death from diabetic ketoacidosis (DKA). Although LADA may appear to initially respond to similar treatment (lifestyle and medications 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.

History
The concept of latent autoimmune diabetes mellitus was first described in 1993 to describe slow-onset type 1 autoimmune diabetes in adults.