Latent autoimmune diabetes

Latent autoimmune diabetes in adults (LADA) is a genetically-linked, hereditary autoimmune disorder that results in the body mistaking the pancreas as foreign and responding by attacking and destroying the insulin-producing beta islet cells of the pancreas. Simply stated, autoimmune disorders, including LADA, are an "allergy to self."

In its early stages LADA typically presents as type 2 diabetes and is often misdiagnosed as such. However, LADA more closely resembles type 1 diabetes and shares common physiological characteristics of type 1 for metabolic dysfunction, genetics, and autoimmune features, but LADA does not affect children and is classified distinctly as being separate from juvenile diabetes.[1][2][7]

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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
• 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.[3]

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). Persons with LADA typically have low levels of C-peptide as the disease progresses. Patients with insulin resistance or type 2 diabetes are more likely to have high levels of C-peptide due to an over production of insulin.[2][4]

Diabetes mellitus autoantibody panel

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

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 do not.[2][9]

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[2][5][6] 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 test 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 rarely do.[2][9]

Other characteristics of LADA that may aid in differential diagnosis include:[1]

• onset usually at 25 years of age or older
• initially mimics non-obese type 2 diabetes (patient is thin or of normal weight)
• lack of family history of type 2 diabetes
• persons with LADA are insulin resistant like Type 2 but at levels less than Type 2
• HLA genes associated with type 1 diabetes are seen in LADA but not in type 2 diabetes[9]

Prevalence

It is estimated that approximately 20% of all persons diagnosed with type 2 diabetes may 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.[3][4]

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. 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. It is not clear whether early insulin therapy is of benefit to the remaining beta islet cells.[1][7]

Initially, a person with LADA may respond to oral diabetes medications and lifestyle changes, but 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. Once 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. But those who test positive for both GAD and IA2 will progress more rapidly to insulin dependence.[2][5][6]

Living with any chronic illness is stressful, and patients with 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 once a patient is insulin dependent and, often, at least once during the night.

Hypoglycemia

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

When 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. Untreated, hypoglycemia can lead to seizures, diabetic coma and death. Onset of hypoglycemia is often 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 themself.

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, untreated, can lead to a deadly state called diabetic ketoacidosis (DKA). When insufficient insulin is present the body cannot use blood glucose as energy. 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 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 insulin-dependent type 1 diabetes (juvenile diabetes). 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 an HbA1c test of 7.0 or lower.

Uncontrolled diabetes results in high blood glucose levels (hyperglycemia) which, over time may cause, diabetic neuropathy, diabetic retinopathy, 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), 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."[8]

Eventually, LADA patients will become dependent upon 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 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 neither classified as type 2 diabetes or type 1 diabetes but considered somewhere in between. It is a form of type 1 diabetes that has similarities and differences to both type 1 and type 2 diabetes.[2]

• Onset: Type 1 diabetes onsets rapidly and at a younger age than does LADA. Both LADA and type 2 onset is slow, over many months or years.

• Family history: There is often an absence of family history of type 2 diabetes in a LADA patient's family, but a genetic marker of HLA genes found in type 1 and LADA, but not in type 2 diabetes. LADA does not affect children and is uncommon in young adults (age 25–30). It is most often diagnosed after age 35.

• Antibodies: Persons with type 1 diabetes and LADA usually test positive for certain (same) antibodies that are not present in type 2 diabetes.

• 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.[2][10]

• Insulin sensitivity: Persons with LADA are not insulin resistant (and may be insulin sensitive) as in the case of type 2 diabetes and prediabetes.

• Lifestyle and excess weight: Type 2 diabetes may onset as a result of a sedentary lifestyle and excess body weight (especially when excess weight is carried about the center, or in those with an "apple" shaped body). These factors are not thought of as contributing factors to the onset of type 1 diabetes or LADA. Persons with LADA are often normal body weight or thin and are not insulin resistant. Persons with type 2 diabetes are often insulin resistant and overweight.

• Prognosis: About 80% of all persons initially diagnosed with type 2, who also have GAD antibodies, will become insulin dependent within six years. Those with both GAD and IA2 antibodies will become insulin dependent sooner. LADA occurs slowly, but progresses towards insulin dependency.[5]

• Treatment: Although LADA may appear to initially respond to similar treatment (lifestyle and medications) as type 2 diabetes, it will not halt or slow the progression of beta cell destruction. People with LADA will eventually become insulin dependent.

References

[1])Latent Autoimmune Diabetes in Adults: Symptoms, Diagnosis, Treatment, and Prognosis. Lahle Wolfe; article updated 05/22/2006. Permission for use of this article granted courtesy of Islets of Hope

[2]Comparison of clinical features between (juvenile)type 1 diabetes, type 2 diabetes and LADA; Islets of Hope (2006)

[3] Latent Autoimmune Diabetes in Adults; Mona Landin-Olsson; Department of Diabetology and Endocrinology, University Hospital, S-221 85 Lund, Sweden; Annals of the New York Academy of Sciences 958:112-116 (2002)

[4]C-peptide test; Labtestsoline.org

[5]Latent Autoimmune Diabetes in Adults; David Leslie, Cristina Valerie DiabetesVoice.org; 2003

[6]Prevalence of GAD65 Antibodies in Lean Subjects with Type 2 Diabetes; A G Unnikrishnan, S K Singh and C B Sanjeevi; Ann. N.Y. Acad. Sci. 1037: 118–121 (2004). doi: 10.1196/annals.1337.018 Copyright © 2004 by the New York Academy of Sciences

[7]Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult: definition, characterization, and potential prevention. Pozzilli P, Di Mario U. Universita Campus Biomedico and the. Universita La Sapienza, Rome, Italy. p.pozilli@caspur.it. Diabetes Care. 2001 Aug;24(8):1460-7; PMID: 11473087 [PubMed - indexed for MEDLINE]

[8]cmd=Retrieve&db=PubMed&list_uids=11460597&dopt=Abstract Progress in the characterization of slowly progressive autoimmune diabetes in adult patients (LADA or type 1.5 diabetes). Schernthaner G, Hink S, Kopp HP, Muzyka B, Streit G, Kroiss A.; Department of Medicine I and Department of Nuclear Medicine, Rudolfstiftung Hospital Vienna, Austria; PMID: 11460597 [PubMed - indexed for MEDLINE]

[9]Understanding Diabetes; uchsc.edu

[10]Diabetes Mellitus, Type 1: A Review; eMedicine.com; updated 07/02/2006