Latent autoimmune diabetes of adults

Latent autoimmune diabetes of adults (LADA), often also late-onset autoimmune diabetes of adulthood or aging,^[1] 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 obesity.

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 can only be treated with the usual oral treatments for type 2 diabetes for a certain period of time,^[2][3] after which 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 of adults are similar to those of other forms of diabetes: excessive thirst and drinking, excessive urination, and often blurry vision.

Compared to childhood type 1 diabetes, the symptoms develop comparatively 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.^[4] Not all people having LADA are thin or skinny, however—there are overweight individuals with LADA 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.^[4]

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, though will not always, have high levels of C-peptide due to an over production of insulin.^[5][6]

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

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.^[5]

Glutamic acid decarboxylase antibodies

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^[5][7][8] 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

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.^[5]

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).” ^[9] 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.^[4][6]

Hypoglycemia

Hypoglycemia, also known as low blood sugar or low blood glucose, is when blood sugar decreases to below normal levels. This may result in a variety of symptoms including clumsiness, trouble talking, confusion, loss of consciousness, seizures, or death. A feeling of hunger, sweating, shakiness, and weakness may also be present. Symptoms typically come on quickly.[1] The most common cause of hypoglycemia is medications used to treat diabetes mellitus such as insulin, sulfonylureas, and biguanides.[2][3] Risk is greater in diabetics who have eaten less than usual, exercised more than usual, or have drunk alcohol.[1] Other causes of hypoglycemia include kidney failure, certain tumors, liver disease, hypothyroidism, starvation, inborn error of metabolism, severe infections, reactive hypoglycemia, and a number of drugs including alcohol.[1][3] Low blood sugar may occur in babies who are otherwise healthy who have not eaten for a few hours.[4] The glucose level that defines hypoglycemia is variable. In people with diabetes levels below 3.9 mmol/L (70 mg/dL) is diagnostic.[1] In adults without diabetes, symptoms related to low blood sugar, low blood sugar at the time of symptoms, and improvement when blood sugar is restored to normal confirm the diagnosis.[5] Otherwise a level below 2.8 mmol/L (50 mg/dL) after not eating or following exercise may be used.[1] In newborns a level below 2.2 mmol/L (40 mg/dL) or less than 3.3 mmol/L (60 mg/dL) if symptoms are present indicates hypoglycemia.[4] Other tests that may be useful in determining the cause include insulin and C peptide levels in the blood.[3] Hyperglycemia, a high blood sugar, is the opposite condition. Among people with diabetes, prevention is by matching the foods eaten, with the amount of exercise, and the medications used. When people feel their blood sugar is low testing with a glucose monitor is recommended. Some people have few initial symptoms of low blood sugar and frequent routine testing in this group is recommended. Treatment of hypoglycemia is by eating foods high in simple sugars or taking dextrose. If a person is not able to take food by mouth, an injection of glucagon may help. The treatment of hypoglycemia unrelated to diabetes include treating the underlying problem as well and a healthy diet.[1] The term "hypoglycemia" is sometimes incorrectly used to refer to idiopathic postprandial syndrome, a controversial condition with similar symptoms that occur following eating but with normal blood sugar levels.

Prognosis

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.). Contrary to popular belief, some people with latent autoimmune diabetes of adults do carry a family history for Type 2 diabetes.^[10][11][12]
• 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. There are also TCF7L2 genes associated with Type 2 diabetes with latent autoimmune diabetes of adults.^[13]
• 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.^[5][14]
• Insulin resistance: People with LADA have insulin resistance similar to long-term type 1 diabetes; some studies showed that people with LADA have less insulin resistance, compared with those with type 2 diabetes; however, others have not found a difference.^[3]
• Lifestyle and weight: People with LADA typically have a normal BMI or may be underweight due to weight loss prior to diagnosis. Some people with LADA, however, may be overweight to mildly obese.^[15] 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 antibodies, will become insulin dependent within 3 to 15 years (according to differing LADA sources).^[16][17] Those with both GAD and IA2 antibodies, however, will become insulin dependent sooner. LADA occurs more slowly than classic rapid-onset Type 1 diabetes, though it progresses towards insulin dependency.^[7]
• 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.^[18] This followed the concept that GAD autoantibodies were a feature of type 1 diabetes and not type 2 diabetes.^[19]

References

1. "Diabetes mellitus: a guide to patient care"; page 20; Lippincott Williams & Wilkins; August 1, 2006; ISBN 978-1-58255-732-8
2. "Latent autoimmune diabetes". Mayo Clinic. Retrieved May 26, 2014.
3. "Latent autoimmune diabetes: a little known type of diabetes". Pharmacy Times. Retrieved May 26, 2014.
4. Landin-Olsson M (April 2002). "Latent autoimmune diabetes in adults". Annals of the New York Academy of Sciences 958: 112–116. doi:10.1111/j.1749-6632.2002.tb02953.x. PMID 12021090.
5. Comparison of clinical features between (juvenile)type 1 diabetes, type 2 diabetes and LADA; Islets of Hope (2006)
6. C-peptide test; Labtestsoline.org
7. Latent Autoimmune Diabetes in Adults; David Leslie, Cristina Valerie DiabetesVoice.org; 2003
8. Unnikrishnan AG, Singh SK, Sanjeevi CB (December 2004). "Prevalence of GAD65 antibodies in lean subjects with type 2 diabetes". Annals of the New York Academy of Sciences 1037: 118–21. doi:10.1196/annals.1337.018. PMID 15699503.
9. American Diabetes, Association (January 2007). "Diagnosis and classification of diabetes mellitus". Diabetes Care. 30 Suppl 1: S42–7. doi:10.2337/dc07-S042. PMID 17192378.
10. "Diabetes 1.5". Healthful Diabetes. Retrieved May 30, 2014.
11. "Family History of Diabetes Involving LADA" (PDF). DiabetesJournals.org. Retrieved May 30, 2014.
12. "Latent Autoimmune Diabetes of Adults". JCEM. Retrieved Mar 23, 2016.
13. "Latent Autoimmune Diabetes of Adults and TCF7L2 Genes". PubMed. Retrieved May 26, 2014.
14. Diabetes Mellitus, Type 1: A Review; eMedicine.com; updated 07/02/2006
15. Insulin resistance leads to LADA (Report). Diabetes Health. Retrieved April 10, 2010.
16. "Prediction of Type I Diabetes". UCDenver.edu. Retrieved Mar 23, 2016.
17. "Type 1.5 Diabetes". Bottom Line Health. Retrieved Mar 23, 2016.
18. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR (February 1993). "Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease". Diabetes 42 (2): 359–62. doi:10.2337/diab.42.2.359. PMID 8425674.
19. Hagopian, W A ; Karlsen, A E ; Gottsäter, A ; Landin-olsson, M ; Grubin, C E ; Sundkvist, G ; Petersen, J S ; Boel, E ; Dyrberg, T ; Lernmark, A (January 1993). "Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type Hagopian, W A ; Karlsen, A E ; Gottsäter, A ; Landin-olsson, M ; Grubin, C E ; Sundkvist, G ; Petersen, J S ; Boel, E ; Dyrberg, T ; Lernmark, A". The Journal of Clinical Investigation 91 (1): 368–74. doi:10.1172/JCI116195. PMC 330036. PMID 8423232.

External links

• Diabetes Research Centre, Melbourne, Australia LADA information, trials, resource links.