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Latent Autoimmune Diabetes in Adults



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Am Fam Physician. 2010 Apr 1;81(7):843-847.

  Related Article

Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes mellitus characterized by older age at diagnosis, the presence of pancreatic autoantibodies, and the lack of an absolute insulin requirement at diagnosis. Although patients with LADA present with more preserved beta cell function than those with classic type 1 diabetes, they tend to have a rapid and progressive loss of beta cell function necessitating intensive insulin intervention. Family physicians care for most patients in the United States with type 2 diabetes and, therefore, should be aware that approximately 10 percent of these patients have LADA.1  Table 1 compares characteristics of type 1 diabetes, type 2 diabetes, and LADA.2

Table 1.

Clinical Features of Type 2 Diabetes, Type 1 Diabetes, and Latent Autoimmune Diabetes of Adulthood

Features Type 2 diabetes Type 1 diabetes [corrected] Latent autoimmune diabetes in adults [corrected]

Ketoacidosis

Usually absent

Will develop rapidly unless patient receives insulin replacement therapy

Absent at diagnosis, but may be present when patient becomes severely insulinopenic

Cardiovascular complications

Risk 2–4 times higher than individuals who are euglycemic

Increased risk of cardiovascular morbidity and mortality related to strokes, acute coronary events, and coronary revascularizations; high incidence rates compared with euglycemic individuals, especially in women

Same risk as patients with T2DM

Microvascular complications (retinopathy, nephropathy, neuropathy)

Increased

Increased

Increased

Pathophysiology

Peripheral insulin resistance; reduced pancreatic beta-cell mass and function; reduced insulin secretion

Autoimmune destruction of pancreatic beta-cells

Latent autoimmune destruction of pancreatic beta-cells

Autoantibodies

Negative

  • GAD-65 autoantibodies

  • Islet-cell antigen-2

  • Insulin autoantibodies

  • note: Unlike LADA, T1DM patients typically are positive for all three autoantibodies

  • GAD-65 autoantibody is typically the only one detected

  • Islet-cell antibodies

Insulin requirements for treatment

Usually late in the disease when the remaining beta-cell mass and function can no longer support acceptable glycemic control achieved by oral agents or incretin mimetics

Insulin is required from the time of diagnosis

Insulin should be initiated as soon as the patient develops autoantibodies


T2DM indicates type 2 diabetes mellitus; GAD-65 indicates glutamic acid decarboxylase; LADA indicates latent autoimmune diabetes in adults; T1DM indicates type 1 diabetes mellitus.

Reprinted with permission from Unger J. Diagnosing and managing latent autoimmune diabetes in adults. Practical Diabetology. 2008;21(1):33.

Table 1.   Clinical Features of Type 2 Diabetes, Type 1 Diabetes, and Latent Autoimmune Diabetes of Adulthood

View Table

Table 1.

Clinical Features of Type 2 Diabetes, Type 1 Diabetes, and Latent Autoimmune Diabetes of Adulthood

Features Type 2 diabetes Type 1 diabetes [corrected] Latent autoimmune diabetes in adults [corrected]

Ketoacidosis

Usually absent

Will develop rapidly unless patient receives insulin replacement therapy

Absent at diagnosis, but may be present when patient becomes severely insulinopenic

Cardiovascular complications

Risk 2–4 times higher than individuals who are euglycemic

Increased risk of cardiovascular morbidity and mortality related to strokes, acute coronary events, and coronary revascularizations; high incidence rates compared with euglycemic individuals, especially in women

Same risk as patients with T2DM

Microvascular complications (retinopathy, nephropathy, neuropathy)

Increased

Increased

Increased

Pathophysiology

Peripheral insulin resistance; reduced pancreatic beta-cell mass and function; reduced insulin secretion

Autoimmune destruction of pancreatic beta-cells

Latent autoimmune destruction of pancreatic beta-cells

Autoantibodies

Negative

  • GAD-65 autoantibodies

  • Islet-cell antigen-2

  • Insulin autoantibodies

  • note: Unlike LADA, T1DM patients typically are positive for all three autoantibodies

  • GAD-65 autoantibody is typically the only one detected

  • Islet-cell antibodies

Insulin requirements for treatment

Usually late in the disease when the remaining beta-cell mass and function can no longer support acceptable glycemic control achieved by oral agents or incretin mimetics

Insulin is required from the time of diagnosis

Insulin should be initiated as soon as the patient develops autoantibodies


T2DM indicates type 2 diabetes mellitus; GAD-65 indicates glutamic acid decarboxylase; LADA indicates latent autoimmune diabetes in adults; T1DM indicates type 1 diabetes mellitus.

Reprinted with permission from Unger J. Diagnosing and managing latent autoimmune diabetes in adults. Practical Diabetology. 2008;21(1):33.

Unlike with type 2 diabetes, LADA tends to become rapidly unresponsive to oral medications and parenteral agents, such as incretin mimetics. The presence of autoantibodies to pancreatic islet cell antigens is the element common to both type 1 diabetes and LADA. Some experts have suggested that patients with LADA should be identified and treated with exogenous insulin therapy. Early and aggressive treatment is thought to preserve the remaining pancreatic beta cell function and lessen the risk of long-term diabetes-related complications; however, this supposition has not been proven in prospective studies.3

Approximately 10 to 30 percent of adults with type 2 diabetes test positive for autoantibodies, depending on the age and ethnicity of participants in the study group, and should be characterized as having LADA.1 In the U.K. Prospective Diabetes Study, glutamic acid decarboxylase antibodies were present in 10 percent of the 5,000 patients with type 2 diabetes.4 The prevalence of glutamic acid decarboxylase antibodies was higher in younger patients; 34 percent of patients 25 to 34 years of age were positive for the antibody. Patients with LADA typically test positive for only one autoantibody, whereas those with type 1 diabetes often have at least two autoantibodies detectable at diagnosis.

Although the exact pathogenesis of LADA is unclear, the underlying immune-mediated destruction of beta cells in patients with the disease leads to insulin dependency more rapidly than in patients with type 2 diabetes. Protective alleles appear to delay absolute exogenous insulin dependency in persons with LADA, compared with those with type 1 diabetes.

Despite the prevalence of LADA, there are no universal recommendations or guidelines regarding testing for islet autoantibodies in adult-onset diabetes. A recent study identified a subset of patients with type 2 diabetes who had characteristics that increased their risk of having LADA to a statistically significant degree (Table 2).5 The prospective validation study showed that the presence of at least two of the five distinguishing clinical features of LADA (i.e., risk score of two or more points at diagnosis) has a 90 percent sensitivity and a 71 percent specificity for detecting LADA via autoantibody testing. Furthermore, a LADA risk score of 1 or 0 points is highly reliable for excluding LADA (negative predictive value of 99 percent).

Table 2.

Clinical Characteristics Predictive of LADA Compared with Type 2 Diabetes Mellitus

Characteristics Percentage of patients with the characteristic
At diagnosis of LADA At diagnosis of type 2 diabetes

Age < 50 years

63

19

Acute symptoms of hyperglycemia*

66

24

Body mass index < 25 kg per m2

33

13

Family history of autoimmune disease†

46

35

Personal history of autoimmune disease†

27

12


note: The presence of two or more of the five features at diagnosis has a 90 percent sensitivity and a 71 percent specificity for detecting LADA via autoantibody testing. Patients with one or no features are unlikely to have LADA (99 percent negative predictive value).

LADA = latent autoimmune diabetes in adults.

*—Polydipsia, polyuria, or unintentional weight loss before diagnosis.

†—Thyroid disorders, celiac disease, type 1 diabetes, rheumatoid arthritis, or any other form of autoimmune disorder.

Information from reference 5.

Table 2.   Clinical Characteristics Predictive of LADA Compared with Type 2 Diabetes Mellitus

View Table

Table 2.

Clinical Characteristics Predictive of LADA Compared with Type 2 Diabetes Mellitus

Characteristics Percentage of patients with the characteristic
At diagnosis of LADA At diagnosis of type 2 diabetes

Age < 50 years

63

19

Acute symptoms of hyperglycemia*

66

24

Body mass index < 25 kg per m2

33

13

Family history of autoimmune disease†

46

35

Personal history of autoimmune disease†

27

12


note: The presence of two or more of the five features at diagnosis has a 90 percent sensitivity and a 71 percent specificity for detecting LADA via autoantibody testing. Patients with one or no features are unlikely to have LADA (99 percent negative predictive value).

LADA = latent autoimmune diabetes in adults.

*—Polydipsia, polyuria, or unintentional weight loss before diagnosis.

†—Thyroid disorders, celiac disease, type 1 diabetes, rheumatoid arthritis, or any other form of autoimmune disorder.

Information from reference 5.

Suspicion of LADA should be heightened in patients with coexisting autoimmune disorders, such as hypothyroidism, who are not excessively overweight and who have deteriorating glycemic control despite intensification of oral therapies and the use of incretin mimetics. Physicians may consider glutamic acid decarboxylase antibody testing to determine whether LADA is present.

Although no treatment guidelines for LADA have been published, theoretical advantages of intensive exogenous insulin therapy exist.6 Eighteen years after the original Diabetes Control and Complications Trial (DCCT), a follow-up study showed that early control of diabetes over 6.5 years seems to provide continued protection against microvascular and macrovascular complications.7,8 This result occurred despite the fact that patients in the DCCT who received intensive treatment had deteriorating A1C levels over time, whereas the conventional treatment group showed improvement upon completion of this landmark study. Early stabilization of glycemic control in patients with type 1 diabetes is postulated to establish “metabolic memory,” which theoretically protects against long-term complications.

The American Diabetes Association currently does not subclassify LADA as a diagnostic entity.2 However, prospective outcomes studies are needed to clarify whether early, intensive insulin therapy for LADA, without oral agents, helps preserve any remaining endogenous pancreatic beta cell function and reduces long-term complications through the induction of metabolic memory.

Address correspondence to Jeff Unger, MD, at jungermd@aol.com. Reprints are not available from the author.

Author disclosure: Nothing to disclose.

REFERENCES

1. Unger J. Introduction to diabetes. In: Diabetes Management in Primary Care. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2007:1–42.

2. Unger J. Diagnosing and managing latent autoimmune diabetes in adults. Practical Diabetology. 2008;21(1):32–37.

3. Stenström G, Gottsäter A, Bakhtadze E, Berger B, Sundkvist G. Latent autoimmune diabetes in adults: definition, prevalence, beta-cell function, and treatment. Diabetes. 2005;54(suppl 2):S68–S72.

4. Turner R, Stratton I, Horton V, et al. UKPDS 25: auto-antibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group Lancet. 1997;350(9087):1288–1293.

5. Fourlanos S, Perry C, Stein MS, Stankovich J, Harrison LC, Colman PG. A clinical screening tool identifies autoimmune diabetes in adults. Diabetes Care. 2006;29(5):970–975.

6. Maruyama T, Shimada A, Kanatsuka A, et al. Multicenter prevention trial of slowly progressive type 1 diabetes with small dose of insulin (the Tokyo study): preliminary report. Ann N Y Acad Sci. 2003;1005:362–369.

7. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977–986.

8. Nathan DM, Cleary PA, Backlund JY, et al., for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643–2653.


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