Latent autoimmune diabetes of adulthood

Unique features that distinguish it from types 1 and 2

Fadi Nabhan, MD; Mary Ann Emanuele, MD; Nicholas Emanuele, MD

VOL 117 / NO 3 / MARCH 2005 / POSTGRADUATE MEDICINE

CME learning objectives

• To be able to identify the various clinical features of latent autoimmune diabetes of adulthood (LADA), type 1 diabetes, and type 2 diabetes
• To understand the autoimmune pathophysiologic process involved in LADA
• To recognize symptoms that suggest the presence of LADA

Dr Nicholas Emanuele has served on the speakers' bureau for Aventis Pharmaceuticals and GlaxoSmithKline. The authors disclose no unlabeled uses of any product mentioned in this article.

Preview: A number of patients with poor glycemic control receive the diagnosis of type 2 diabetes despite the fact that they do not exhibit some of the traditional characteristics of the disease, such as obesity. A more accurate diagnosis for many of these patients is latent autoimmune diabetes of adulthood (LADA). In this article, Dr Nabhan and coauthors describe features that LADA has in common with type 1 and type 2 diabetes, as well as those that distinguish LADA from these more widely recognized forms of diabetes. The authors also describe the pathogenesis of the disease, potential complications, and treatment options.
Nabhan F, Emanuele MA, Emanuele N. Latent autoimmune diabetes of adulthood: unique features that distinguish it from types 1 and 2. Postgrad Med 2005;117(3):7-12

A 37-year-old man presented for ongoing care of type 2 diabetes, which had been diagnosed 10 months earlier. He had undergone evaluation with a nutritionist, had attended diabetes patient education classes, and was adhering to prescribed diet guidelines. In addition, he was attempting to exercise for 45 minutes five times a week. He was being treated with metformin and a sulfonylurea, both at maximal doses, but was still experiencing hyperglycemia. His hemoglobin A_1c level of 8.6% confirmed suboptimal control of the disease.

The patient weighed 77.9 kg (173 lb) and was 172.7 cm (68 in) tall. His blood pressure was 126/80 mm Hg. Findings on physical examination were unremarkable. The patient expressed concern about his poor diabetes control. He was told that he had type 2 diabetes, that this was evident from his lack of ketoacidosis, and that he would not require insulin.

Characteristics of LADA

At first glance, a case such as this one usually results in a diagnosis of type 2 diabetes. However, this patient's relatively young age, absence of obesity, and difficulty in achieving glycemic control using oral hypoglycemic agents should prompt reconsideration of such a diagnosis. The patient probably has LADA, a disease characterized by immune markers typical of type 1 diabetes but that initially does not require insulin (1).

Patients with LADA have several features of both type 1 and type 2 diabetes (table 1). Like patients with type 1 diabetes, they have a positive test for pancreatic autoantibodies, which indicates the autoimmune nature of the disease. Among these antibodies are glutamic acid decarboxylase antibodies, islet cell antibodies, insulin autoantibodies, and tyrosine phosphatase antibodies (3). Like patients with type 2 diabetes, patients with LADA do not require insulin initially and may, to a variable degree, have insulin resistance.

The prevalence of LADA can be inferred from the UK Prospective Diabetes Study (UKPDS) (4), which measured glutamic acid decarboxylase antibodies and islet cell antibodies in adult patients with diabetes. Tests for glutamic acid decarboxylase antibodies and islet cell antibodies were positive in 10% and 6%, respectively, of the entire cohort. The prevalence of these antibodies is higher in younger patients. In UKPDS, tests for glutamic acid decarboxylase antibodies and islet cell antibodies were positive in 34% and 21%, respectively, of patients aged 25 to 34 years.

Pathogenesis

Because patients with LADA have an autoimmune process similar to that found in type 1 diabetes, it is understandable that insulin dependency develops at an earlier stage than in patients with type 2 diabetes. But why, then, do patients with LADA experience a slower progression of beta cell destruction and tend to become insulin-dependent at a later stage than patients with type 1 diabetes? To answer this question, it is useful to review the pathogenesis of type 1 diabetes.

Type 1 diabetes develops as a result of immune-mediated destruction of islet beta cells. A genetic predisposition in patients with type 1 diabetes contributes to this immune destruction. The rapidity of the destruction determines the patient's age at onset of disease and the rate of progression to insulin dependency.

The presence of HLA-DR4-DQ8 antigens is associated with a more aggressive progression (3). The fact that HLA-DR4-DQ8 antigens are more common in type 1 diabetes than in LADA may explain why patients with LADA do not become dependent on insulin as rapidly as patients with type 1 diabetes (3). In addition, it has been postulated that immune tolerance to beta cell antigens may occur in LADA, which in turn may protect these patients from extensive destruction of beta cells (1).

In summary, the underlying immune-mediated destruction of beta cells in patients with LADA leads to insulin dependency more rapidly than in type 2 diabetes, but the more attenuated genetic and immune factors associated with LADA compared with type 1 diabetes lead to an older age at onset and a slower progression to insulin dependency.

Diagnosis

A diagnosis of LADA is established by the presence of elevated levels of pancreatic autoantibodies in patients with recently diagnosed diabetes that does not require insulin (1). Not only do these antibodies identify LADA, they also predict the rate of progression to insulin dependency. In one study (5), positive tests for glutamic acid decarboxylase antibodies, islet cell antibodies, and tyrosine phosphatase antibodies predicted insulin dependency within 3 years in 92%, 86%, and 75% of cases, respectively. The presence of all three autoantibodies predicted insulin dependency in 100% of cases.

Insulin autoantibodies are more common in type 1 diabetes than in LADA. Glutamic acid decarboxylase antibodies appear to be the most sensitive marker in patients with LADA, but tests for islet cell antibodies may be positive even in the absence of glutamic acid decarboxylase antibodies (3).

It is logical to start screening for LADA by measuring glutamic acid decarboxylase antibody levels. However, in cases of increased suspicion of LADA despite a negative test for glutamic acid decarboxylase antibodies, measurement of the other antibodies can help establish the diagnosis. After LADA is confirmed, it is also useful to measure levels of C peptide (a marker of pancreatic beta cell function), which can help identify the degree of beta cell destruction and direct management. (For example, a patient with a low C-peptide level will not benefit from a medication that stimulates insulin secretion.)

In which patients should LADA be suspected? Is it appropriate to measure levels of immune markers in every adult with diabetes of new onset? Since it is probably not cost-effective to test for these antibodies in all diabetic patients, an alternative approach is to target patients with a high likelihood of LADA. Clues that can raise clinical suspicion of LADA are an absence of metabolic syndrome features, uncontrolled hyperglycemia despite use of oral agents, and evidence of other autoimmune diseases, such as Graves' disease, Hashimoto's thyroiditis, pernicious anemia, premature gonadal failure, and hypoparathyroidism.

Because tests for pancreatic autoantibodies may be positive in obese patients with type 2 diabetes, some authorities suggest classifying LADA as either "thin" or "obese." Others prefer to identify patients with LADA who exhibit features of metabolic syndrome as having type 1.5 diabetes (6). The features of metabolic syndrome include hypertension, glucose intolerance, dyslipidemia, and central obesity. Three of these features are required for diagnosis of metabolic syndrome.

Acute and chronic complications

Patients with LADA do not present with ketoacidosis at the time of diagnosis, owing to the slow progression of beta cell destruction. However, insulin dependency develops at an earlier stage than in type 2 diabetes, and patients in the insulinopenic state are at risk for ketoacidosis.

Overall, LADA carries a risk for cardiovascular disease similar to that of type 2 diabetes. However, hyperglycemia is a stronger risk factor for cardiovascular disease in patients with LADA, which could be related to the lower prevalence of metabolic syndrome features (7). The characteristics that define metabolic syndrome may play major roles in increasing cardiovascular disease risk in patients with type 2 diabetes.

Patients with LADA carry the same risk for microvascular complications (ie, retinopathy, nephropathy, and neuropathy) as those with type 2 diabetes (7). However, a study in an Australian community (2) showed that patients with LADA may have an increased prevalence of retinopathy compared with patients with type 2 diabetes. It should be noted that in this study, patients with LADA had poor glycemic control, which could explain the increased prevalence of retinopathy.

Pharmacologic management

Treatment of LADA, like treatment of type 1 and type 2 diabetes, should focus on controlling hyperglycemia and preventing complications. The slow destruction of beta cell mass in LADA may allow the opportunity to preserve beta cell function, which is important for two reasons. First, preservation of beta cell function may avert the inconvenience of insulin injections. Second, studies of patients with type 1 diabetes show that such preservation is associated with better glycemic control and less proliferative retinopathy (8).

Insulin secretagogues
Sulfonylureas stimulate the pancreatic beta cells to secrete insulin. Although they may be effective at controlling hyperglycemia initially, they carry the theoretical risk of releasing more antigenic products and actually accelerating the immune process that originally triggered the beta cell destruction. The potential for such risk is supported by the Tokyo study (9), which compared sulfonylurea treatment with insulin in patients with LADA. The investigators concluded that pancreatic function, as measured by C-peptide response to a 75-g glucose load, decreased more rapidly in the group that received sulfonylurea treatment. More data are needed to conclusively define the role of sulfonylureas in LADA therapy. The same may be said about the other two insulin secretagogues, the meglitinides repaglinide (Prandin) and nateglinide (Starlix), a phenylalanine derivative.

Metformin
Insulin resistance may be present to a variable degree in patients with LADA. Therapy with metformin hydrochloride (Glucophage), which inhibits hepatic gluconeogenesis and makes the liver more sensitive to insulin, is beneficial. This increased sensitivity decreases the need for insulin secretion, which theoretically may slow the immune destruction of beta cells. However, this hypothesis is not supported by animal experimental data, and more research is needed (10).

Thiazolidinediones
This class of drugs, which includes rosiglitazone maleate (Avandia) and pioglitazone hydrochloride (Actos), primarily reduces insulin resistance in peripheral tissues, muscle, and fat. Use of these drugs may also improve the secretory function of the beta cells. In a recent study (11), rosiglitazone and troglitazone (which is no longer on the market) reduced the incidence of type 1 diabetes in the nonobese diabetic mouse (an animal model at high risk for type 1 diabetes) by more than 50%. This reduction may result from the anti-inflammatory effects of these drugs, which may modulate and slow the immune destruction of beta cells (11).

The potential to restore beta cell function may give thiazolidinediones a potential advantage over the other drug classes. Yet it is premature to recommend this class to every patient with LADA until more conclusive data are available, especially considering the cost of these medications and the required liver-function monitoring.

Insulin
Insulin therapy decreases endogenous insulin secretion, which in turn may slow the immune process of islet cell destruction, as shown in the Tokyo study (9). The better a patient's beta cell functioning upon entry into the study and the higher the level of his or her glutamic acid decarboxylase antibodies, the more effectively insulin preserved beta cell function. A recent trial (12), however, showed that insulin intervention in patients at high risk for type 1 diabetes was not successful in preserving beta cells and preventing diabetes.

The difference between these study outcomes may be related to the different pace of islet cell destruction in type 1 diabetes compared with LADA. Because LADA has a slower immune process, it may be hypothesized that insulin intervention is more effective in LADA than in type 1 diabetes, in which beta cell destruction occurs more rapidly. Administering insulin to protect patients from insulin dependency may seem counterintuitive, but a preserved pancreas may be associated with less retinopathy and hypoglycemia. It is important to discuss this aspect of care with the patient.

Conclusion

LADA is often seen in patients who initially are considered to have type 2 diabetes on the basis of their age at presentation, lack of ketoacidosis, and initial response to oral agents. Failure to maintain glycemic control with oral-agent combinations and dose adjustment in a lean patient who does not have the usual clinical features of metabolic syndrome should heighten suspicion of LADA.

Patients with LADA have autoimmune characteristics similar to those of type 1 diabetes, which lead to a more rapid progression to insulin dependency than is seen in type 2 diabetes. However, attenuated genetic, environmental, and immune factors in the pathogenesis of LADA lead to a later onset and a slower progression to complete beta cell destruction and insulin dependency than in type 1 diabetes.

It is important to identify patients who may have LADA, because its natural history and treatment strategy are different from those of type 2 diabetes. An explanation of LADA will give patients a better understanding of their prognosis and the fact that they may require insulin earlier than would be expected with type 2 diabetes.

In addition to controlling hyperglycemia and preventing diabetes complications, proper management of LADA has the potential to restore beta cell function. No specific treatment recommendations currently exist, but early data suggest that thiazolidinediones and insulin both have the potential to restore beta cell function in these patients.

References

1. Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care 2001;24(8):1460-7
2. Balme M, McAllister I, Davis WA, et al. Retinopathy in latent autoimmune diabetes of adults: the Fremantle Diabetes Study. Diabet Med 2002;19(7):602-5
3. Falorni A, Calcinaro F. Autoantibody profile and epitope mapping in latent autoimmune diabetes in adults. Ann N Y Acad Sci 2002;958: 99-106
4. Turner R, Stratton I, Horton V, et al. UKPDS 25: autoantibodies 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):1288-93 [Erratum, Lancet 1998;351(9099):376]
5. Torn C, Landin-Olsson M, Ostman J, et al. Glutamic acid decarboxylase autoantibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as type 1 diabetes on clinical grounds. Diabetes Metab Res Rev 2000;16(6):442-7
6. Palmer JP, Hirsch IB. What's in a name: latent autoimmune diabetes of adults, type 1.5, adult-onset, and type 1 diabetes. Diabetes Care 2003;26(2):536-8
7. Isomaa B, Almgren P, Henricsson M, et al. Chronic complications in patients with slowly progressing autoimmune type 1 diabetes (LADA). Diabetes Care 1999;22(8):1347-53
8. Nakanishi K, Kobayashi T, Inoko H, et al. Residual beta-cell function and HLA-A24 in IDDM: markers of glycemic control and subsequent development of diabetic retinopathy. Diabetes 1995;44(11):1334-9
9. 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;1005:362-9
10. Beales PE, Giorgini A, Annovazzi A, et al. Metformin does not alter diabetes incidence in the NOD mouse. Horm Metab Res 1997;29(6):261-3
11. Beales PE, Pozzilli P. Thiazolidinediones for the prevention of diabetes in the non-obese diabetic (NOD) mouse: implications for human type 1 diabetes. Diabetes Metab Res Rev 2002;18(2):114-7
12. Diabetes Prevention Trial Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;346(22):1685-91

Dr Nabhan is assistant professor of medicine, division of endocrinology and metabolism, Loyola University Medical Center, Maywood, Illinois. Dr Mary Ann Emanuele is professor of medicine and Dr Nicholas Emanuele is professor of medicine and director of the division of endocrinology and metabolism, Loyola University Medical Center and Edward Hines Veterans Administration Medical Center, Hines, Illinois. Correspondence: Fadi Nabhan, MD, Department of Medicine, Division of Endocrinology and Metabolism, Loyola University Medical Center, Bldg 117, Room 11, 2160 S 1st Ave, Maywood, IL 60153. E-mail: fnabhan@lumc.edu.

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