" 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. "

": 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"

"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"

"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."

" 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). "

"). 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. "

" 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. "

" 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. "

" 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. "

" 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). "

" 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
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