Spiros Fourlanos, MBBS
Peter G. Colman MBBS, FRACP, MD
First published in the Diabetes Management Journal. Reprinted with permission of the Diabetes Management Journal and Diabetes Australia.
Type 1 diabetes (T1D) is an autoimmune disease in which immune cells target and destroy insulin-producing beta cells in the islets of the pancreas. Glutamic acid decarboxylase antibody (GADAb), is a well-recognized sensitive and specific marker of autoimmune beta-cell destruction. Although T1D classically afflicts children and young adults, presentation in older adults is increasingly recognized. In 1997 a substudy of the UK Prospective Diabetes Study (UKPDS) assessed 3672 patients with presumed type 2 diabetes for islet autoantibody status at diagnosis and identified 361 of 3672 (10%) with GADAb (1). This study, and several previous smaller studies, confirm that a significant subset of adults who present with presumed type 2 diabetes have a specific marker for beta-cell autoimmunity. This syndrome has been termed latent autoimmune diabetes in adults (LADA).
Prospective follow-up has shown that these patients have a different clinical course compared to people with classical type 2 diabetes. In the UKPDS, after a 6 year follow-up, 84% of patients with GADAb required insulin, compared with 14% of antibody-negative patients. This result has been validated by many other studies, which have shown that people with LADA generally display an early requirement for insulin treatment. In fact, in contrast to patients with type 2 diabetes, they are primarily insulin deficient rather than insulin resistant. Thus clinically these patients have a poor or only short term response to diet and oral hypoglycaemic treatment.
The key clinical features to identify people with LADA are gradual onset diabetes in adult life with the presence of islet autoantibodies, most commonly GADAb. The presence of GADAb has been associated with a slightly lower body mass index (BMI) than typically seen in type 2 diabetes patients. However, it is not possible to specify a cut-off BMI for the diagnosis of LADA as GADAb has been detected in obese individuals with diabetes. The presence of GADAb in patients with adult-onset diabetes is a sensitive marker for future insulin dependence. The positive predictive value of GADAb for long-term insulin requirement is between 84-95% and its presence has been demonstrated to be a better predictor of eventual insulin requirement compared to clinical judgment (2).
Which patients should be tested for GADAb and what is the benefit of identifying patients with LADA? This is still not definitively established. Certainly, these patients require insulin treatment early in the course of their disease and may benefit from early insulin treatment. In patients with classical type 1 diabetes presenting at a younger age there is evidence that close glycemic control with intensive insulin leads to continued endogenous insulin production for longer (3). Continued endogenous insulin secretion may be associated with reduced development of complications. There has been only one clinical trial of early insulin administration in patients with LADA. In this study low doses of subcutaneous insulin improved C-peptide response to an oral glucose tolerance test and decreased HbA1c compared to patients treated with sulphonylureas alone (4).
The recognition of the numbers of patients with LADA greatly increases the percentage of the diabetic population with autoimmune diabetes. Currently an international research effort is targeting prevention of autoimmune diabetes. We thus suggest it is important to identify people with LADA not only for prediction of insulin dependence but also because it is possible that future therapeutic strategies aimed at preventing progression to insulin dependence may be applicable to this group.
1. Turner R et al (1997). UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet 350:1288-1293.
2. Littorin B et al (1999). Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. Diabetes Care 22:409-412.
3. The diabetes control and complications research group (1998). Effect of Intensive therapy on residual beta cell function in patients with type 1 diabetes in the diabetes control and complications trial. Ann Intern Med. 113:49-51.
4. Kobayashi T, Nakanishi K, Murase T, Kosaka K (1996). Small doses of subcutaneous insulin as a strategy for preventing slowly progressive b-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes 45:622-626.
