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Why is it important?

Despite the classification of diabetes into two major types, type 1 (insulin-dependent) diabetes and type 2 (non-insulin-dependent) diabetes, it is apparent that there are some forms of diabetes which do not fit comfortably into these categories. Indeed, there is one form of diabetes which appears to straddle the two major types, presenting with non-insulin requiring diabetes in adults, but with many of the genetic, immune and metabolic features of type 1 diabetes and with a high risk of progression to insulin dependency. This form of latent autoimmune diabetes of adults (LADA) is found in about 10% of initially non-insulin requiring diabetes patients and is therefore probably far more prevalent than classic type 1 diabetes. A major European Union initiative (ACTIONLADA) plans to learn more about it.

Background to LADA:

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The development of the non-insulin requiring diabetes mellitus is projected to reach epidemic proportions over the next 10-20 years. WHO data indicate that in 1994 there were nearly 100 million affected individuals world-wide and that by the year 2010 this number will increase to over 215 million. In most Western societies, the overall prevalence has reached 4-6% and as high as 10-12% among the 60-70 year old individuals. Annual health costs caused by diabetes and its consequences are around 6-12% of the over-all health expenditures. Whilst non-insulin requiring diabetes plays a major role in contributing to mortality and morbidity in most countries, a proportion of people (about 25%) presenting with non-insulin requiring diabetes at diagnosis subsequently progress to insulin treatment. In some cases this progression results from the inadequacy of our therapy, but in many cases it is due to progression of the disease process with progressive and severe loss of insulin secretory capacity. Those people with non insulin requiring diabetes and diabetes associated auto antibodies are defined as having LADA, and are at high risk of progression to insulin dependency.

The prevalence of LADA has been estimated in a number of studies of both European and non-European populations. Wide variation has been described, partly depending on the markers chosen to define the condition, but also the characteristics of the subjects tested (for example, whether newly diagnosed or according to age at diagnosis). LADA, within Europe, when defined as non-insulin requiring diabetes diagnosed in individuals aged 30 to 50 years with GAD (glutamic acid decarboxylase) antibodies (a marker of autoimmune diabetes), is found in about 10% of cases. In populations outside Europe the frequency varies from zero in Papua New Guinea to 16% in the Congo and 16% in a Chinese population. Since type 1 diabetes is not common, but type 2 diabetes is common, and since an appreciable proportion of non-insulin requiring diabetic subjects have GAD auto antibodies, it follows that autoimmune non-insulin requiring diabetes, that is LADA, is probably substantially more prevalent than classic type 1 diabetes.

Genetics and immunology of LADA:

Subjects with LADA often have the histocompatability (HLA) genes and immune changes normally associated with type 1 diabetes. Indeed the HLA genes associated with LADA are the same as those associated with type 1 diabetes. In addition, the presence of GAD auto antibodies, which are also associated with type 1 diabetes, partly defines LADA. But individuals with LADA can also show other diabetes associated serum auto antibodies including islet cell auto antibodies and IA-2 auto antibodies Those with GAD and IA-2 auto antibodies progress more rapidly to insulin dependency than those with GAD auto antibodies alone.

Clinical features of LADA:

These genetic and immune features of LADA are consistent with these people having an immune -mediated disease process which resembles type 1 diabetes. Subjects with LADA also show many of the clinical characteristics of type 1 diabetes, for example, they tend not to be obese and show a striking insulin secretory deficiency.

About 80% of individuals with recently diagnosed non-insulin requiring diabetes of adult age with GAD auto antibodies (i.e. LADA) progress to insulin requirement within 6 years. Metabolic decompensation to insulin therapy in LADA is accelerated compared with those with initially non-insulin requiring diabetes who do not have GAD auto antibodies Even in those who progress to insulin therapy, the average interval between starting oral hypoglycaemic therapy and progression to requiring insulin was approximately 4 years in a LADA group but as long 8 years within that group who do not have diabetes-associated auto antibodies At present, no treatment can stop this progression to insulin requiring diabetes, but it is clearly of major public health importance since LADA is so prevalent.

Management of LADA:

There is no established management strategy for people diagnosed with LADA. The potential value of identifying this group at high risk of progression to insulin dependence includes:

• Avoidance of using metformin treatment given the theoretical associated risks of metformin in patients becoming insulin dependent.
• Early introduction of insulin therapy.
• Application of intervention trials to arrest or reverse the destructive disease process.

For those people diagnosed with diabetes in whom the primary defect is loss of insulin secretion, treatment should aim to restore islet insulin secretion. Therapy to prevent progression towards insulin dependency could include immunotherapy, insulin or oral hypoglycaemic drugs. The efficacy of sulphonylureas has not been formally tested but it is evident that they do not arrest progression to insulin dependency in subjects with LADA. Whether metformin is of benefit is unclear and the drug may be contraindicted in those with LADA as there is a theoretical risk of severe metabolic disturbance in individuals who progress to insulin dependency whilst on it.

The European Union have funded a major initiative (ACTIONLADA) to study the characteristics of LADA and report on how to treat it.

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