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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.
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:
Clinical features of LADA:
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:
• Avoidance of using metformin treatment given the theoretical
associated risks of metformin in patients becoming insulin dependent.
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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