Natural history of pre-type 1 diabetes
Type 1 diabetes is a chronic, progressive autoimmune disorder, which typically develops in association with markers of increased genetic susceptibility. A minority of those with increased genetic susceptibility progress to diabetes, whether in response to an undefined environmental insult or a combination of stimuli. This leads to immune activation, as witnessed by the appearance of humoral and cellular markers of immune processes directed against islet cells. These result, after the lapse of months or years, in progressive subclinical beta cell failure, which can be identified by loss of glucose tolerance and early abnormalities of insulin secretion. These culminate in overt hyperglycaemia. Beta cell function may recover briefly following diagnosis of diabetes (the 'honeymoon period'), but fades progressively thereafter. Most eventually lose all capacity for insulin secretion, but a minority preserve partial beta cell function over long periods of time, and appear to enjoy a more benign clinical course in consequence. This model has been used to characterise the natural history of type 1 diabetes and to define strategies for intervention.
The current model of type 1 diabetes as a chronic progressive autoimmune disorder was first proposed by Eisenbarth.
It has been used to characterise the natural history of type 1 diabetes and to define successive levels for potential intervention.
Stage 1: Primary prevention
This stage is defined by genetic susceptibility, identified by family history or genetic testing, and the absence of any evidence of immune activation directed against the islets. In practice, this stage is represented by the newborn. Interventions are designed to prevent the appearance of islet autoimmunity, and might potentially use either the appearance of autoantibodies or the onset of diabetes as their endpoint.
Stage 2: Secondary prevention
This stage is characterised by the presence of markers of immune activation, and the aim of intervention, typically undertaken in genetically susceptible autoantibody-positive individuals, is to prevent or delay the onset of diabetes.
Stage 3: Tertiary prevention
Primary and secondary prevention have the limitation that only a proportion of those subjected to the intervention will actually develop the disease. Intervention in the newly-diagnosed overcomes this problem, and is designed to salvage (and potentially to regenerate) residual beta cell function. Even partial success at this stage of the disease process could strengthen the rationale for use of the same intervention in secondary prevention.
Prospective studies from birth
Several research groups have initiated prospective studies from birth which have examined the development of islet autoimmunity and progression to diabetes within the general population. These include the German BABYDIAB study, the Finnish DIPP project, the DAISY study from Colorado, the Australian BABYDIAB study and the PANDA study from Florida. These studies have made a major contribution to our current understanding of the pathogenesis of childhood diabetes. Insights include the appearance of islet autoimmunity early in life, genetic factors influencing its development, and those characteristics of islet autoantibodies most strongly associated with progression to type 1 diabetes.
The major type 1 susceptibility genes identified to date all share a functional relationship to the immune system, including involvement in antigen presentation, antigen expression, immune regulation or signal transduction in immune cells. Some genes contribute to immune dysregulation and breakdown of immune tolerance to islet autoantigens, whereas others can be protective. Hence different combinations of susceptibility genes play a role in determining patterns of islet autoimmunity, associated diabetes risk and/or speed of progression to disease.
The aetiology of type 1 diabetes, however, is still unknown. An international multicentre study called The Environmental Determinants of Diabetes in the Young (TEDDY) has been launched to examine the environmental contribution to the autoimmunity that culminates in disease. Information gained from these studies in pre-type 1 diabetes will enable more effective identification of individuals who may benefit from intervention to halt autoimmunity, and thus help pave the way to prevention of type 1 diabetes.
^ Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med 1986;314:1360–68
^ Ziegler AG et al. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes 1999;48:460–8
^ Kimpimaki T et al. The first signs of beta-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type 1 Diabetes Prediction and Prevention Study. J Clin Endocrinol Metab 2001;86:4782–8
^ Barker JM et al. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). J Clin Endocrinol Metab 2004;89:3896–902
^ Colman PG et al. Islet autoimmunity in infants with a Type I diabetic relative is common but is frequently restricted to one autoantibody. Diabetologia 2000;43:203–9
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^ Hagopian WA et al. TEDDY--The Environmental Determinants of Diabetes in the Young: an observational clinical trial. Ann N Y Acad Sci 2006;1079:320–6