Etiology

Natural history of prediabetes

Over the past 30 years, the ability to predict the development of T1D has improved dramatically with the combined use of genetic, autoantibody, and metabolic markers. The most often cited model of the natural history of T1D suggests that genetically susceptible individuals with a fixed number of beta cells are exposed to a putative environmental trigger that induces beta cell autoimmunity [11]. The development of islet reactive autoantibodies is a marker of ongoing autoimmune disease, but it is predominantly activated autoreactive T cells that destroy beta cells, which results in a progressive and predicable loss in insulin secretory function. Because clinical T1D typically does not present until approximately 80% to 90% of the beta cells have been destroyed, there is a marked gap between the onset of autoimmunity and the onset of diabetes (Fig. 1).

Recently, some aspects of the classic model have been challenged. For example, data suggest that pancreatic beta cells have considerable regenerative properties [12]. The degree of beta cell destruction required for symptomatic onset is also questioned, with recent studies suggesting that 40% to 50% of beta cells are viable at the onset of hyperglycemia. This finding may explain why, despite persistent autoimmunity, insulin secretory function may remain stable for long periods of time in persons with T1D. Only when autoimmunity overwhelms the regenerative capabilities of the beta cells does insulin secretory function decline (denoted by loss of first phase insulin secretion measured during intravenous glucose tolerance testing). Loss of first phase insulin response is followed by a period of glucose intolerance and a period of clinically "silent" diabetes.

An improved understanding of the natural history of prediabetes remains critical for directing future studies aimed at the prevention of T1D. Improved markers of disease risk, further identification of environmental agents that influence the disease, and continued identification of genes that influence disease

Immune Environmental Dysregulation Triggers and Regulators

Immune Environmental Dysregulation Triggers and Regulators

Pre-Diabetes

Overt Diabetes

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Pre-Diabetes

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Fig. 1. Model of the pathogenesis and natural history of T1D. The modern model expands and updates the traditional model by inclusion of information gained through an improved understanding of the roles for genetics, immunology, and environment in the natural history of T1D. FPIR, first phase insulin response; GAD, glutamic acid decarboxylase autoantibodies; IAA, insulin autoantibodies; ICA, islet cell autoantibodies; ICA 512, autoantibodies against the islet tyrosine phosphatase; IVGTT, intravenous glucose tolerance test. (Adaptedfrom Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 2001;358(9277):225; with permission.)

susceptibility are all examples of information needed to impact efforts toward the goal of disease prevention.

Despite being strongly influenced by genetic factors, T1D does not fit any mendelian pattern of inheritance and is considered a complex, multifactorial disease. Early familial aggregation and twin studies supported the aforementioned importance for genetic and environmental risk factors in T1D. Individuals in the United States who have a first-degree relative with T1D have a 1 in 20 risk of developing T1D, whereas the general population has a 1 in 300 lifetime risk [13]. Monozygotic twins have a concordance rate of 30% to 50%, whereas dizygotic twins have a concordance rate of 6% to 10%. Eighty-five percent of cases of T1D occur in individuals with no family history of the disease. Differences in risk also depend on which parent has diabetes. Children of mothers who have T1D have only a 2% risk of developing T1D, whereas children of fathers who have T1D have a 7% risk (Box 1) [14]. To date, more than two dozen susceptibility loci have been associated with susceptibility to T1D (Table 1). In and of itself, no single gene is either necessary or sufficient to predict the development of T1D.

The first T1D susceptibility locus identified, the human leukocyte antigen (HLA) complex, provides the greatest contribution (40%-60%) to genetic susceptibility. There are three classes of HLA genes, with class II genes having the strongest association with T1D. Because class II HLA genes encode for molecules that participate in antigen presentation, the effect of major histocom-

Genetics

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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