Stages In Development

The development and course of Type 1 diabetes can be divided into a number of stages, the earlier of which are depicted in Figure 4A.2. The Type 1 diabetes process in any individual may progress through some or all of them. The purpose of dividing the disease into these stages is to note that interruption of the sequence at any stage, preventing the development of the next stage, is likely to be an important advance. Primary prevention may not be possible, in the strictest sense, particularly if the diseases process is initiated in utero.

Stage 1. The first stage is genetic susceptibility, modulated by genetic protection. This stage is identified by finding of susceptibility genes without dominant protective genes.

Stage 2. In the second stage, an environmental trigger initiates autoimmunity. This eventuates in an anti-beta-cell cellular immune response leading to an immune mediated islet infiltrate (insulitis), with consequent beta-cell injury, impairment of

Figure 4A.2 Schematic depiction of the evolution of Type 1 diabetes through stages, as discussed in text

beta-cell function, and some loss of beta-cell mass. As beta-cells are injured, a presumably secondary humoral immune response develops, with the appearance of beta-cell autoantibodies. The principal antibodies are islet cytoplasmic antibodies (ICA), insulin autoantibodies (IAA), glutamic acid decarboxylase antibodies (GADA), and antibodies to islet tyrosine phosphatases (IA2 and IA2$). (The antibodies to IA2 include the antibody ICA512 directed at a component of IA2, while the antibodies to IA2^ include one directed against an insulin granule membrane protein, phogrin [phosphatase homologue of granules from rat insulinoma].) This stage is identified by the presence of autoantibodies.

Stage 3. In the third stage, there is sufficient impairment of beta-cell function and/or loss of beta-cell mass to result in loss of first-phase insulin response (FPIR) during an intravenous glucose tolerance test (IVGTT). This stage is identified by loss of FRIP in an IVGTT.

Stage 4. In the fourth stage, there is impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), but without overt diabetes. This stage is identified by glucose levels either fasting (IFG) or after a glucose challenge (IGT), that are elevated above the upper limit of normal, but have not reached the diagnostic threshold for diabetes. Stage 5. The fifth stage is marked by the clinical onset of Type 1 diabetes. At the beginning of this stage it is estimated that over 80% of beta-cell function and/or mass has been lost, but the residual beta-cell function (evidenced by c-peptide production) remains an important contributor to metabolic homeostasis. These individuals are identified by hyperglycemia exceeding the diagnostic threshold for diabetes, and by measurement of intact c-peptide secretion. Stage 6. The onset of the sixth stage is marked by loss of all beta-cell function and mass (evidenced by lack of any c-peptide response to provocative challenge), and has been called 'total' diabetes. Diabetes becomes more difficult to control. As beta-cell function is lost and 'total' diabetes evolves, antibodies tend to decrease in titer and/or disappear. These individuals are identified by fluctuating glycemia and by absence of c-peptide secretion.

Stage 7. In the seventh stage, diabetic complications (retinopathy, nephropathy, neuropathy) develop. These individuals are identified by clinical and laboratory abnormalities signifying the presence of these complications. Stage 8. In the eighth stage, one or another diabetic complication has progressed to blindness, renal failure, amputation, or other clinical disability.

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