Patterns of Metabolic Progression to Type 1 Diabetes in the Diabetes Prevention Trial-Type 1

Columbia University, New York, New York, United States
Diabetes Care (Impact Factor: 8.42). 04/2006; 29(3):643-9. DOI: 10.2337/diacare.29.03.06.dc05-1006
Source: PubMed


There is little information regarding the pattern of metabolic deterioration before the onset of type 1 diabetes. The goal of this study was to utilize data from the Diabetes Prevention Trial-Type 1 (DPT-1) to obtain a picture of the metabolic progression to type 1 diabetes over a period of approximately 2.5 years before its diagnosis.
Fifty-four DPT-1 participants (22 in the parenteral trial and 32 in the oral trial) were studied. All had oral glucose tolerance tests (OGTTs) at 6-month intervals from approximately 30 to 6 months before diagnosis. The vast majority also had OGTTs at diagnosis. Changes in OGTT glucose and C-peptide indexes from 30 to 6 months before diagnosis were examined by calculating slopes of the indexes for each individual over that time period. Changes from 6 months before diagnosis to diagnosis were examined by paired comparisons of the OGTT metabolic indexes between the time points.
Glucose levels increased gradually from 30 to 6 months before diagnosis in both the parenteral and oral groups (P < 0.001 for all indexes). Area under the curve (AUC) C-peptide (P < 0.05) and AUC C-peptide-to-AUC glucose ratio (P < 0.001) values decreased in the oral group; peak C-peptide-to-2-h glucose ratio values decreased in both groups (P < 0.001). In participants who also had OGTTs at diagnosis, AUC C-peptide (parenteral group, P < 0.05) and peak C-peptide (oral group, P < 0.05) values decreased from the last 6 months before diagnosis; stimulated C-peptide-to-glucose ratio values decreased in both groups (P < 0.001). Conversely, fasting C-peptide levels increased in both groups (oral group, P < 0.01). Fasting C-peptide-to-fasting glucose ratio values remained constant throughout the 30-month follow-up.
These data indicate that over a period of at least 2 years, glucose tolerance gradually deteriorates as stimulated C-peptide levels slowly decline in a substantial number of individuals who develop type 1 diabetes. However, fasting C-peptide levels are maintained, even at diagnosis.

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Available from: David D Cuthbertson, Aug 31, 2015
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    • "Studies by Tsai et al. (2006) and Sosenko et al. (2008), using data from the DPT-1 effort have identified a progressive decline in C-peptide responses that are relatively modest during the prediabetic period compared with the changes after diagnosis with hyperglycemia. Interpretation of the changes in C-peptide responses may be more complicated in children because there is an age-related increase in C-peptide levels and therefore, the absence of an increase may be equivalent to a decline in response (Sosenko et al. 2006, 2008; Tsai et al. 2006). After the onset of disease, the decline over time appears to be more dramatic. "
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    ABSTRACT: Type 1 diabetes (T1D), also known as insulin-dependent diabetes mellitus, is a chronic disorder that results from autoimmune destruction of insulin-producing β cells in the islets of Langerhans within the pancreas ( Atkinson and Maclaren 1994). This disease becomes clinically apparent only after significant destruction of the β-cell mass, which reduces the ability to maintain glycemic control and metabolic function. In addition, it continues for years after clinical onset until, generally, there is complete destruction of insulin secretory capacity. Because prevention and therapy strategies are targeted to this pathologic process, it becomes imperative to have methods with which it can be monitored. This work discusses current research-based approaches to monitor the autoimmunity and metabolic function in T1D patients and their potential for widespread clinical application.
    Cold Spring Harbor Perspectives in Medicine 06/2012; 2(6):a007708. DOI:10.1101/cshperspect.a007708 · 9.47 Impact Factor
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    • "Subjects also experienced a decrease in T cell response to insulin and increase in antibody which were consistent with mucosal insulin tolerance. Other trials, however, have indicated that insulin-treated prediabetic subjects were no less likely to develop T1D or experience a delay in T1D onset than their placebo-treated counterparts and that insulin therapy could possibly cause accelerated beta-cell destruction (Skyler et al., 2005; Sosenko et al., 2006). While assessment of the results of clinical trials has demonstrated feasibility, evaluation of efficacy produced the conclusion that none of the agents currently under clinical investigation hold the key for the cure as a sole therapy. "
    Type 1 Diabetes - Pathogenesis, Genetics and Immunotherapy, 11/2011; , ISBN: 978-953-307-362-0
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    • "At this stage, various amounts of beta-cell antibodies are present (169), but the process may still be reversible. However, after repeated similar attacks more and more effector T cells are raised and more and more beta cells are destroyed (170), and a point of no return is passed. The insulitis process perpetuates by itself and clinical diabetes will occur. "
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    ABSTRACT: Buschard K. What causes type 1 diabetes? Lessons from animal models. APMIS 2011; 119 (Suppl. 132): 1–19 To study type 1 diabetes (T1D), excellent animal models exist, both spontaneously diabetic and virus-induced. Based on knowledge from these, this review focuses on the environmental factors leading to T1D, concentrated into four areas which are: (1) The thymus-dependent immune system: T1D is a T cell driven disease and the beta cells are destroyed in an inflammatory insulitis process. Autoimmunity is breakdown of self-tolerance and the balance between regulator T cells and aggressive effector T cells is disturbed. Inhibition of the T cells (by e.g. anti-CD3 antibody or cyclosporine) will stop the T1D process, even if initiated by virus. Theoretically, the risk from immunotherapy elicits a higher frequency of malignancy. (2) The activity of the beta cells: Resting beta cells display less antigenicity and are less sensitive to immune destruction. Beta-cell rest can be induced by giving insulin externally in metabolic doses or by administering potassium-channel openers. Both procedures prevent T1D in animal models, whereas no good human data exist due to the risk of hypoglycemia. (3) NKT cells: According to the hygiene hypothesis, stimulation of NKT cells by non-pathogen microbes gives rise to less T cell reaction and less autoimmunity. Glycolipids presented by CD1 molecules are central in this stimulation. (4) Importance of the intestine and gliadin intake: Gluten-free diet dramatically inhibits T1D in animal models, and epidemiological data are supportive of such an effect in humans. The mechanisms include less subclinical intestinal inflammation and permeability, and changed composition of bacterial flora, which can also be obtained by intake of probiotics. Gluten-free diet is difficult to implement, and short-term intake has no effect. Regarding the onset of the T1D disease process, slow-acting enterovirus and gliadin deposits are speculated to be etiological in genetically susceptible individuals, followed by the mentioned four pathogenetic factors acting in concert. Neutralization of any one of these factors is capable of stopping T1D development, as lessons are learned from the animal models.
    APMIS. Supplementum 07/2011; 132(s132):1-19. DOI:10.1111/j.1600-0463.2011.02765.x
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