Age-Corrected Beta Cell Mass Following Onset of Type 1 Diabetes Mellitus Correlates with Plasma C-Peptide in Humans

Department of Chemical Engineering, West Virginia University, Morgantown, West Virginia, United States of America.
PLoS ONE (Impact Factor: 3.23). 11/2011; 6(11):e26873. DOI: 10.1371/journal.pone.0026873
Source: PubMed


The inability to produce insulin endogenously precipitates the clinical symptoms of type 1 diabetes mellitus. However, the dynamic trajectory of beta cell destruction following onset remains unclear. Using model-based inference, the severity of beta cell destruction at onset decreases with age where, on average, a 40% reduction in beta cell mass was sufficient to precipitate clinical symptoms at 20 years of age. While plasma C-peptide provides a surrogate measure of endogenous insulin production post-onset, it is unclear as to whether plasma C-peptide represents changes in beta cell mass or beta cell function. The objective of this paper was to determine the relationship between beta cell mass and endogenous insulin production post-onset.
Model-based inference was used to compare direct measures of beta cell mass in 102 patients against contemporary measures of plasma C-peptide obtained from three studies that collectively followed 834 patients post-onset of clinical symptoms. An empirical Bayesian approach was used to establish the level of confidence associated with the model prediction. Age-corrected estimates of beta cell mass that were inferred from a series of landmark pancreatic autopsy studies significantly correlate (p>0.9995) with contemporary measures of plasma C-peptide levels following onset.
Given the correlation between beta cell mass and plasma C-peptide following onset, plasma C-peptide may provide a surrogate measure of beta cell mass in humans. The clinical relevance of this study is that therapeutic strategies that provide an increase in plasma C-peptide over the predicted value for an individual may actually improve beta cell mass. The model predictions may establish a standard historical "control" group - a prior in a Bayesian context - for clinical trials.

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    • "However, beta cell loss is not absolute and, in several patients insulin-positive beta cells and glucose transporters [29], are detectable for many years after diagnosis [31••]. These results, together with the persistence of insulitis, further support the concept that the disease process is chronic; importantly, these findings challenge the traditional view that beta cell loss is virtually complete at the time of clinical onset, as also suggested by a meta-analysis of previously published cases [65, 66]. Importantly, evidence for significant dysfunction of pancreatic beta cells is emerging from unpublished data from the new onset patients in the DiVid study [52] and from our own pancreas transplant recipients with disease recurrence, in which impaired beta cell function is shown despite the presence of insulin-positive cells at biopsy. "
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    • "Because type 1 diabetes is a complex multifactor disease with a strong genetic component and significant environmental influences, a broad immunological assessment and multifactor algorithm to pick patterns is likely needed to dissect the complex pathogenesis and identify key patterns of disease progression. By using a multivariate logistic regression analysis adjusted for age, BMI, and the value of fasting C-pep at disease onset, we identified here two specific immune cell populations, both measured at disease onset, that were capable to predict C-pep secretion as a surrogate measure of β-cell mass in humans with type 1 diabetes (29). Indeed, the number of CD3+CD16+CD56+ T cells and the percentage of mDC1s were independent predictors of residual C-pep secretion 12 months after diagnosis. "
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    • "In addition, the mathematical model provides a prediction of the beta cell mass required to maintain glucose homeostasis. As a validation of the model, one finds that the difference between the observed and predicted beta cell mass (i.e., residual beta cell mass) parallels the observed changes in C-peptide following diagnosis (see Figure 5), as described in [34]. In summary, this model (i.e., prototype) suggests that clinical presentation of the disease is not attributed solely to the destruction of beta cell mass but is the result of a dynamic balance between the production of insulin (i.e., beta cell mass) and the size of the system (i.e., body weight). "
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