Abstract
BackgroundThe 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.Methods and FindingsModel-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.ConclusionsGiven 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.
Highlights
The regulation of human metabolism is a complicated process that has evolved to match the intermittent nature of the availability of metabolic substrates with the constant energetic requirements for life [1]
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
One possible explanation for the observed reduction in beta cell mass at onset could be attributed to the dynamic imbalance between the number of beta cells and the insulin requirements for a growing body
Summary
The regulation of human metabolism is a complicated process that has evolved to match the intermittent nature of the availability of metabolic substrates with the constant energetic requirements for life [1] The dysregulation of this process may manifest itself in multiple ways, including clinical presentation with the symptoms of diabetes. While a reduction in endogenous insulin production precipitates the onset of hyperglycemia, it is commonly stated that the onset of hyperglycemia occurs when 80–95% of an individual’s beta cells are destroyed [7,8] This common wisdom is based largely on a small number of biopsy studies from individuals with recent disease onset who died soon after diabetes onset (e.g., [9,10,11]). The objective of this paper was to determine the relationship between beta cell mass and endogenous insulin production post-onset
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