Abstract
There is growing evidence that transplantation of cadaveric human islets is an effective therapy for type 1 diabetes. However, gauging the suitability of islet samples for clinical use remains a challenge. We hypothesized that islet quality is reflected in the expression of specific genes. Therefore, gene expression in 59 human islet preparations was analyzed and correlated with diabetes reversal after transplantation in diabetic mice. Analysis yielded 262 differentially expressed probesets, which together predict islet quality with 83% accuracy. Pathway analysis revealed that failing islet preparations activated inflammatory pathways, while functional islets showed increased regeneration pathway gene expression. Gene expression associated with apoptosis and oxygen consumption showed little overlap with each other or with the 262 probeset classifier, indicating that the three tests are measuring different aspects of islet cell biology. A subset of 36 probesets surpassed the predictive accuracy of the entire set for reversal of diabetes, and was further reduced by logistic regression to sets of 14 and 5 without losing accuracy. These genes were further validated with an independent cohort of 16 samples. We believe this limited number of gene classifiers in combination with other tests may provide complementary verification of islet quality prior to their clinical use.
Highlights
The pathophysiology of Type 1 Diabetes Mellitus (T1DM) is the result of autoimmune destruction of insulin-producing beta cells in the pancreas
To identify a gene signature associated with islet quality, each islet preparation was assigned to one of two classes based on their ability to reverse diabetes, namely good islets, which resulted in reversal of diabetes after transplantation into diabetic mice, and bad islets, those which failed to reverse diabetes
In each iteration Group 1 was used to identify microarray probesets representing individual genes that were associated with either good or bad islet preparations, Group 2 was used to test each of the resultant probesets for the ability to correctly predict the category of each islet preparation
Summary
The pathophysiology of Type 1 Diabetes Mellitus (T1DM) is the result of autoimmune destruction of insulin-producing beta cells in the pancreas. In addition to problems with alloimmune rejection and residual auto-immunity directed against the islet graft, the ability of human islet isolation centers to consistently provide viable and functional islet cells varies widely within and especially between transplant centers [8,9]. This is confounded by the lack of robust, reproducible and standardized methods for gauging the suitability of specific islet preparations for clinical transplantation [10,11,12]
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