Beta Cell Identity Changes with Mild Hyperglycemia: Implications for Function, Growth, and Vulnerability

Abstract Objective As diabetes develops marked reductions of insulin secretion are associated with very modest elevations of glucose. We asked if such glucose changes disrupt beta cell differentiation enough to account for the altered function. Methods Rats were subjected to 90% partial pancreatectomies and those with only mild glucose elevations 4 wk or 10 wk after surgery were found to have major alterations of gene expression in islets as determined by RNAseq. Results Changes associated with glucose toxicity were found such that many of the critical genes responsible for insulin secretion were downregulated while the expression of normally suppressed genes was increased. Also, there were marked changes in genes associated replication, aging, senescence, stress, inflammation, as well as increased expression of genes controlling both class I and II MHC antigens. Conclusions These findings suggest that mild glucose elevations in the early stages of diabetes lead to phenotypic changes that adversely affect beta cell function, growth, and vulnerability.