Enhanced β-cell mass without increased proliferation following chronic mild glucose infusion

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Abstract
The physiological mechanisms underlying pancreatic β-cell mass (BCM) homeostasis are complex and not fully resolved. Here we examined the factors contributing to the increased BCM following a mild glucose infusion (GI) whereby normoglycemia was maintained through 96 h. We used morphometric and immunochemical methods to investigate enhanced β-cell growth and survival in Sprague-Dawley rats. BCM was elevated >2.5-fold over saline-infused control rats by 48 h and increased modestly thereafter. Unexpectedly, increases in β-cell proliferation were not observed at any time point through 4 days. Instead, enhanced numbers of insulin+ cell clusters and small islets (400–12,000 μm2; ∼23- to 124-μm diameter), mostly scattered among the acini, were observed in the GI rats by 48 h despite no difference in the numbers of medium to large islets. We previously showed that increased β-cell growth in rodent models of insulin resistance and pancreatic regeneration involves increased activated Akt/PKB, a key β-cell signaling intermediate, in both islets and endocrine cell clusters. GI in normal rats also leads to increased Akt activation in islet β-cells, as well as in insulin+ and insulin− cells in the common duct epithelium and endocrine clusters. This correlated with strong Pdx1 expression in these same cells. These results suggest that mechanisms other than proliferation underlie the rapid β-cell growth response following a mild GI in the normal rat and involve Akt-regulated enhanced β-cell survival potential and neogenesis from epithelial precursors.