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

• Published in: American journal of physiology: endocrinology and metabolism 2008-04, Vol.294 (4), p.E679-E687
• Main Authors: Jetton, Thomas L, Everill, Brian, Lausier, James, Roskens, Violet, Habibovic, Aida, LaRock, Kyla, Gokin, Alexander, Peshavaria, Mina, Leahy, Jack L
• Format: Article
• Language: English
• Subjects: Animals; Cell Division - drug effects; Cell Division - physiology; Cell Survival - drug effects; Cell Survival - physiology; Glucose - pharmacology; Insulin - blood; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; Islets of Langerhans - cytology; Islets of Langerhans - growth & development; Islets of Langerhans - physiology; Male; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Regeneration - drug effects; Regeneration - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Sodium Chloride - pharmacology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00569.2007

The physiological mechanisms underlying pancreatic beta-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 beta-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 beta-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 microm(2); approximately 23- to 124-microm 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 beta-cell growth in rodent models of insulin resistance and pancreatic regeneration involves increased activated Akt/PKB, a key beta-cell signaling intermediate, in both islets and endocrine cell clusters. GI in normal rats also leads to increased Akt activation in islet beta-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 beta-cell growth response following a mild GI in the normal rat and involve Akt-regulated enhanced beta-cell survival potential and neogenesis from epithelial precursors.