Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes

Abstract

Mouse models of Streptozotocin (STZ) induced diabetes represent the most widely used preclinical diabetes research systems. We applied state of the art optical imaging schemes, spanning from single islet resolution to the whole organ, providing a first longitudinal, 3D-spatial and quantitative account of β-cell mass (BCM) dynamics and islet longevity in STZ-treated mice. We demonstrate that STZ-induced β-cell destruction predominantly affects large islets in the pancreatic core. Further, we show that hyperglycemic STZ-treated mice still harbor a large pool of remaining β-cells but display pancreas-wide downregulation of glucose transporter type 2 (GLUT2). Islet gene expression studies confirmed this downregulation and revealed impaired β-cell maturity. Reversing hyperglycemia by islet transplantation partially restored the expression of markers for islet function, but not BCM. Jointly our results indicate that STZ-induced hyperglycemia results from β-cell dysfunction rather than β-cell ablation and that hyperglycemia in itself sustains a negative feedback loop restraining islet function recovery.The authors thank Lars Haag and Lisa Sjöwall at Karolinska Institutet’s electron microscopy shared facility for providing TEM images. Dr. S. Willekens is acknowledged for help with editing of the manuscript. This project was funded by the Swedish Research Council, the Kempe foundations, Umeå University, Lenanders stiftelse, The strategic Research program in Diabetes at Karolinska Institutet, the Novo Nordisk Foundation, the Swedish Diabetes Association, the Family Knut and Alice Wallenberg Foundation, Diabetes Research and Wellness Foundation, the Stichting af Jochnick Foundation, the Family Erling-Persson Foundation, Berth von Kantzow’s Foundation, the Skandia Insurance Company, Ltd., ERC-2013-AdG 338936-BetaImage, the European Union’s Seventh Framework Program under grant agreements nos. 289932 and 613879