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Glucose Infusion in Mice

A New Model to Induce ß-Cell Replication

¹ Division of Endocrinology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
² Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
³ Department of Developmental Biology, Stanford University, Stanford, California
⁴ Department of Medicine, Oncology Division, Stanford University, Stanford, California

Address correspondence and reprint requests to Laura C. Alonso, University of Pittsburgh, Division of Endocrinology, 200 Lothrop St., BST E1140, Pittsburgh, PA 15261. E-mail: alonsol{at}dom.pitt.edu

Abbreviations: BrdU, bromodeoxyuridine; cdk, cyclin-dependent kinase; TUNEL, transferase-mediated dUTP nick-end labeling

Developing new techniques to induce ß-cells to replicate is a major goal in diabetes research. Endogenous ß-cells replicate in response to metabolic changes, such as obesity and pregnancy, which increase insulin requirement. Mouse genetic models promise to reveal the pathways responsible for compensatory ß-cell replication. However, no simple, short-term, physiological replication stimulus exists to test mouse models for compensatory replication. Here, we present a new tool to induce ß-cell replication in living mice. Four-day glucose infusion is well tolerated by mice as measured by hemodynamics, body weight, organ weight, food intake, and corticosterone level. Mild sustained hyperglycemia and hyperinsulinemia induce a robust and significant fivefold increase in ß-cell replication. Glucose-induced ß-cell replication is dose and time dependent. ß-Cell mass, islet number, ß-cell size, and ß-cell death are not altered by glucose infusion over this time frame. Glucose infusion increases both the total protein abundance and nuclear localization of cyclin D2 in islets, which has not been previously reported. Thus, we have developed a new model to study the regulation of compensatory ß-cell replication, and we describe important novel characteristics of mouse ß-cell responses to glucose in the living pancreas.

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