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Ablation of the Glucagon Receptor Gene Increases Fetal Lethality and Produces Alterations in Islet Development and Maturation

Departments of Pediatrics (P.M.V.) and Biochemistry (P.M.V., L.C., R.W.G., M.J.C.), Albert Einstein College of Medicine, Bronx, New York 10461; Department of Anatomy and Cell Biology (M.H.K., Y.G., M.N., G.T.), State University of New York-Downstate Medical Center, Brooklyn, New York 11203; and Metabolex Inc. (R.W.G.), Hayward, California 94545

Address all correspondence and requests for reprints to: Patricia Vuguin, Division of Pediatric Endocrinology, Children’s Hospital at Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10476. E-mail: vuguin{at}aecom.yu.edu.

Although glucagon (GLU) plays a pivotal role in glucose homeostasis, its role in the regulation of fetal growth and maturation is poorly understood. These issues were examined in a line of mice with a global deletion of the GLU receptor (Gcgr^–/–), which are characterized by lower blood glucose levels and by - and -cell hyperplasia in adults. Ablation of Gcgr was deleterious to fetal survival; it delayed ß-cell differentiation and perturbed the proportion of ß- to -cells in embryonic islets. In adults, the mutation inhibited the progression of -cells to maturity, affected the expression of several ß-cell-specific genes, and resulted in an augmentation of the -, ß-, and -cell mass. This increase was due to an augmentation in both islet number and in the rate of proliferation of cells expressing GLU or insulin. These findings suggest that GLU participates in a feedback loop that regulates the proportion of the different endocrine cell types in islets, the number of islets per pancreas, and development of the mature -cell phenotype.

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