Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation.
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 alpha- and delta-cell hyperplasia in adults. Ablation of Gcgr was deleterious to fetal survival; it delayed beta-cell differentiation and perturbed the proportion of beta- to alpha-cells in embryonic islets. In adults, the mutation inhibited the progression of alpha-cells to maturity, affected the expression of several beta-cell-specific genes, and resulted in an augmentation of the alpha-, beta-, and delta-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 alpha-cell phenotype.
Vuguin
Patricia M
PM
Division of Pediatric Endocrinology, Children's Hospital at Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10476, USA. vuguin@aecom.yu.edu
Kedees
Mamdouh H
MH
Cui
Lingguang
L
Guz
Yelena
Y
Gelling
Richard W
RW
Nejathaim
Morris
M
Charron
Maureen J
MJ
Teitelman
Gladys
G
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division; D025461:Feedback, Physiological; D005260:Female; D005313:Fetal Death / Q000235:genetics*; D047109:Fetal Development / Q000235:genetics; D017353:Gene Deletion; D005838:Genotype; D005934:Glucagon / Q000032:analysis / Q000502:physiology*; D006965:Hyperplasia; D007328:Insulin / Q000032:analysis; D007515:Islets of Langerhans / Q000196:embryology* / Q000254:growth & development* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D011247:Pregnancy; D018027:Receptors, Glucagon / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D001786:Blood Glucose; D007328:Insulin; D018027:Receptors, Glucagon; D005934:Glucagon