Glucagon-like peptide 1 (GLP-1) amplifies glucose-induced insulin release in vivo and in vitro. Activation of GLP-1 receptor (GLP-1R) signaling leads to differentiation of exocrine cells towards a #-cell phenotype in vitro and stimulation of islet cell proliferation in vitro and in vivo, suggesting a potential role for GLP-1 in the modulation of islet growth and differentiation. To determine whether basal levels of GLP-1R signaling are essential for islet development, we examined islet cell composition and topography in GLP-1R-/- mice. Total #-cell volume and number are not altered, but the topography of # cells is markedly different in GLP-1R-/- mice compared with GLP-1R+/+ controls. The distribution of # cells is shifted from large to small and medium-sized islets in the absence of GLP-1R signaling (large islets: 50-3% in GLP-1R+/+ vs 28-4% in GLP-1R-/-, P<0.01 and medium islets: 32-2% in GLP-1R+/+ vs 48-3% in GLP-1R-/-, P<0.001). Furthermore, GLP-1R-/- islets exhibit abnormalities in cell topography, with two to threefold more centrally located ! cells detected in GLP-1R-/- islets. These alterations in !- and #-cell topography indicate that basal levels of GLP-1 signaling in the normal rodent are involved in the normal cellular organization of the endocrine pancreas.