During pregnancy, maternal β-cells undergo compensatory changes including increased β-cell mass and enhanced glucose-stimulated insulin secretion. Failure of these adaptations to occur results in gestational diabetes mellitus. The secreted protein, Connective tissue growth factor (Ctgf), is critical for normal β-cell development and promotes regeneration after partial β-cell ablation. During embryogenesis, Ctgf is expressed in pancreatic ducts, vasculature, and β-cells. In adult pancreas, Ctgf is expressed only in the vasculature. Here we show that pregnant mice with global Ctgf haploinsufficiency (Ctgf^LacZ/+) have an impairment in maternal β-cell proliferation; no difference was observed in virgin Ctgf^LacZ/+ females. Using a conditional Ctgf allele, we found that mice with a specific inactivation of Ctgf in endocrine cells (Ctgf^Endo) develop gestational diabetes during pregnancy, but this is due to a reduction in glucose-stimulated insulin secretion rather than impaired maternal β-cell proliferation. Moreover, virgin Ctgf^Endo females also display impaired GSIS with glucose intolerance, indicating that underlying β-cell dysfunction precedes the development of gestational diabetes in this animal model. This is the first time a role for Ctgf in β-cell function has been reported.