Connective tissue growth factor is critical for proper β -cell function and pregnancy-induced β-cell hyperplasia in adult mice

Abstract

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 (CtgfLacZ/+) have an impairment in maternal β -cell proliferation; no difference was observed in virgin CtgfLacZ/+ females. Using a conditional CTGF allele, we found that mice with a specific inactivation of CTGF in endocrine cells (CtgfΔEndo) 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 CtgfΔEndo 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.