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 (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(ΔEndo)) 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(ΔEndo) 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.

Placental growth factor in beta cells plays an essential role in gestational beta-cell growth

“…Other mice were time-mated with male C57BL/6 mice. The pregnant mice were sacrificed at G16, the peak of beta-cell proliferation as reported by us14 and by others5–10 (figure 3A). At G16, we detected red fluorescent cells only in beta cells (about 80% of beta cells were red) from the mice that had received either AAV–RIP–shPlGF or AAV–RIP–scrambled, suggesting that these viruses only transduced beta cells, which again confirmed the specificity of the RIP in the viral structure (figure 3B–C).…”

“…Studies on pregnant women and rodents have suggested that the gestational increases in insulin production and secretion by beta cells may be largely attributable to beta-cell growth during this period 5–10. Indeed, numerous studies have shown that gestational increase in beta-cell mass primarily stems from beta-cell proliferation 11–14.…”

“…Failure to adequately increase beta-cell mass may cause glucose intolerance or even gestational diabetes. To date, the molecular mechanisms underlying gestational beta-cell growth are not fully understood 5–10…”

Signals in the pancreatic islet microenvironment influence β‐cell proliferation

“…Enhanced β‐cell proliferation in this model occurs through CTGF upregulation of ERK/MAPK‐dependent TGFβ signaling and other growth factors . CTGF is also required for pregnancy‐induced β‐cell hyperplasia and for normal β‐cell function . The role of CTGF in human β‐cell function and β‐cell mass regulation is unknown.…”

The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes

“…Other islet endothelial-derived factors can also modulate beta cell expansion. Haploinsufficiency of Ctgf (the gene encoding connective tissue growth factor [CTGF]) resulted in decreased beta cell proliferation during pregnancy [14], while genetic deletion of the anti-angiogenic factor thrombospondin-1 (THBS1), results in islet hyperplasia in young adult mice [15]. Despite the opposing effects of CTGF vs THBS1 deficiency on beta cell regeneration, both molecules exert positive effects on beta cell function.…”