Vitamin B6 deficiency during pregnancy impairs pancreatic beta-cell development and glucose metabolism in the male offspring

Poor intrauterine nutrition adversely influences the long-term glucose metabolism in the offspring. Vitamin B6 is an essential micronutrient serving as a coenzyme for numerous metabolic pathways, including tryptophan catabolism that plays a role in perinatal beta-cell proliferation. Our study aims to elucidate the effects of in utero vitamin B6 deficiency on perinatal beta-cell proliferation, beta cell mass, and long-term glucose metabolism in the offspring. C57BL/6 females were fed a “control” diet (6 mg/kg of pyridoxine-HCl) or a “low VB6” diet (0.5 mg/kg of pyridoxine-HCl) for 3 weeks prior to mating, during mating and gestation. Sixteen-week-old offspring were subjected to glucose tolerance test (GTT) and in vivo glucose stimulated insulin secretion (GSIS). Perinatal pancreatic beta-cell proliferation and mass, metabolite abundance, and gene expression were analysed using immunostaining, liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and quantitative polymerase chain reaction (qPCR), respectively. In utero vitamin B6 deficiency is associated with glucose intolerance and lower plasma insulin in response to glucose administration in the adult male offspring. Perinatal pancreatic beta-cells from male offspring subjected to low vitamin B6 had lower proliferation and mass. Additionally, tryptophan catabolites including serotonin and NAD + were lower, and the mitochondrial metabolite, succinate, higher in the low VB6 perinatal pancreases. Gene expression analysis revealed lower gene expression, including cell cycle regulators Foxm1 , Ccnb1, and Ccnb2 and beta-cell identity and function-related genes Pdx-1 and Gck in the perinatal pancreases from low VB6 male offspring. Vitamin B6 deficiency during pregnancy is associated with glucose intolerance and impaired beta-cell development in the male offspring. One potential mechanism is the cumulative disruption of mitogenic signals important for perinatal beta-cell proliferation, including serotonin and mitochondrial function. Our findings provide a novel role for vitamin B6 for beta-cell development and long-term metabolic health.