Multiparity increases the risk of diabetes by impairing the proliferative capacity of pancreatic β cells

Abstract

Pregnancy imposes a substantial metabolic burden on women, but little is known about whether or how multiple pregnancies increase the risk of maternal postpartum diabetes. In this study, we assessed the metabolic impact of multiple pregnancies in humans and in a rodent model. Mice that underwent multiple pregnancies had increased adiposity, but their glucose tolerance was initially improved compared to those of age-matched virgin mice. Later, however, insulin resistance developed over time, but insulin secretory function and compensatory pancreatic beta cell proliferation were impaired in multiparous mice. The beta cells of multiparous mice exhibited aging features, including telomere shortening and increased expression of Cdkn2a. Single-cell RNA-seq analysis revealed that the beta cells of multiparous mice exhibited upregulation of stress-related pathways and downregulation of cellular respiration- and oxidative phosphorylation-related pathways. In humans, women who delivered more than three times were more obese, and their plasma glucose concentrations were elevated compared to women who had delivered three or fewer times, as assessed at 2 months postpartum. The disposition index, which is a measure of the insulin secretory function of beta cells, decreased when women with higher parity gained body weight after delivery. Taken together, our findings indicate that multiple pregnancies induce cellular stress and aging features in beta cells, which impair their proliferative capacity to compensate for insulin resistance. Researchers used a mouse model to investigate the impact of multiple pregnancies on long-term metabolic health of female, discovering that pancreatic beta cells in multiparous mice lost their proliferative capacity, leading to hyperglycemia. Transcriptomic analyses showed features of senescence and increased cellular stress in these cells. In humans, women with a higher number of pregnancies had reduced glucose tolerance compared to those with fewer deliveries. Multiparous women who gained weight after delivery had impaired insulin secretory function while multiparous women who maintained or lost weight maintained their pancreatic beta cell function. The study highlights the need for careful monitoring and lifestyle modifications, such as weight reduction, in women who have undergone multiple pregnancies to reduce the risk of postpartum diabetes.