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

[Author]
Joon Ho Moon1,2,7, Joonyub Lee1,3,7, Kyun Hoo Kim1,4,7, Hyun Jung Kim1 , Hyeongseok Kim 1,5, Hye-Na Cha6 , Jungsun Park1 , Hyeonkyu Lee1 , So-young Park 6 , Hak Chul Jang2 and Hail Kim1,4

1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
2 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea.
3 Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
4 Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
5 Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon, Korea.
6 Department of Physiology, College of Medicine, Yeongnam University, Daegu, Korea.
7 These authors contributed equally: Joon Ho Moon, Joonyub Lee, Kyun Hoo Kim. ✉email: janghak@snu.ac.kr; hailkim@kaist.edu

[Journal] 

Experimental & Molecular Medicine volume 55, pages2269–2280 (2023)


[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 β cell proliferation were impaired in multiparous mice. The β cells of multiparous mice exhibited aging features, including telomere shortening and increased expression of Cdkn2a. Single-cell RNA-seq analysis revealed that the β 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 β 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 β cells, which impair their proliferative capacity to compensate for insulin resistance.