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Experimental & molecular medicine
10, 2023;55 (10): 2269-2280.

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

Joon Ho Moon, Joonyub Lee, Kyun Hoo Kim, Hyun Jung Kim, Hyeongseok Kim, Hye-Na Cha, Jungsun Park, Hyeonkyu Lee, So-Young Park, Hak Chul Jang, Hail Kim
Author Information
  1. Joon Ho Moon: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea.
  2. Joonyub Lee: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea.
  3. Kyun Hoo Kim: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea.
  4. Hyun Jung Kim: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea.
  5. Hyeongseok Kim: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea. ORCID
  6. Hye-Na Cha: Department of Physiology, College of Medicine, Yeongnam University, Daegu, Korea.
  7. Jungsun Park: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea.
  8. Hyeonkyu Lee: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea.
  9. So-Young Park: Department of Physiology, College of Medicine, Yeongnam University, Daegu, Korea. ORCID
  10. Hak Chul Jang: Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea. janghak@snu.ac.kr.
  11. Hail Kim: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea. hailkim@kaist.edu.
PMID: 37903900 DOI: 10.1038/s12276-023-01100-2

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.

References

  1. Institute of Medicine Committee on Nutritional Status During, P. & Lactation. in Nutrition During Pregnancy: Part I Weight Gain: Part II Nutrient Supplements (National Academies Press (US) Copyright © 1990 by the National Academy of Sciences, 1990).
  2. Catalano, P. M. Obesity, insulin resistance, and pregnancy outcome. Reproduction 140, 365–371 (2010). [PMID: 20457594]
  3. Henry, O. A. & Beischer, N. A. Long-term implications of gestational diabetes for the mother. Baillieres Clin. Obstet. Gynaecol. 5, 461–483 (1991). [PMID: 1954723]
  4. Kritz-Silverstein, D., Barrett-Connor, E. & Wingard, D. L. The effect of parity on the later development of non-insulin-dependent diabetes mellitus or impaired glucose tolerance. N. Engl. J. Med. 321, 1214–1219 (1989). [PMID: 2797087]
  5. Butler, A. E. et al. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia 53, 2167–2176 (2010). [PMID: 20523966]
  6. Rieck, S. & Kaestner, K. H. Expansion of beta-cell mass in response to pregnancy. Trends Endocrinol. Metab. 21, 151–158 (2010). [PMID: 20015659]
  7. Scaglia, L., Smith, F. E. & Bonner-Weir, S. Apoptosis contributes to the involution of beta cell mass in the post partum rat pancreas. Endocrinology 136, 5461–5468 (1995). [PMID: 7588296]
  8. Banerjee, R. R. et al. Gestational diabetes mellitus from inactivation of prolactin receptor and MafB in islet β cells. Diabetes 65, 2331–2341 (2016). [PMID: 27217483]
  9. Kim, H. et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat. Med. 16, 804–808 (2010). [PMID: 20581837]
  10. Moon, J. H. et al. Lactation improves pancreatic beta cell mass and function through serotonin production. Sci. Transl .Med. 12 https://doi.org/10.1126/scitranslmed.aay0455 (2020).
  11. Talchai, C., Xuan, S., Lin, H. V., Sussel, L. & Accili, D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150, 1223–1234 (2012). [PMID: 22980982]
  12. Li, P. et al. MECHANISMS IN ENDOCRINOLOGY: parity and risk of type 2 diabetes: a systematic review and dose-response meta-analysis. Eur. J. Endocrinol. 175, R231–R245 (2016). [PMID: 27334332]
  13. Araneta, M. R. & Barrett-Connor, E. Grand multiparity is associated with type 2 diabetes in Filipino American women, independent of visceral fat and adiponectin. Diabetes Care 33, 385–389 (2010). [PMID: 19918009]
  14. Szot, G. L., Koudria, P. & Bluestone, J. A. Murine pancreatic islet isolation. J. Vis. Exp. 255 https://doi.org/10.3791/255 (2007).
  15. O'Callaghan, N. J. & Fenech, M. A quantitative PCR method for measuring absolute telomere length. Biol. Proced. Online 13, 3 (2011). [PMID: 21369534]
  16. Sergushichev, A. A. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. bioRxiv, 060012 https://doi.org/10.1101/060012 (2016).
  17. Moon, J. H. et al. Weight gain and progression to type 2 diabetes in women with a history of gestational diabetes mellitus. J. Clin. Endocrinol. Metab. 100, 3548–3555 (2015). [PMID: 26171796]
  18. Pyke, D. A. Parity and the incidence of diabetes. Lancet 270, 818–820 (1956). [PMID: 13320894]
  19. Stupin, J. H. & Arabin, B. Overweight and obesity before, during and after pregnancy: part 1: pathophysiology, molecular biology and epigenetic consequences. Geburtshilfe Frauenheilkd. 74, 639–645 (2014). [PMID: 25100878]
  20. Rebholz, S. L. et al. Multiparity leads to obesity and inflammation in mothers and obesity in male offspring. Am. J. Physiol. Endocrinol. Metab. 302, E449–E457 (2012). [PMID: 22127227]
  21. Kirwan, J. P. et al. Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling. J. Clin. Endocrinol. Metab. 89, 4678–4684 (2004). [PMID: 15356080]
  22. Davis, E. M., Zyzanski, S. J., Olson, C. M., Stange, K. C. & Horwitz, R. I. Racial, ethnic, and socioeconomic differences in the incidence of obesity related to childbirth. Am. J. Public Health 99, 294–299 (2009). [PMID: 19059856]
  23. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961). [PMID: 13905658]
  24. Lloyd, A. C. Limits to lifespan. Nat. Cell Biol. 4, E25–E27 (2002). [PMID: 11835050]
  25. Charles, M. A. et al. Gravidity, obesity, and non-insulin-dependent diabetes among Pima Indian women. Am. J. Med. 97, 250–255 (1994). [PMID: 8092174]
  26. Hanley, A. J. G. et al. Association of parity with risk of type 2 diabetes and related metabolic disorders. Diabetes Care 25, 690–695 (2002). [PMID: 11919126]
  27. Boyko, E. J., Alderman, B. W., Keane, E. M. & Baron, A. E. Effects of childbearing on glucose tolerance and NIDDM prevalence. Diabetes Care 13, 848–854 (1990). [PMID: 2209319]
  28. Manson, J. E. et al. Parity and incidence of non-insulin-dependent diabetes mellitus. Am. J. Med. 93, 13–18 (1992). [PMID: 1626567]
  29. Bader, E. et al. Identification of proliferative and mature beta-cells in the islets of Langerhans. Nature 535, 430–434 (2016). [PMID: 27398620]
  30. Puri, S. et al. Replication confers beta cell immaturity. Nat. Commun. 9, 485 (2018). [PMID: 29396395]
  31. Helman, A. et al. p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion. Nat. Med. 22, 412–420 (2016). [PMID: 26950362]
  32. Butler, A. E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003). [PMID: 12502499]
  33. Dai, C. et al. Age-dependent human beta cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. J. Clin. Invest. 127, 3835–3844 (2017). [PMID: 28920919]
  34. Helman, A. et al. Effects of ageing and senescence on pancreatic beta-cell function. Diabetes Obes. Metab. 18, 58–62 (2016). [PMID: 27615132]
  35. Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006). [PMID: 16957737]
  36. Nagaraj, V. et al. Elevated basal insulin secretion in type 2 diabetes caused by reduced plasma membrane cholesterol. Mol. Endocrinol. 30, 1059–1069 (2016). [PMID: 27533789]
  37. Tsang, S. W. et al. Increased basal insulin secretion in Pdzd2-deficient mice. Mol. Cell Endocrinol. 315, 263–270 (2010). [PMID: 19932150]
  38. Makkar, G. et al. Lrrc55 is a novel prosurvival factor in pancreatic islets. Am. J. Physiol. Endocrinol. Metab. 317, E794–e804 (2019). [PMID: 31526288]
  39. Horn, S. et al. Research resource: a dual proteomic approach identifies regulated islet proteins during β cell mass expansion in vivo. Mol. Endocrinol. 30, 133–143 (2016). [PMID: 26649805]
  40. Finlin, B. S. et al. RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer. J. Biol. Chem. 276, 42259–42267 (2001). [PMID: 11533059]
  41. Zhao, W. et al. RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma. J. Exp. Clin. Cancer Res. 36, 88 (2017). [PMID: 28659184]
  42. Hong, H. J. et al. Mitoribosome insufficiency in β cells is associated with type 2 diabetes-like islet failure. Exp. Mol. Med. 54, 932–945 (2022). [PMID: 35804190]
  43. Kim, H. et al. PRMT1 is required for the maintenance of mature β cell identity. Diabetes 69, 355–368 (2020). [PMID: 31848151]
  44. Zhang, C. et al. ATF3 drives senescence by reconstructing accessible chromatin profiles. Aging Cell 20, e13315 (2021). [PMID: 33539668]
  45. Liu, J. et al. Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy. Am. J. Physiol. Cell Physiol. 308, C621–C630 (2015). [PMID: 25567807]
  46. Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). [PMID: 23454759]
  47. Aguayo-Mazzucato, C. et al. Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 30, 129–142.e124 (2019). [PMID: 31155496]
  48. Aguayo-Mazzucato, C. et al. β cell aging markers have heterogeneous distribution and are induced by insulin resistance. Cell Metab. 25, 898–910.e895 (2017). [PMID: 28380379]
  49. Thompson, P. J. et al. Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab. 29, 1045–1060.e1010 (2019). [PMID: 30799288]
  50. Dominguez, V. et al. Class II phosphoinositide 3-kinase regulates exocytosis of insulin granules in pancreatic beta cells. J. Biol. Chem. 286, 4216–4225 (2011). [PMID: 21127054]
  51. Rankin, M. M. & Kushner, J. A. Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes 58, 1365–1372 (2009). [PMID: 19265026]
  52. Moon, J. H. & Jang, H. C. Gestational diabetes mellitus: diagnostic approaches and maternal-offspring complications. Diabetes Metab. J. 46, 3–14 (2022). [PMID: 35135076]
  53. Kim, C., Newton, K. M. & Knopp, R. H. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 25, 1862–1868 (2002). [PMID: 12351492]
  54. Tobias, D. K. et al. Healthful dietary patterns and type 2 diabetes mellitus risk among women with a history of gestational diabetes mellitus. Arch. Intern. Med. 172, 1566–1572 (2012). [PMID: 22987062]

MeSH Term

Humans
Pregnancy
Female
Animals
Mice
Insulin-Secreting Cells
Insulin Resistance
Parity
Diabetes, Gestational
Insulin
Obesity
Blood Glucose

Chemicals

Insulin
Blood Glucose
Journal Article Research Support, Non-U.S. Gov't
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Word Cloud

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