Abnormal infant islet morphology precedes insulin resistance in PCOS-like monkeys
Open accessAbstract
Polycystic ovary syndrome (PCOS) is prevalent in reproductive-aged women and confounded by metabolic morbidities, including insulin resistance and type 2 diabetes. Although the etiology of PCOS is undefined, contribution of prenatal androgen (PA) exposure has been proposed in a rhesus monkey model as premenopausal PA female adults have PCOS-like phenotypes in addition to insulin resistance and decreased glucose tolerance. PA female infants exhibit relative hyperinsulinemia, suggesting prenatal sequelae of androgen excess on glucose metabolism and an antecedent to future metabolic disease. We assessed consequences of PA exposure on pancreatic islet morphology to identify evidence of programming on islet development. Islet counts and size were quantified and correlated with data from intravenous glucose tolerance tests (ivGTT) obtained from dams and their offspring. Average islet size was decreased in PA female infants along with corresponding increases in islet number, while islet fractional area was preserved. Infants also demonstrated an increase in both the proliferation marker Ki67 within islets and the beta to alpha cell ratio suggestive of enhanced beta cell expansion. PA adult females have reduced proportion of small islets without changes in proliferative or apoptotic markers, or in beta to alpha cell ratios. Together, these data suggest in utero androgen excess combined with mild maternal glucose intolerance alter infant and adult islet morphology, implicating deviant islet development. Marked infant, but subtle adult, morphological differences provide evidence of islet post-natal plasticity in adapting to changing physiologic demands: from insulin sensitivity and relative hypersecretion to insulin resistance and diminished insulin response to glucose in the mature PCOS-like phenotype.
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In a nonhuman primate model of early gestational androgen exposure, transient pancreatic dysfunction manifested by hypoglycemia, an increased number of β-cells, small islets, and relative hyperinsulinemia has been observed.
“Curiously, transient pancreatic dysfunction manifested by hypoglycemia, an increased number of β-cells, small islets, and relative hyperinsulinemia have been observed in this NHP model of early gestational androgen exposure [80].”
From Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls (2019) · cites this paper as [80]
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References 35 · Cited by 41
- Authors
- Nicol, L. E., O’Brien, T. D., Dumesic, D. A., Grogan, T., Tarantal, A. F., & Abbott, D. H.
- Affiliations
- University of Wisconsin–Madison (US)
- University of Minnesota (US)
- University of California, Los Angeles (US)
- University of California, Davis (US)
- Corresponding author
- Nicol, Lindsey E.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-09-10
- Volume
- 9
- Issue
- 9
- Pages
- e106527
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4160158
- OpenAlex
- W1998299798
- Cited by
- 41
- References
- 35
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 5 · 2015: 4
- FWCI
- 4.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- University of Minnesota
- Endocrine Fellows Foundation
- National Institutes of Health (UL1TR000124, HD044405, OD-011107, P51OD011106, P51OD011107)
- School of Medicine and Public Health, University of Wisconsin-Madison
- National Cancer Institute (P30CA077598)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007786, T32-DK07786)
- National Center for Research Resources (C06RR020141, RR 15459-01, C06RR015459, RR 020141-01)
- National Center for Advancing Translational Sciences (Grant UL1TR000124, UCLA CTSI Grant UL1TR000124)
- California National Primate Research Center (OD 011107, P51OD011107)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD044405)
- Clinical and Translational Science Institute, University of California, Los Angeles (UL1TR000124)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- polycystic ovary syndrome, prenatal androgen exposure, pancreatic islet morphology, insulin resistance, beta-cell proliferation, islet development, maternal glucose intolerance, rhesus monkey model, developmental programming, hyperinsulinemia
- MeSH terms
- Animals, Female, Humans, Infant, Insulin Resistance, Islets of Langerhans, Macaca mulatta, Polycystic Ovary Syndrome, Pregnancy, Biomarkers, Apoptosis, Cell Proliferation
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