Abnormal infant islet morphology precedes insulin resistance in PCOS-like monkeys

Lindsey E. Nicol, Timothy D. O'Brien, Daniel A. Dumesic, Tristan Grogan, Alice F. Tarantal, David H. Abbott

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33 Scopus citations


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.

Original languageEnglish (US)
Article number0106527
JournalPloS one
Issue number9
StatePublished - Sep 2014

Bibliographical note

Funding Information:
This project was supported by The Endocrine Fellows Foundation Grant and NIH grants T32 DK07786 (postdoctoral fellows training grant), P50 HD044405, P51 OD011106 (WNPRC base operating grant) and P51 OD011107 (CNPRC base operating grant), and was partly conducted at a facility (WNPRC) constructed with support from Research Facilities Improvement Program grant numbers RR15459-01 and RR020141-01. Statistical analysis for the frequency distribution curves was funded by NIH/NCATS/UCLA CTSI Grant UL1TR000124. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors thank Elizabeth Grey, Research Animal Resource Center, University of Wisconsin and Gennadiy Bondarenko (WNPRC) for histology expertise; Robert Becker (WNPRC) for assistance with figure preparation, and Amber Edwards (WNPRC) for technical and protocol support; Joshua Parker, Veterinary Population Medicine Department, University of Minnesota for imaging software expertise; and the faculty in the Pediatric Endocrinology Division, University of Wisconsin School of Medicine and Public Health for continued review of the project and manuscript, and clinical expertise.

Publisher Copyright:
© 2014 Nicol et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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