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

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

doi:10.1371/journal.pone.0106527

Abstract

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.

Highlights

Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine and metabolic disorders in reproductive-aged women, but its etiology is still not understood
While the data presented in this pilot study are constrained by low animal numbers, an inherent problem in the use of nonhuman primates (NHP) models, our results are congruent with a growing body of evidence that links altered fetal environment to adult metabolic disease, abnormal glucose regulation
Experiment 1: Infants The islet morphology changes in infant prenatally androgenized (PA) monkeys result from a multi-factorial intrauterine exposure: namely, androgen excess and hyperglycemia neither of which can be assessed independently in these experiments, but both can be argued to play a potential role in islet programming. [16] [17] [11,12,18]

Summary

Introduction

Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine and metabolic disorders in reproductive-aged women, but its etiology is still not understood. Female rhesus monkeys exposed to prenatal androgen excess have shown the most comprehensive adult PCOS-like phenotype, meeting all three diagnostic criteria in addition to the metabolic comorbidities of insulin resistance, impaired pancreatic beta cell function and increased prevalence of type 2 diabetes mellitus [4]. This adult metabolic phenotype is preceded by excessive insulin sensitivity, increased insulin secretion relative to insulin sensitivity in infancy and increased rapidity of glucose clearance [9]

Methods

Results

Conclusion