TY - JOUR
T1 - Developmental programming
T2 - Prenatal testosterone excess disrupts pancreatic islet developmental trajectory in female sheep
AU - Jackson, Ian J.
AU - Puttabyatappa, Muraly
AU - Anderson, Miranda
AU - Muralidharan, Meha
AU - Veiga-Lopez, Almudena
AU - Gregg, Brigid
AU - Limesand, Sean
AU - Padmanabhan, Vasantha
N1 - Funding Information:
We are grateful to Mr Douglas Doop for his expert animal care, facility management, and help with generation of the experimental animals; Drs Mohankumar PS and Sheba Mohankumar with surgeries for fetal collection, Mr. Jim Lee, Ms Carol Herkimer, Dr Bachir Abi Salloum, Mr Evan Beckett, Ms Alexandra Spencer, and Ms Genevieve Ray and students of the Undergraduate Research Opportunity Program (UROP) for assistance with prenatal T treatment, fetal and adult tissue collections. This work was supported by the National Institutes of Health P01 HD44232 and R01 HD095867. IJ received Summer Fellowship support through R25 DK088752. MP is supported via Ruth L. Kirschstein Institutional Training Grant T32 ES007062S.
Funding Information:
This work was supported by the National Institutes of Health P01 HD44232 and R01 HD095867 . IJ received Summer Fellowship support through R25 DK088752 . MP is supported via Ruth L. Kirschstein Institutional Training Grant T32 ES007062 S.
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Prenatal testosterone (T)- treated female sheep manifest juvenile insulin resistance, post-pubertal increase in insulin sensitivity and return to insulin resistance during adulthood. Since compensatory hyperinsulinemia is associated with insulin resistance, altered pancreatic islet ontogeny may contribute towards metabolic defects. To test this, pregnant sheep were treated with or without T propionate from days 30–90 of gestation and pancreas collected from female fetuses at gestational day 90 and female offspring at 21 months-of-age. Uterine (maternal) and umbilical (fetal) arterial blood insulin/glucose ratios were determined at gestational day 90. The morphological and functional changes in pancreatic islet were assessed through detection of 1) islet hormones (insulin, glucagon) and apoptotic beta cells at fetal day 90 and 2) islet hormones (insulin, glucagon and somatostatin), and pancreatic lipid and collagen accumulation in adults. At gestational day 90, T-treatment led to maternal but not fetal hyperinsulinemia, decrease in pancreatic/fetal weight ratio and alpha cells, and a trend for increase in beta cell apoptosis in fetal pancreas. Adult prenatal T-treated female sheep manifested 1) significant increase in beta cell size and a tendency for increase in insulin and somatostatin stained area and proportion of beta cells in the islet; and 2) significant increase in pancreatic islet collagen and a tendency towards increased lipid accumulation. Gestational T-treatment induced changes in pancreatic islet endocrine cells during both fetal and adult ages track the trajectory of hyperinsulinemic status with the increase in adult pancreatic collagen accumulation indicative of impending beta cell failure with chronic insulin resistance.
AB - Prenatal testosterone (T)- treated female sheep manifest juvenile insulin resistance, post-pubertal increase in insulin sensitivity and return to insulin resistance during adulthood. Since compensatory hyperinsulinemia is associated with insulin resistance, altered pancreatic islet ontogeny may contribute towards metabolic defects. To test this, pregnant sheep were treated with or without T propionate from days 30–90 of gestation and pancreas collected from female fetuses at gestational day 90 and female offspring at 21 months-of-age. Uterine (maternal) and umbilical (fetal) arterial blood insulin/glucose ratios were determined at gestational day 90. The morphological and functional changes in pancreatic islet were assessed through detection of 1) islet hormones (insulin, glucagon) and apoptotic beta cells at fetal day 90 and 2) islet hormones (insulin, glucagon and somatostatin), and pancreatic lipid and collagen accumulation in adults. At gestational day 90, T-treatment led to maternal but not fetal hyperinsulinemia, decrease in pancreatic/fetal weight ratio and alpha cells, and a trend for increase in beta cell apoptosis in fetal pancreas. Adult prenatal T-treated female sheep manifested 1) significant increase in beta cell size and a tendency for increase in insulin and somatostatin stained area and proportion of beta cells in the islet; and 2) significant increase in pancreatic islet collagen and a tendency towards increased lipid accumulation. Gestational T-treatment induced changes in pancreatic islet endocrine cells during both fetal and adult ages track the trajectory of hyperinsulinemic status with the increase in adult pancreatic collagen accumulation indicative of impending beta cell failure with chronic insulin resistance.
KW - Beta cells
KW - Developmental programming
KW - Insulin resistance
KW - Pancreas
KW - Sheep
KW - Testosterone
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U2 - 10.1016/j.mce.2020.110950
DO - 10.1016/j.mce.2020.110950
M3 - Article
C2 - 32726642
AN - SCOPUS:85089156291
VL - 518
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
M1 - 110950
ER -