Characterization of glucose-insulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus

Alice S. Green, Antoni R. Macko, Paul J. Rozance, Dustin T. Yates, Xiaochuan Chen, William W. Hay, Sean W. Limesand

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


GSIS is often measured in the sheep fetus by a square-wave hyperglycemic clamp, but maximal β-cell responsiveness and effects of fetal number and sex difference have not been fully evaluated. We determined the dose-response curve for GSIS in fetal sheep (0.9 of gestation) by increasing plasma glucose from euglycemia in a stepwise fashion. The glucose- insulin response was best fit by curvilinear third-order polynomial equations for singletons (y = 0.018x3 - 0.26x2 + 1.2x - 0.64) and twins (y = -0.012x3 + 0.043x2 + 0.40x - 0.16). In singles, maximal insulin secretion was achieved at 3.4 ± 0.2 mmol/l glucose but began to plateau after 2.4 ± 0.2 mmol/l glucose (90% of maximum), whereas the maximum for twins was reached at 4.8 ± 0.4 mmol/l glucose. In twin (n = 18) and singleton (n = 49) fetuses, GSIS was determined with a square-wave hyperglycemic clamp >2.4 mmol/l glucose. Twins had a lower basal glucose concentration, and plasma insulin concentrations were 59 (P < 0.01) and 43% (P < 0.05) lower in twins than singletons during the euglycemic and hyperglycemic periods, respectively. The basal glucose/insulin ratio was approximately doubled in twins vs. singles (P < 0.001), indicating greater insulin sensitivity. In a separate cohort of fetuses, twins (n = 8) had lower body weight (P < 0.05) and β-cell mass (P < 0.01) than singleton fetuses (n = 7) as a result of smaller pancreata (P < 0.01) and a positive correlation (P < 0.05) between insulin immunopositive area and fetal weight (P < 0.05). No effects of sex difference on GSIS or β-cell mass were observed. These findings indicate that insulin secretion is less responsive to physiological glucose concentrations in twins, due in part to less β-cell mass.

Original languageEnglish (US)
Pages (from-to)E817-E823
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number5
StatePublished - May 2011


  • Glucose-stimulated insulin secretion
  • Pancreas
  • Twin
  • β-cell

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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