title: Characterization of glucose-insulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus.
abstract: 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 = 0.018x(3) - 0.26x(2) + 1.2x - 0.64) and twins (y = -0.012x(3) + 0.043x(2) + 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.
authors.affiliation: Dept. of Animal Sciences, Univ. of Arizona, 1650 E. Limberlost Dr., Tucson, AZ 85719, USA.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Green
authors.forename: Antoni R
authors.initials: AR
authors.lastname: Macko
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rozance
authors.forename: Dustin T
authors.initials: DT
authors.lastname: Yates
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Chen
authors.forename: William W
authors.initials: WW
authors.lastname: Hay
authors.forename: Sean W
authors.initials: SW
authors.lastname: Limesand
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood* / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D010179:Pancreas / Q000033:anatomy & histology / Q000187:drug effects; D011247:Pregnancy; D012727:Sex Characteristics; D034561:Sheep, Domestic; D013268:Stimulation, Chemical
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D005947:Glucose