title: Chronic pulsatile hyperglycemia reduces insulin secretion and increases accumulation of reactive oxygen species in fetal sheep islets.
abstract: Children from diabetic pregnancies have a greater incidence of type 2 diabetes. Our objective was to determine if exposure to mild-moderate hyperglycemia, by modeling managed diabetic pregnancies, affects fetal β-cell function. In sheep fetuses, β-cell responsiveness was examined after 2 weeks of sustained hyperglycemia with 3 pulses/day, mimicking postprandial excursions, and compared to saline-infused controls (n = 10). Two pulsatile hyperglycemia (PHG) treatments were studied: mild (mPHG, n = 5) with +15% sustained and +55% pulse; and moderate (PHG, n = 10) with +20% sustained and +100% pulse. Fetal glucose-stimulated insulin secretion and glucose-potentiated arginine insulin secretion were lower (P < 0.05) in PHG (0.86 ± 0.13 and 2.91 ± 0.39  ng/ml plasma insulin) but not in mPHG fetuses (1.21 ± 0.08 and 4.25 ± 0.56  ng/ml) compared to controls (1.58 ± 0.25 and 4.51 ± 0.56  ng/ml). Islet insulin content was 35% lower in PHG and 35% higher in mPHG vs controls (P < 0.01). Insulin secretion and maximally stimulated insulin release were also reduced (P < 0.05) in PHG islets due to lower islet insulin content. Isolated PHG islets also had 63% greater (P < 0.01) reactive oxygen species (ROS) accumulation at 11.1  mmol/l glucose than controls (P < 0.01), but oxidative damage was not detected in islet proteins. PHG fetuses showed evidence of oxidative damage to skeletal muscle proteins (P < 0.05) but not insulin resistance. Our findings show that PHG induced dysregulation of islet ROS handling and decreased islet insulin content, but these outcomes are independent. The β-cell outcomes were dependent on the severity of hyperglycemia because mPHG fetuses had no distinguishable impairments in ROS handling or insulin secretion but greater insulin content.
authors.affiliation: Department of Animal Sciences, University of Arizona, 1650 East Limberlost Drive, Tucson, Arizona 85719, USA.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Green
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Chen
authors.forename: Antoni R
authors.initials: AR
authors.lastname: Macko
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Anderson
authors.forename: Amy C
authors.initials: AC
authors.lastname: Kelly
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Hart
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Lynch
authors.forename: Sean W
authors.initials: SW
authors.lastname: Limesand
mesh_terms: D000818:Animals; D005260:Female; D015870:Gene Expression; D006943:Hyperglycemia / Q000503:physiopathology / Q000662:veterinary*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000196:embryology* / Q000503:physiopathology; D008431:Maternal-Fetal Exchange; D010507:Periodicity; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012756:Sheep; D012757:Sheep Diseases / Q000503:physiopathology*
chemical_list: D007328:Insulin; D017382:Reactive Oxygen Species