Decreased nutrient-stimulated insulin secretion in chronically hypoglycemic late-gestation fetal sheep is due to an intrinsic islet defect.
We measured in vivo and in vitro nutrient-stimulated insulin secretion in late gestation fetal sheep to determine whether an intrinsic islet defect is responsible for decreased glucose-stimulated insulin secretion (GSIS) in response to chronic hypoglycemia. Control fetuses responded to both leucine and lysine infusions with increased arterial plasma insulin concentrations (average increase: 0.13 +/- 0.05 ng/ml leucine; 0.99 +/- 0.26 ng/ml lysine). In vivo lysine-stimulated insulin secretion was decreased by chronic (0.37 +/- 0.18 ng/ml) and acute (0.27 +/- 0.19 ng/ml) hypoglycemia. Leucine did not stimulate insulin secretion following acute hypoglycemia but was preserved with chronic hypoglycemia (0.12 +/- 0.09 ng/ml). Isolated pancreatic islets from chronically hypoglycemic fetuses had normal insulin and DNA content but decreased fractional insulin release when stimulated with glucose, leucine, arginine, or lysine. Isolated islets from control fetuses responded to all nutrients. Therefore, chronic late gestation hypoglycemia causes defective in vitro nutrient-regulated insulin secretion that is at least partly responsible for diminished in vivo GSIS. Chronic hypoglycemia is a feature of human intrauterine growth restriction (IUGR) and might lead to an islet defect that is responsible for the decreased insulin secretion patterns seen in human IUGR fetuses and low-birth-weight human infants.
Perinatal Research Center, University of Colorado Health Sciences Center, Aurora, CO 80045, USA. Paul.Rozance@uchsc.edu
Paul J
PJ
Rozance
Sean W
SW
Limesand
William W
WW
Hay
D000601:Amino Acids, Essential / Q000008:administration & dosage*; D000818:Animals; D002908:Chronic Disease; D005260:Female; D005865:Gestational Age; D005947:Glucose / Q000008:administration & dosage*; D007003:Hypoglycemia / Q000196:embryology* / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D011247:Pregnancy; D012756:Sheep
D000601:Amino Acids, Essential; D007328:Insulin; D005947:Glucose