title: Hyperthyroidism impairs pancreatic beta cell adaptations to late pregnancy and maternal liporegulation in the rat.
abstract: OBJECTIVE
  Hyperthyroidism modifies lipid dynamics (increased oxidation), impairs insulin action and can suppress insulin secretion. We therefore examined the impact of hyperthyroidism on the relationship between glucose-stimulated insulin secretion (GSIS) and insulin action, using late pregnancy as a model of physiological insulin resistance that is associated with compensatory insulin hypersecretion to maintain glucose tolerance. Our aim was to examine whether hyperthyroidism compromises the regulation of insulin secretion and the ability of insulin to modulate circulating lipid concentrations in late pregnancy.
  
  
  METHODS
  Hyperthyroidism was induced by tri-iodothyronine (T(3)) administration from day 17 to 19 of pregnancy. GSIS was assessed during an IVGTT and during hyperglycaemic clamps in vivo and in vitro, using step-up and -down islet perifusions.
  
  
  RESULTS
  Hyperthyroidism in pregnancy elevated the glucose threshold for GSIS and impaired GSIS at low and high glucose concentrations in islet perifusions. In the intact animal, insulin secretion (after bolus glucose) was more rapidly curtailed following removal of the glucose stimulus to secretion. In contrast, GSIS was maintained during protracted hyperglycaemia (hyperglycaemic clamps) in the hyperthyroid pregnant state in vivo.
  
  
  CONCLUSIONS
  Hyperthyroidism in vivo during late pregnancy blunts GSIS in subsequently isolated and perifused islets at low and high glucose concentrations. It also adversely affects GSIS under conditions of an acute glucose challenge in vivo. In contrast, GSIS is maintained during sustained hyperglycaemia in vivo, suggesting that in vivo factors can rescue GSIS. The ability of insulin to suppress systemic lipid levels during hyperglycaemic clamps was impaired. We therefore suggest that higher circulating lipids may preserve GSIS under conditions of sustained hyperglycaemia in the hyperthyroid pregnancy.
authors.affiliation: Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Holness
authors.forename: G K
authors.initials: GK
authors.lastname: Greenwood
authors.forename: N D
authors.initials: ND
authors.lastname: Smith
authors.forename: M C
authors.initials: MC
authors.lastname: Sugden
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D020567:Fetal Weight; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism; D006980:Hyperthyroidism / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D050356:Lipid Metabolism; D010477:Perfusion; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015430:Weight Gain
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D005947:Glucose