title: Neonatal exendin-4 reduces growth, fat deposition and glucose tolerance during treatment in the intrauterine growth-restricted lamb.
abstract: BACKGROUND
  IUGR increases the risk of type 2 diabetes mellitus (T2DM) in later life, due to reduced insulin sensitivity and impaired adaptation of insulin secretion. In IUGR rats, development of T2DM can be prevented by neonatal administration of the GLP-1 analogue exendin-4. We therefore investigated effects of neonatal exendin-4 administration on insulin action and β-cell mass and function in the IUGR neonate in the sheep, a species with a more developed pancreas at birth.
  
  
  METHODS
  Twin IUGR lambs were injected s.c. daily with vehicle (IUGR+Veh, n = 8) or exendin-4 (1 nmol.kg⁻¹, IUGR+Ex-4, n = 8), and singleton control lambs were injected with vehicle (CON, n = 7), from d 1 to 16 of age. Glucose-stimulated insulin secretion and insulin sensitivity were measured in vivo during treatment (d 12-14). Body composition, β-cell mass and in vitro insulin secretion of isolated pancreatic islets were measured at d 16.
  
  
  RESULTS
  IUGR+Veh did not alter in vivo insulin secretion or insulin sensitivity or β-cell mass, but increased glucose-stimulated insulin secretion in vitro. Exendin-4 treatment of the IUGR lamb impaired glucose tolerance in vivo, reflecting reduced insulin sensitivity, and normalised glucose-stimulated insulin secretion in vitro. Exendin-4 also reduced neonatal growth and visceral fat accumulation in IUGR lambs, known risk factors for later T2DM.
  
  
  CONCLUSIONS
  Neonatal exendin-4 induces changes in IUGR lambs that might improve later insulin action. Whether these effects of exendin-4 lead to improved insulin action in adult life after IUGR in the sheep, as in the PR rat, requires further investigation.
authors: Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia. kathy.gatford@adelaide.edu.au
authors: Kathryn L
authors: KL
authors: Gatford
authors: Siti A
authors: SA
authors: Sulaiman
authors: Saidatul N B
authors: SN
authors: Mohammad
authors: Miles J
authors: MJ
authors: De Blasio
authors: M Lyn
authors: ML
authors: Harland
authors: Rebecca A
authors: RA
authors: Simmons
authors: Julie A
authors: JA
authors: Owens
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001823:Body Composition / Q000187:drug effects; D049628:Body Size / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D000077270:Exenatide; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000378:metabolism* / Q000503:physiopathology; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D012756:Sheep; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide