title: Steroid-induced insulin resistance and impaired glucose  tolerance are both associated with a progressive decline  of incretin effect in first-degree relatives of patients  with type 2 diabetes.
abstract: OBJECTIVE
  The aim of this study was to evaluate the separate impact of insulin resistance and impaired glucose tolerance (IGT) on the incretin effect.
  
  
  METHODS
  Twenty-one healthy glucose-tolerant first-degree relatives of patients with type 2 diabetes underwent a 75 g OGTT, an isoglycaemic i.v. glucose test and a mixed meal to evaluate the incretin effect before and after treatment with dexamethasone to increase insulin resistance. Beta cell glucose sensitivity, beta cell index and fasting proinsulin were measured as indices of beta cell function.
  
  
  RESULTS
  After dexamethasone, ten individuals had increased insulin resistance but normal glucose tolerance (NGT), while 11 individuals with an equal increase in insulin resistance developed IGT. In the NGT and IGT groups, the incretin effects were 71 ± 3.2% and 67 ± 4.6% (p = 0.4) before treatment, but decreased significantly in both groups to 58 ± 5.2% and 32 ± 8.8% (p < 0.05 between groups) after treatment. Dexamethasone increased total glucagon-like peptide-1 and glucose-dependent insulinotropic peptide responses to the OGTT. The impaired incretin effect in NGT was observed in the absence of reductions in beta cell glucose sensitivity and beta cell index during i.v. glucose, corrected for insulin resistance, but in parallel with increased proinsulin/C-peptide ratio.
  
  
  CONCLUSIONS
  Insulin resistance and IGT, representing two stages in the path towards diabetes, are associated with differential reductions in the incretin effect seen before the development of IGT and overt type 2 diabetes. The reduction is unrelated to secretion of incretin hormones, but is related to insulin resistance and subtle beta cell defects, and is further aggravated on development of IGT.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00784745.
  
  
  BACKGROUND
  This study was supported by a grant from the Novo Nordisk Foundation.
authors.affiliation: Department of Endocrinology, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen, Denmark. David_hebbelstrup_Jensen@hotmail.com
authors.forename: D H
authors.initials: DH
authors.lastname: Jensen
authors.forename: K
authors.initials: K
authors.lastname: Aaboe
authors.forename: J E
authors.initials: JE
authors.lastname: Henriksen
authors.forename: A
authors.initials: A
authors.lastname: Vølund
authors.forename: J J
authors.initials: JJ
authors.lastname: Holst
authors.forename: S
authors.initials: S
authors.lastname: Madsbad
authors.forename: T
authors.initials: T
authors.lastname: Krarup
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000139:chemically induced* / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D054795:Incretins / Q000097:blood* / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D005938:Glucocorticoids; D054795:Incretins; D003907:Dexamethasone