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GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH2

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  • Lærke S Gasbjerg
  • Bolette Hartmann
  • Mikkel B Christensen
  • Amalie R Lanng
  • Tina Vilsbøll
  • Niklas R Jørgensen
  • Jens J Holst
  • Mette M Rosenkilde
  • Filip K Knop
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Infusion of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) suppresses the bone resorption marker carboxy-terminal type 1 collagen crosslinks (CTX). Using separate and combined infusions of the selective GIP receptor (GIPR) antagonist, GIP(3-30)NH2, and GIP, we investigated how GIPR inhibition affects bone turnover markers. Ten healthy men (median age 22.5 years (range 21-25), BMI 21.3 kg/m2 (19.9-24.7)) participated in a randomized, doubled blinded, placebo-controlled, crossover study with four 1 -h 12 mmol/l-hyperglycemic clamps on four separate study days with concomitant infusions of GIP, GIP + GIP(3-30)NH2, GIP(3-30)NH2, and placebo, respectively, separated by a period of at least one week. GIP was infused at 1.5 pmol/kg/min and GIP(3-30)NH2 at 800 pmol/kg/min. Plasma glucose was clamped at 12.0 ± 1.2 mmol/l and plasma levels of GIP and GIP(3-30)NH2 amounted to ∼80 pmol/l and ∼50 nmol/l, respectively. GIP suppressed CTX more than placebo (baseline-subtracted AUC -6,811 ± 1,260 vs. -3,012 ± 3,018 ng/l × min, P =  0.002) and resulted in CTX values of 53 ± 6.9% (GIP) versus 81 ± 10% of baseline (placebo), respectively (P = 0.0006), at the end of the hyperglycemic clamp. Co-infusion of GIP and GIP(3-30)NH2 attenuated the GIP-induced CTX suppression by 51 ± 33% (P = 0.01). The peak value of the bone formation marker N-terminal propeptide of type 1 procollagen (P1NP) peaked at higher levels during GIP (109 ± 6.7% of baseline) than during GIP(3-30)NH2 infusion (101 ± 8.9%) (P = 0.049) and GIP suppressed PTH levels compared to GIP(3-30)NH2 alone (P = 0.0158). In conclusion, blockade of the GIPR with GIP(3-30)NH2 diminished GIP-induced CTX and P1NP responses, showing that these effects are GIPR-mediated and that GIPR antagonism might interfere with bone resorption.

TidsskriftThe Bone
StatusUdgivet - 1 jan. 2020

ID: 58170331