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

• Published in: Bone (New York, N.Y.) N.Y.), 2020-01, Vol.130, p.115079-115079, Article 115079
• Main Authors: Gasbjerg, Lærke S., Hartmann, Bolette, Christensen, Mikkel B., Lanng, Amalie R., Vilsbøll, Tina, Jørgensen, Niklas R., Holst, Jens J., Rosenkilde, Mette M., Knop, Filip K.
• Format: Article
• Language: English
• Subjects: Glucose-dependent insulinotropic polypeptide; Glucose-dependent insulinotropic polypeptide receptor antagonist; Gut-bone axis
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2019.115079

•GIP infusion suppresses CTX by ∼30% of baseline during hyperglycemia.•CTX and P1NP responses are both affected during GIP infusion.•GIP infusion suppresses PTH during hyperglycemia.•The GIPR antagonist GIP(3–30)NH2 reduces GIP-induced changes in CTX, P1NP, and PTH. 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 21.3kg/m2 (19.9–24.7)) participated in a randomized, doubled blinded, placebo-controlled, crossover study with four 1h 12mmol/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 1.5pmol/kg/min and GIP(3–30)NH2 at 800pmol/kg/min. Plasma glucose was clamped at 12.0±1.2mmol/l and plasma levels of GIP and GIP(3–30)NH2 amounted to ∼80pmol/l and ∼50nmol/l, respectively. GIP suppressed CTX more than placebo (baseline-subtracted AUC −6,811±1,260 vs. −3,012±3,018ng/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.