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

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
Artikelnummer115079
TidsskriftBone
Vol/bind130
Antal sider6
ISSN8756-3282
DOI
StatusUdgivet - jan. 2020

Fingeraftryk

Peptides
Placebos
Collagen Type I
Osteogenesis
Cross-Over Studies
Area Under Curve
Hormones

Citer dette

Gasbjerg, L. S., Hartmann, B., Christensen, M. B., Lanng, A. R., Vilsbøll, T., Jørgensen, N. R., ... Knop, F. K. (2020). GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH2. Bone, 130, [115079]. https://doi.org/10.1016/j.bone.2019.115079
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. / GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH2. I: Bone. 2020 ; Bind 130.
@article{ef76c7b89e704878ac698ecb4a68b0b5,
title = "GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH2",
abstract = "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.",
author = "Gasbjerg, {L{\ae}rke S} and Bolette Hartmann and Christensen, {Mikkel B} and Lanng, {Amalie R} and Tina Vilsb{\o}ll and J{\o}rgensen, {Niklas R} and Holst, {Jens J} and Rosenkilde, {Mette M} and Knop, {Filip K}",
note = "Copyright {\circledC} 2019 Elsevier Inc. All rights reserved.",
year = "2020",
month = "1",
doi = "10.1016/j.bone.2019.115079",
language = "English",
volume = "130",
journal = "Bone",
issn = "8756-3282",
publisher = "Elsevier",

}

Gasbjerg, LS, Hartmann, B, Christensen, MB, Lanng, AR, Vilsbøll, T, Jørgensen, NR, Holst, JJ, Rosenkilde, MM & Knop, FK 2020, 'GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH2', Bone, bind 130, 115079. https://doi.org/10.1016/j.bone.2019.115079

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

I: Bone, Bind 130, 115079, 01.2020.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH2

AU - Gasbjerg, Lærke S

AU - Hartmann, Bolette

AU - Christensen, Mikkel B

AU - Lanng, Amalie R

AU - Vilsbøll, Tina

AU - Jørgensen, Niklas R

AU - Holst, Jens J

AU - Rosenkilde, Mette M

AU - Knop, Filip K

N1 - Copyright © 2019 Elsevier Inc. All rights reserved.

PY - 2020/1

Y1 - 2020/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.bone.2019.115079

DO - 10.1016/j.bone.2019.115079

M3 - Journal article

VL - 130

JO - Bone

JF - Bone

SN - 8756-3282

M1 - 115079

ER -

Gasbjerg LS, Hartmann B, Christensen MB, Lanng AR, Vilsbøll T, Jørgensen NR et al. GIP's effect on bone metabolism is reduced by the selective GIP receptor antagonist GIP(3-30)NH2. Bone. 2020 jan;130. 115079. https://doi.org/10.1016/j.bone.2019.115079