Abstract
ABSTRACTBones have been suggested to be a target for glucagon‐like peptide ‐1 (GLP‐1); however, studies of the effects on human bones so far have given diverging results. We hypothesized that GLP‐1, together with glucagon‐like peptide‐2 and glucose‐dependent insulinotropic polypeptide, plays a role in the gut–bone axis. We examined the acute effect of three GLP‐1 receptor ligands [GLP‐1 (7‐36)amide, GLP‐1 (9‐36)amide, and exenatide] on markers of bone remodeling. Eight healthy, normal‐weight participants, with a mean age of 24.3 years, were studied for 4 days in a double‐blinded, randomized clinical trial. Blood was collected before and after s.c. injection of GLP‐1 (7‐36)amide (1.5 nmol/kg), GLP‐1 (9‐36)amide (1.5 nmol/kg), exenatide (2.4 nmol/subject), or saline. Plasma was analyzed for bone markers and for osteoprotegerin (OPG), PTH, and IGF‐1 levels. All ligands were tested in vitro for their cAMP‐inducing activity on the human GLP‐1 receptor. GLP‐1 (7‐36)amide decreased CTX‐levels, compared with placebo (area under the curve [AUC] ±SD 0 to 120 min = –2143 ± 1294 % × min versus –883 ± 1557 % × min; p < 0.05). No difference was observed between placebo and GLP‐1 (9‐36)amide, or between placebo and exenatide, although exenatide had a similar potency as GLP‐1 (7‐36)amide for cAMP formation in vitro (EC50 of 0.093 and 0.054 nmol/L). However, exenatide reached maximum plasma concentration at 90 min versus 15 min for GLP‐1 (7‐36)amide, and plasma CTX was significantly decreased during the second hour of the study after exenatide injections compared with placebo (AUC ±SD –463.1 ± 218 % × min and –136 ± 91 % × min; p < 0.05). There was no effect of the injections on bone formation markers (P1NP and osteocalcin) or on OPG, PTH and IGF‐1 levels. In conclusion, we show that GLP‐1 receptor agonists, but not the primary metabolite GLP‐1 (9‐36)amide, decrease bone resorption, and suggest that GLP‐1 may be part of the gut–bone axis. © 2019 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
Highlights
IntroductionBone remodeling shows a diurnal variation, in particular, a decrease in bone resorption is observed postprandially, which can be eliminated by fasting.(12,13) Clowes and colleagues showed that the postprandial decrease in bone resorption can be eliminated by the administration of a somatostatin analogue before meal ingestion.(14) Another effect of somatostatin is to powerfully inhibit the secretion of gut hormones, Glucagon‐like peptide‐1 (GLP‐1), glucagon‐like peptide‐2 (GLP‐2), and glucose‐dependent insulinotropic polypeptide (GIP)
Glucagon‐like peptide‐1 (GLP‐1) is a peptide hormone secreted from enteroendocrine L‐cells upon meal ingestion.(1) Active GLP‐1, GLP‐1 (7‐36)amide, has an apparent plasma half‐life of approximately 2 min, as it is rapidly degraded to GLP‐1 (9‐36)amide by the enzyme, dipeptidyl peptidase‐4 (DPP‐4).(2)
GLP‐1 is primarily known as an insulinotropic hormone, which together with glucose‐dependent insulinotropic polypeptide (GIP), is responsible for the incretin effect, ie, the markedly increased insulin secretion after oral as opposed to i.v.‐administered glucose.(3) The effect of GLP‐1 on insulin secretion is being exploited in the treatment of type 2 diabetes mellitus, where GLP‐
Summary
Bone remodeling shows a diurnal variation, in particular, a decrease in bone resorption is observed postprandially, which can be eliminated by fasting.(12,13) Clowes and colleagues showed that the postprandial decrease in bone resorption can be eliminated by the administration of a somatostatin analogue before meal ingestion.(14) Another effect of somatostatin is to powerfully inhibit the secretion of gut hormones, GLP‐1, glucagon‐like peptide‐2 (GLP‐2), and GIP. Both GIP and GLP‐2 acutely decrease CTX plasma levels(15,16); we hypothesized that the highly related hormone GLP‐1 might have a similar effect. GLP‐1 receptors have been observed on premature human osteoblasts, but not on mature human osteoblasts.(21) In mice, GLP‐1 receptors have been observed on both premature and mature osteoblasts.(22) Nuche‐Berenguer and colleagues found that GLP‐1 binding to the murine osteoblast cell line, MC3T3‐E1, increases glycosylphosphatidylinositol‐/inositolphosphoglycan‐ associated activity, but not cAMP levels, as normally seen after activation of the single GLP‐1 receptor.(23) Yet, in other studies, GLP‐1 receptors could not be demonstrated in murine osteoblasts.(24,25)
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