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Bones 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.

Background The metabolic syndrome (MetS) is a complication to overweight and obesity, which can be observed already in childhood. Ectopic lipid accumulation in muscle and liver has been shown to associate with the development of insulin resistance and dyslipidemia. Thus, the interaction between Mets and ectopic fat may offer clinical relevance. Objectives To investigate the prevalence of MetS, or components hereof, and ectopic fat accumulation in liver and skeletal muscle tissue in children, as well as interactions between these. Methods Two-hundred-and-sixteen children and adolescents (95 boys) with overweight/obesity were investigated, as well as 47 controls (22 boys) with normal weight. The assessments included anthropometry, fasting blood biochemistry, and blood pressure measurements. Liver and muscle lipid contents were assessed by proton magnetic resonance spectroscopy. Results We observed an odds ratio in girls with overweight/obesity of 12.2 (95% CI: [3.8; 49.0]) for exhibiting MetS when hepatic steatosis was present, whereas no association was observed in boys with overweight/obesity (odds ratio 0.7 [0.2; 2.7]). The odds ratio of exhibiting MetS in the presence of muscular steatosis was 3.5 [1.4; 9.5] in girls with overweight/obesity and 1.0 [0.2; 5.6] in boys with overweight/obesity. Similar results were seen for girls with overweight/obesity exhibiting concurrent hepatic and muscular steatoses. Conclusion Hepatic and muscular steatoses were associated with MetS among girls, but not among boys with overweight/obesity. Trial registration ClinicalTrials.gov registration number: NCT00928473, the Danish Childhood Obesity Biobank. Registered June 25, 2009.

Glucose‐dependent insulinotropic polypeptide (GIP) was established as a gut hormone more than 40 years ago, and there is good experimental support for its role as an incretin hormone although deletion of the GIP receptor or the GIP cells or GIP receptor mutations have only minor effects on glucose metabolism. Unlike the related hormone, GLP‐1, GIP stimulates the secretion of glucagon, which in healthy individuals may help to stabilize glucose levels, but in people with type 2 diabetes may contribute to glucose intolerance. A role in lipid metabolism is supported by numerous indirect observations and by resistance to diet‐induced obesity after deletion of the GIP receptor. However, a clear effect on lipid clearance could not be identified in humans, raising doubt about its importance. The GIP receptor is widely expressed in the body and also appears to be expressed on bone cells, and experimental studies in rodent point to effects on bone metabolism. Recent studies revealed pronounced inhibitory effects of GIP on bone resorption markers in humans and suggest that GIP may be (one of the) gastrointestinal regulators of bone turn‐over. In support of this, a loss‐of‐function GIP receptor mutation in humans is associated with a marked increase in fracture risk. The lack of a reliable GIP receptor antagonist contributes to the uncertainty regarding the physiological role of GIP.