Exendin-4 exerts osteogenic actions in insulin-resistant and type 2 diabetic states

Nuche-Berenguer, Bernardo; Moreno, Paola; Portal‐Núñez, Sergio; Dapía, Sonia; Esbrit, Pedro; Villanueva-Peñacarrillo, María Luisa

doi:10.1016/j.regpep.2009.06.010

Cited by 127 publications

(109 citation statements)

References 47 publications

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“…The demonstration that GLP-1 agonists improve trabecular bone mass in ovariectomised mice, confirms previous studies that have reported osteogenic effects of GLP-1 agonist treatment in normal, IR, T2DM and ovariectomised rodent models (32)(33)(34)(35)(36)(37). The novelty of our study is that we have investigated the longer term skeletal effect of LIR and Ex-4 in OVX mice, having administered these drugs daily for 4 weeks, and that we examined bone architecture together with bone cellular activity in situ.…”

Section: Discussionsupporting

confidence: 88%

“…As a result, LIR treatment is formulated as once daily injection in contrast to Ex-4 which is formulated as twice daily injections because of its short half-life (57). However, in our study we administrated both treatments once daily and thus this may have contributed to the less pronounced effect of Ex-4 on bone, although the doses for both drugs were chosen because they had osteogenic effects in previous studies (32)(33)(34)(35)37). Clinical studies have shown that LIR is more efficacious than Ex-4 in patients with T2DM, as it induces a significant greater reduction in HbA1c (56).…”

Section: Discussionmentioning

confidence: 98%

“…Similarly, double incretin receptor knock-out (DIRKO) mice exhibit dramatic and profound alterations of bone microarchitecture and strength, confirming the importance of incretin hormones in the regulation of bone quality (31). 3 days' infusion or daily injections of GLP-1 agonist for 3 days was shown to be anabolic in bone of normal, insulin-resistant (IR) and T2DM rodent models (32)(33)(34)(35)(36). In addition, it was recently demonstrated that long-term treatment with the GLP-1 agonist Ex-4 prevents osteopenia in aged ovariectomised rats, a model of bone loss that mimics osteoporosis (37).…”

Section: Introductionmentioning

confidence: 89%

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Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Pereira

Jeyabalan

Jorgensen

et al. 2015

Bone

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 89%

See 1 more Smart Citation

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Pereira

Jeyabalan

Jorgensen

et al. 2015

Bone

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“…The effects of GLP-1RAs on osteocalcin production by osteoblasts were examined and once again the results are inconsistent. While Kim and coworkers and Nuche-Berenguer and coworkers demonstrate an increase in serum osteocalcin levels with exenatide in T2DM and IR rats, this was not the case with liraglutide treatment (Conte et al 2015, Kim et al 2013, Nuche-Berenguer et al 2010a. A recent study demonstrates that incretins inhibit thyroid hormone-stimulated osteocalcin synthesis in osteoblasts in vitro, suggesting that incretins could stimulate bone formation by reducing the osteocalcin levels (Kainuma et al 2016), although this is not confirmed in vivo.…”

Section: Osteocalcinmentioning

confidence: 97%

“…The effects of GLP-1RAs in diabetic animal models have also been reported. The use of exenatide at a regimen of 10 µg/kg/day for 3 days in T2DM animals resulted in an improvement in trabecular microarchitecture at the femur and lumbar spine (Nuche-Berenguer et al 2010a. The use of liraglutide was also investigated in the Goto-Kakizaki T2DM rat model at a dose of 0.4 mg/kg/day for 4 weeks.…”

Section: Effects Of Glp-1ras On Bone Microarchitecturementioning

confidence: 99%

Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

Mabilleau

Pereira

Chenu

2018

Journal of Endocrinology

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Type 2 diabetes mellitus (T2DM) leads to bone fragility and predisposes to increased risk of fracture, poor bone healing and other skeletal complications. In addition, some anti-diabetic therapies for T2DM can have notable detrimental skeletal effects. Thus, an appropriate therapeutic strategy for T2DM should not only be effective in re-establishing good glycaemic control but also in minimising skeletal complications. There is increasing evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), now greatly prescribed for the treatment of T2DM, have beneficial skeletal effects although the underlying mechanisms are not completely understood. This review provides an overview of the direct and indirect effects of GLP-1RAs on bone physiology, focusing on bone quality and novel mechanisms of action on the vasculature and hormonal regulation. The overall experimental studies indicate significant positive skeletal effects of GLP-1RAs on bone quality and strength although their mechanisms of actions may differ according to various GLP-1RAs and clinical studies supporting their bone protective effects are still lacking. The possibility that GLP-1RAs could improve blood supply to bone, which is essential for skeletal health, is of major interest and suggests that GLP-1 anti-diabetic therapy could benefit the rising number of elderly T2DM patients with osteoporosis and high fracture risk.

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Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment

Jensen,

Sørensen,

Sandsdal

et al. 2024

JAMA Netw Open

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ImportanceA major concern with weight loss is concomitant bone loss. Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may protect bone mass despite weight loss.ObjectiveTo investigate bone health at clinically relevant sites (hip, spine, and forearm) after diet-induced weight loss followed by a 1-year intervention with exercise, liraglutide, or both combined.Design, Setting, and ParticipantsThis study was a predefined secondary analysis of a randomized clinical trial conducted between August 2016 and November 2019 at the University of Copenhagen and Hvidovre Hospital in Denmark. Eligible participants included adults aged 18 to 65 years with obesity (body mass index of 32-43) and without diabetes. Data analysis was conducted from March to April 2023, with additional analysis in February 2024 during revision.InterventionsAfter an 8-week low-calorie diet (800 kcal/day), participants were randomized to 1 of 4 groups for 52 weeks: a moderate- to vigorous-intensity exercise program (exercise alone), 3.0 mg daily of the GLP-1 RA liraglutide (liraglutide alone), the combination, or placebo.Main Outcomes and MeasuresThe primary outcome was change in site-specific bone mineral density (BMD) at the hip, lumbar spine, and distal forearm from before the low-calorie diet to the end of treatment, measured by dual-energy x-ray absorptiometry in the intention-to-treat population.ResultsIn total, 195 participants (mean [SD] age, 42.84 [11.87] years; 124 female [64%] and 71 male [36%]; mean [SD] BMI, 37.00 [2.92]) were randomized, with 48 participants in the exercise group, 49 participants in the liraglutide group, 49 participants in the combination group, and 49 participants in the placebo group. The total estimated mean change in weight losses during the study was 7.03 kg (95% CI, 4.25-9.80 kg) in the placebo group, 11.19 kg (95% CI, 8.40-13.99 kg) in the exercise group, 13.74 kg (95% CI, 11.04-16.44 kg) in the liraglutide group, and 16.88 kg (95% CI, 14.23-19.54 kg) in the combination group. In the combination group, BMD was unchanged compared with the placebo group at the hip (mean change, −0.006 g/cm2; 95% CI, −0.017 to 0.004 g/cm2; P = .24) and lumbar spine (−0.010 g/cm2; 95% CI, −0.025 to 0.005 g/cm2; P = .20). Compared with the exercise group, BMD decreased for the liraglutide group at the hip (mean change, −0.013 g/cm2; 95% CI, −0.024 to −0.001 g/cm2; P = .03) and spine (mean change, −0.016 g/cm2; 95% CI, −0.032 to −0.001 g/cm2; P = .04).Conclusions and RelevanceIn this randomized clinical trial, the combination of exercise and GLP-1RA (liraglutide) was the most effective weight loss strategy while preserving bone health. Liraglutide treatment alone reduced BMD at clinically relevant sites more than exercise alone despite similar weight loss.Trial RegistrationEudraCT: 2015-005585-32

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Exendin-4 exerts osteogenic actions in insulin-resistant and type 2 diabetic states

Cited by 127 publications

References 47 publications

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment

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