glucagon-like-peptide-1 and Osteoporosis

This review summarizes current knowledge about glucagon-like peptide 1 receptor agonists (GLP-1 RA) and their effects on bone metabolism and fracture risk. Recent in vivo and in vitro experiments indicated that GLP-1 RA could improve bone metabolism. GLP-1 could affect the fat-bone axis by promoting osteogenic differentiation and inhibiting adipogenic differentiation of bone mesenchymal precursor cells (BMSCs), which express the GLP-1 receptor. GLP-1 RA may also influence the balance between osteoclasts and osteoblasts, thus leading to more bone formation and less bone resorption. Wnt/β-catenin signalling is involved in this process. Mature osteocytes, which also express the GLP-1 receptor, produce sclerostin which inhibits Wnt/β-catenin signalling by binding to low density lipoprotein receptor-related protein (LRP) 5 and preventing the binding of Wnt. GLP-1 RA also decreases the expression of sclerostin (SOST) and circulating levels of SOST. In addition, GLP-1 receptors are expressed in thyroid C cells, where GLP-1 induces calcitonin release and thus indirectly inhibits bone resorption. Furthermore, GLP-1 RA influences the osteoprotegerin(OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK) system by increasing OPG gene expression, and thus reverses the decreased bone mass in rats models. However, a recent meta-analysis and a cohort study did not show a significant relationship between GLP-RA use and fracture risk. Future clinical trials will be necessary to investigate thoroughly the relationship between GLP-1 RA use and fracture risk in diabetic patients.

Topics: Animals; beta Catenin; Bone Density; Calcitonin; Diabetes Mellitus, Type 2; Fractures, Bone; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Osteoporosis; RANK Ligand; Risk; Wnt Signaling Pathway

Patients with type 1 diabetes mellitus (T1DM) traditionally had a low body mass index and microangiopathic complications were common. The Diabetes Control and Complications Trial, published in 1993, demonstrated that therapy aimed at maintaining HbA1c levels as close to normal as feasible reduced the incidence of microangiopathy. Since then, the use of intensive insulin therapy to optimise metabolic control became generalised, with two main side effects: a higher rate of severe hypoglycaemia and increased weight gain. Approximately 50% of patients with T1DM are currently obese or overweight, which reduces or nullifies the benefits of good metabolic control, and which has other negative consequences; therefore, strategies to achieve weight control in patients with T1DM are necessary. At present, treatment with GLP-1 and SGLT-2 inhibitors has yielded promising short-term results that need to be confirmed in studies with larger numbers of patients and long-term follow-up. It is possible that, in coming years, the applicability of bariatric surgery in obese patients with T1DM will be similar to that of the general population or T2DM.

Topics: Adolescent; Adult; Bariatric Surgery; Body Mass Index; Depression; Diabetes Complications; Diabetes Mellitus, Type 1; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Hirsutism; Humans; Hypoglycemic Agents; Hypogonadism; Insulin; Life Style; Male; Metabolic Syndrome; Obesity; Osteoporosis; Overweight; Polycystic Ovary Syndrome; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Weight Gain

The present brief review looks at the evidence on the role of GLP-1 and its agonists in osteopenia and osteoporosis in type 2 diabetes (T2DM). There is accumulating data to suggest a favourable effect of GLP-1 on bone metabolism. However, most data is from experimental studies, while clinical confirmation is still inadequate. Moreover, little is known on the precise mechanisms underlying these effects. Therefore, we need randomised clinical trials in T2DM patients to learn more on the action of GLP-1 on bone metabolism and its potential clinical implications.

Topics: Bone and Bones; Bone Diseases, Metabolic; Calcitonin; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Male; Osteoporosis; Peptides; Receptors, Glucagon; Treatment Outcome; Venoms

Type 2 Diabetes Mellitus (T2D) and osteoporosis have been found recently to be tightly correlated. In fact, T2D can result in bone loss through different mechanisms resulting in alteration of bone matrix and inhibition of bone formation. Fracture risk also increases significantly. New antidiabetic agents, dipeptidyl peptidase-4 inhibitors and glucagon like peptide -1 agonists have shown promise in many fields beyond glycemic control. Benefits on the skeletal system are multiple through direct stimulation of osteoblasts, inhibition of advanced glycation end products and inhibition of bone resorption. However, clinical evidence in humans is still not enough to allow definitive conclusions.

Topics: Animals; Blood Glucose; Bone Density; Bone Density Conservation Agents; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Osteoporosis

GLP-1 and GIP play an important role as incretin to stimulate insulin secretion from pancreatic β-cells and to maintain the homeostasis of glucose metabolism. As GLP-1 receptors are expressed in thyroid C cells and GIP receptors are expressed in osteoblasts, incretin contributes to bone metabolism. GIP maintains the homeostasis of bone metabolism through transiently activating osteoblasts.

Topics: Animals; Bone and Bones; Diabetes Complications; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Osteoporosis

Diabetes-associated osteoporosis are partly caused by accumulation of advanced glycation endproducts (AGEs). Glucagon-like peptide-1 (GLP-1) has been shown to regulate bone turnover. Here we explore whether GLP-1 receptor agonist (GLP1RA) can have a beneficial effect on bone in diabetes by ameliorating AGEs.. In the present study, we evaluated the effects of the GLP-1 receptor agonist liraglutide, insulin and dipeptidyl peptidase-4 inhibitor saxagliptin on Zucker diabetic fatty rats. Meanwhile, we observed the effect of GLP-1 on AGEs-mediated osteoblast proliferation and differentiation and the signal pathway.. Liraglutide prevented the deterioration of trabecular microarchitecture and enhanced bone strength. Moreover, it increased serum Alpl, Ocn and P1NP levels and decreased serum CTX. In vitro we confirmed that GLP-1 could attenuate AGEs-mediated damage in osteogenic proliferation and differentiation. Besides, GLP-1 down-regulated the ROS that caused by AGEs and the mRNA and protein expression of Rage .. Altogether, our findings suggest that GLP-1 receptor agonist promotes osteoblastogenesis and suppresses bone resorption on obese type 2 diabetic rats to a certain degree. The mechanism of these effects may be partly mediated by AGEs-RAGE-ROS pathway via the interaction with GLP-1 receptor.

Topics: Animals; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Liraglutide; Osteoporosis; Rats; Rats, Zucker; Reactive Oxygen Species

Topics: Animals; Cellular Senescence; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Glucocorticoids; Mice; Osteoporosis; Signal Transduction

DMB (6,7-dichloro-2-methylsulfonyl-3-Ntert-butylaminoquinoxaline) is a quinoxaline-based compound that has been investigated as a glucagon-like peptide-1 receptor (GLP-1R) agonist. To clarify anti-osteoporosis effect of DMB, an osteoporotic mice model was established by ovariectomy (OVX) operation. The OVX mice were given intraperitoneally DMB, exendin-4 (EX-4), or 17β-estradiol (E

Topics: Animals; Bone Density; Bone Resorption; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Menopause; Mice; Mice, Inbred C57BL; Osteoclasts; Osteogenesis; Osteoporosis; Quinoxalines

Energy deprivation leads to a decrease in white adipose tissue and bone mineral density (BMD), while simultaneously inducing the expansion of marrow adipose tissue (MAT). In short bowel syndrome (SBS), parenteral nutrition mitigates the deterioration of nutritional status, including decreases in MAT. Osteoporosis is, however, a frequent complication of SBS. The objective of our study here was to evaluate the association of fat deposit sites (subcutaneous and visceral adipose tissues: intrahepatic lipid (IHL) and MAT) and the incretin glucagon-like peptide 1 (GLP1) with BMD in individuals with SBS. MAT was negatively correlated with lumbar spine BMD in normal individuals, but not in those in the SBS group, who otherwise showed a positive correlation between MAT and GLP1. In addition, in individuals with SBS, IHL was negatively associated with lumbar spine BMD and positively associated with C-terminal telopeptide of type 1 collagen (a serum biomarker of bone turnover). Caloric maintenance in individuals with SBS, therefore, seems to positively affect the relationship between MAT and BMD, which may be modulated, at least in part, by GLP1.

Topics: Adipose Tissue; Adult; Bone Density; Bone Marrow; Bone Remodeling; Case-Control Studies; Cross-Sectional Studies; Female; Glucagon-Like Peptide 1; Humans; Incretins; Male; Middle Aged; Osteoporosis; Parenteral Nutrition; Short Bowel Syndrome

To provide recommendations on the effect of antidiabetic drugs on bone fragility to help select the most adequate antidiabetic treatment, especially in diabetic patients with high risk of fracture.. Members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology.. The GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) was used to establish both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed) using the following terms associated to the name of each antidiabetic drug: AND "osteoporosis", "fractures", "bone mineral density", "bone markers", "calciotropic hormones". Papers in English with publication date before 30 April 2016 were reviewed. Recommendations were jointly discussed by the Working Group.. The document summaries the data on the potential effects of antidiabetic drugs on bone metabolism and fracture risk.

Topics: Aged; Bone Remodeling; Bone Resorption; Contraindications, Drug; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Fractures, Spontaneous; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Osteoporosis; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones

Inflammation, insulin resistance, dyslipidemia, and glucagon-like peptide-1 (GLP-1) are risk factors for osteoporosis. Dipeptidyl peptidase-4 (DPP4) is a newly identified adipokine related to these risk factors.. To investigate the association between plasma DPP4 activities and osteoporosis.. This was a cross-sectional study conducted in Guilin, China. A total of 744 postmenopausal women with normal glucose tolerance were studied.. Plasma DPP4 activity, inflammatory markers, blood lipids, homeostatic model assessment of insulin resistance (HOMA-IR), active GLP-1, bone turnover markers, and bone mineral density (BMD) were measured in all participants.. Participants in the highest quartile of DPP4 activity had higher triglyceride, total cholesterol, HOMA-IR, IL-6, high-sensitivity C-reactive protein (hs-CRP), C-terminal telopeptide of type I collagen, and osteocalcin and lower BMD (lumbar spine and femoral neck) and active GLP-1 compared with participants in the lowest quartile (P < .05). DPP4 activities were associated positively with triglyceride, total cholesterol, HOMA-IR, IL-6, hs-CRP, C-terminal telopeptide of type I collagen, and osteocalcin and negatively with active GLP-1 and BMD (P < .05). In the highest DPP4 quartile, osteoporosis risk was significantly higher (odds ratio, 3.01; 95% confidence interval, 1.66-5.43) than in the lowest quartile after adjustment for potential confounders. The risk for osteoporosis increased more with higher levels of DPP4 activity, HOMA-IR, IL-6, and hs-CRP (P < .05), but not with higher levels of triglyceride and total cholesterol or lower levels of active GLP-1.. This study shows that increased DPP4 activities are independently associated with osteoporosis. The mechanisms may be partly explained by the effect of DPP4 on inflammation and insulin resistance.

Topics: Aged; Biomarkers; Bone Density; Cross-Sectional Studies; Dipeptidyl Peptidase 4; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin Resistance; Lipids; Middle Aged; Osteoporosis; Postmenopause; Prevalence

Poor control of glucose homeostasis accounts for diabetes-related bone loss. Incretins - GLP-1 and GIP - have been proposed to affect bone turnover. GLP-1, apart from its anti-diabetic and other actions, has shown to exert a bone anabolic effect in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rats. Exendin-4 (Ex-4), a peptide of non-mammalian nature, is sharing with GLP-1 part of its structural sequence, and also several glucoregulatory effects in mammals in an even more efficient manner. We have explored the effect of continuous administration (3 days by osmotic pump) of Ex-4 or saline (control) on bone turnover factors and bone structure in T2D and IR rats, compared to N, and the possible interaction of Ex-4 with the Wnt signalling pathway. Blood was taken before and after treatment for plasma measurements; tibiae and femurs were collected for gene expression of bone markers (RT-PCR) and structure (microCT) analysis; we also measured the mRNA levels of LRP5 - an activator of the Wnt pathway - and those of DKK1 and sclerostin (SOST) - both blockers of LRP5 activity. Compared to N-control, plasma glucose and insulin were respectively higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b (TRAP5b) were lower; after Ex-4, these turnover markers were further reduced in T2D and IR, while TRAP5b increased in N. Bone OC, osteoprogeterin (OPG) and receptor activator of NF-kB ligand (RANKL) mRNA were lower in T2D and IR; Ex-4 increased OC in all groups and OPG in N and IR, reduced RANKL in N and T2D but increased it in IR; the LRP5/DKK1 and LRP5/SOST mRNA ratios were similarly decreased in T2D, but in IR, the latter ratio was reduced while the former was increased; after Ex-4, both ratios augmented in N, and that of LRP5/DKK1 tended to normalize in T2D and IR. In conclusion, Ex-4 exerts osteogenic effects in T2D and IR models, and interacts with the Wnt pathway to promote bone formation.

Topics: Animals; Blood Glucose; Bone Morphogenetic Proteins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Fructose; Gastric Inhibitory Polypeptide; Genetic Markers; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; LDL-Receptor Related Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Male; Osteocalcin; Osteogenesis; Osteoporosis; Peptides; Rats; Rats, Wistar; Sweetening Agents; Venoms; Wnt Proteins