glucagon-like-peptide-1 and Bone-Diseases--Metabolic

The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases.. Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Bone and Bones; Bone Diseases, Metabolic; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Cellular Senescence; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor I; Mesenchymal Stem Cells; Obesity; Parathyroid Hormone; Receptor for Advanced Glycation End Products; Receptor, Insulin

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

There are two kinds of incretin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) . GIP directly affects osteoblasts and osteoclasts, resulting in increasing bone mass by enhancing bone formation and suppressing bone resorption. On the other hand, GLP-1 does not affect bone directly. GLP-1 is reported to stimulate calcitonin secretion in thyroid gland and then indirectly increase bone mass. Dipeptidyl peptidase-4 inhibitors, which activate the function of incretin, may decrease the risk of osteoporotic fractures. In addition, it has been shown that osteoblast-derived osteocalcin stimulates GLP-1 secretion. Therefore, there may be an interaction between bone and digestive tract.

Topics: Animals; Bone and Bones; Bone Diseases, Metabolic; Glucagon-Like Peptide 1; Humans; Incretins; Life Style

Increased fat mass contributes to bone deterioration. Glucagon-like peptide 1 (GLP-1) and its related peptide exendin 1-39 amide (Ex-4), two lipid-lowering peptides, exert osteogenic effects in diabetic states. We examined the actions of 3-day administration of GLP-1 or Ex-4 on bone remodeling markers and on bone mass and structure in hyperlipidic (HL) and hypercaloric rats. Wistar rats on a hyperlipidemic diet for 35 days were subcutaneously administered GLP-1 (0.86  nmol/kg per h), Ex-4 (0.1  nmol/kg per h), or saline (control) by continuous infusion for 3 days. After killing, tibiae were removed for total RNA and protein isolation, as well as femurs and L1-L4 vertebrae for bone mass and quality assessment. Body weight and plasma insulin were unaltered in HL rats, which showed osteopenia (by dual-energy X-ray absorptiometry), associated with hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. GLP-1 or Ex-4 administration decreased the levels of glucose, triglycerides, and total cholesterol in plasma but increased osteocalcin (OC) gene expression and the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio - at the expense of an augmented OPG - above corresponding control values in the tibia. Each tested peptide similarly reversed the decreased femoral and vertebral bone mass in these rats, whereas the deteriorated trabecular structure in the vertebrae improved associated with normalization of bone remodeling. These findings demonstrate that GLP-1 and Ex-4 are similarly efficient in reversing the bone alterations in this HL rat model, which has proven to be useful for studying the fat-bone relationships.

Topics: Animals; Biomarkers; Bone Density; Bone Diseases, Metabolic; Dietary Fats; Drug Evaluation, Preclinical; Exenatide; Glucagon-Like Peptide 1; Humans; Hyperlipidemias; Hypoglycemic Agents; Incretins; Lumbar Vertebrae; Osteogenesis; Peptides; Rats; Rats, Wistar; Venoms