GLP-1 and exendin-4 can reverse hyperlipidic-related osteopenia

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.

Download Full-text

Glucagon-like peptide 1 and Glucagon-like peptide 2 in relation to osteoporosis in non-diabetic postmenopausal women

Scientific Reports ◽

10.1038/s41598-019-50117-z ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

María Cristina Montes Castillo ◽

María José Martínez Ramírez ◽

Rubén Soriano Arroyo ◽

Isabel Prieto Gomez ◽

Ana Belén Segarra Robles ◽

...

Keyword(s):

Postmenopausal Women ◽

Bone Remodeling ◽

Plasma Levels ◽

Dipeptidyl Peptidase ◽

Mineral Density ◽

Dipeptidyl Peptidase 4 ◽

Bone Remodeling Markers ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Osteoporosis Risk

Abstract Osteoporosis results from an imbalance in bone remodeling, which is known to follow a circadian rhythm determined by a functional relationship between intestine and bone tissue. Specific intestinal peptides have been identified as mediators. Glucagon-like peptide 1 and glucagon-like peptide 2, have been associated with bone health. Our main objective was to determine whether postprandial plasma levels of glucagon-like peptide 1, glucagon-like peptide 2 and dipeptidyl-peptidase 4 activity, are associated with osteoporosis in non-diabetic postmenopausal women. We studied non-diabetic postmenopausal women with osteoporosis diagnosed by dual-energy X-ray absorptiometry (cases, n = 43) and age-matched (±1 yr) controls without osteoporosis or a history of osteoporotic fracture (n = 43). We measured postprandial plasma levels of glucagon-like peptide 1, glucagon-like peptide 2, and dipeptidyl-peptidase 4 activity, bone mineral density, and baseline levels of bone remodeling markers and analyzed the food intake using a food-frequency questionnaire. Postprandial glucagon-like peptide 1 values were lower (p < 0.001) in cases, μ (SEM) = 116.25 (2.68), than in controls, μ (SEM) = 126.79 (2.68). Glucagon-like peptide 1 was associated with reduced osteoporosis risk in the crude logistic regression analysis [OR (95% CI) = 0.724 (0.53–0.97), p = 0.031] and adjusted analysis [OR = 0.603 (0.38–0.94), p = 0.027]. We found no association of glucagon-like peptide 2, or dipeptidyl-peptidase 4 activity with osteoporosis. Postprandial glucagon-like peptide 1 levels are related to osteoporosis and osteoporosis risk in non-diabetic postmenopausal women. Further studies are required to verify these findings.

Download Full-text

Does short-term administration of glucagon-like peptide type 2 affect bone mass and markers of bone remodeling in short bowel patients?

Gastroenterology ◽

10.1016/s0016-5085(01)81558-4 ◽

2001 ◽

Vol 120 (5) ◽

pp. A314-A314

Author(s):

K HADERSLEV ◽

P JEPPESEN ◽

B HARTMANN ◽

J THULESEN ◽

J GRAFF ◽

...

Keyword(s):

Bone Mass ◽

Bone Remodeling ◽

Short Term ◽

Short Bowel ◽

Term Administration ◽

Glucagon Like Peptide

Download Full-text

Liraglutide, a glucagon-like peptide-1 receptor agonist, improves bone mass and architecture in ovariectomised mice

Endocrine Abstracts ◽

10.1530/endoabs.34.p8 ◽

2014 ◽

Author(s):

Marie Pereira ◽

Jeshmi Jeyabalan ◽

Camilla Sofie Jorgensen ◽

Mark Cleasby ◽

Mark Hopkinson ◽

...

Keyword(s):

Bone Mass ◽

Receptor Agonist ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Download Full-text

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

Bone ◽

10.1016/j.bone.2015.08.006 ◽

2015 ◽

Vol 81 ◽

pp. 459-467 ◽

Cited By ~ 52

Author(s):

M. Pereira ◽

J. Jeyabalan ◽

C.S. Jørgensen ◽

M. Hopkinson ◽

A. Al-Jazzar ◽

...

Keyword(s):

Bone Mass ◽

Trabecular Bone ◽

Chronic Administration ◽

Receptor Agonists ◽

Trabecular Bone Mass ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Download Full-text

Does short-term administration of glucagon-like peptide type 2 affect bone mass and markers of bone remodeling in short bowel patients?

Gastroenterology ◽

10.1016/s0016-5085(08)81558-2 ◽

2001 ◽

Vol 120 (5) ◽

pp. A314

Author(s):

Kent V. Haderslev ◽

Palle B. Jeppesen ◽

Bolette Hartmann ◽

Jesper Thulesen ◽

Jesper Graff ◽

...

Keyword(s):

Bone Mass ◽

Bone Remodeling ◽

Short Term ◽

Short Bowel ◽

Term Administration ◽

Glucagon Like Peptide

Download Full-text

Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21165722 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5722

Author(s):

Motoyasu Kojima ◽

Hirokazu Takahashi ◽

Takuya Kuwashiro ◽

Kenichi Tanaka ◽

Hitoe Mori ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Nonalcoholic Steatohepatitis ◽

Fasting Blood Glucose ◽

Saline Control ◽

Control Group ◽

Receptor Agonists ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive β-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.

Download Full-text

Evaluation of interactions between CCK and GLP-1 in their effects on appetite, energy intake, and antropyloroduodenal motility in healthy men

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00732.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. R1477-R1485 ◽

Cited By ~ 42

Author(s):

Ixchel M. Brennan ◽

Kate L. Feltrin ◽

Michael Horowitz ◽

Andre J. P. M. Smout ◽

James H. Meyer ◽

...

Keyword(s):

Energy Intake ◽

Synergistic Effects ◽

Isotonic Saline ◽

Saline Control ◽

Pressure Waves ◽

Double Blind ◽

Healthy Men ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Desire To Eat

There is evidence that CCK and glucagon-like peptide-1 (GLP-1) mediate the effects of nutrients on appetite and gastrointestinal function and that their interaction may be synergistic. We hypothesized that intravenous CCK-8 and GLP-1 would have synergistic effects on appetite, energy intake, and antropyloroduodenal (APD) motility. Nine healthy males (age 22 ± 1 yr) were studied on four separate days in a double-blind, randomized fashion. Appetite and APD pressures were measured during 150-min intravenous infusions of 1) isotonic saline (control), 2) CCK-8 (1.8 pmol·kg−1·min−1), 3) GLP-1 (0.9 pmol·kg−1·min−1), or 4) both CCK-8 (1.8 pmol·kg−1·min−1) and GLP-1 (0.9 pmol·kg−1·min−1). At 120 min, energy intake at a buffet meal was quantified. CCK-8, but not GLP-1, increased fullness, decreased desire to eat and subsequent energy intake, and increased the number and amplitude of isolated pyloric pressure waves and basal pyloric pressure ( P < 0.05). Both CCK-8 and GLP-1 decreased the number of antral and duodenal pressure waves (PWs) ( P < 0.05), and CCK-8+GLP-1 decreased the number of duodenal PWs more than either CCK-8 or GLP-1 alone ( P < 0.02). This was not the case for appetite or isolated pyloric PWs. In conclusion, at the doses evaluated, exogenously administered CCK-8 and GLP-1 had discrepant effects on appetite, energy intake, and APD pressures, and the effects of CCK-8+GLP-1, in combination, did not exceed the sum of the effects of CCK-8 and GLP-1, providing no evidence of synergism.

Download Full-text

SUN-347 Glucagon-like Peptide 1 (GLP-1) Acts Directly On Human Osteoclasts To Increase Differentiation And Bone Resorptive Activity

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.080 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Morten Steen Hansen ◽

Kent Søe ◽

Caroline Gorvin ◽

Morten Frost

Keyword(s):

Bone Mass ◽

Bone Cells ◽

Direct Action ◽

Human Bone ◽

Bovine Bone ◽

Insulin Resistant ◽

Osteoblast Activity ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Resorptive Activity

Abstract Glucagon-like peptide 1 (GLP-1) is an intestinal hormone released in response to nutrient intake that promotes glucose-dependent insulin secretion by acting upon the pancreatic GLP-1 receptor (GLP-1R). GLP-1R agonists (GLP-1RAs) are widely used in treatment of type 2 diabetes. Preclinical data indicate that GLP-1RAs could be repurposed to treat low bone mass as GLP-1R-depleted mice have higher bone resorption and thinner cortical bones, while insulinopenic and insulin resistant rats have improved bone formation and reduced bone mass deterioration when treated with GLP-1 or GLP-1RAs. However, the effect of GLP-1 and GLP-1RAs on human bone cells remains undetermined. We aimed to elucidate the effect of GLP-1 on primary human osteoclast (OC) and osteoblast (OB) cultures. OCs were differentiated over 10 days from human blood-derived CD14+ monocytes and OBs over 4–6 weeks from human bone. Cells were seeded on bovine bone slices and studies performed using fetal bovine serum, MCSF and RANKL (OC monocultures) or MCSF only (OB monocultures and OB+OC co-cultures). We first investigated the effect of GLP-1 on bone resorptive activity of mature OCs on bovine bone slices. GLP-1 increased the eroded bone surface percentage compared to vehicle in both OC monocultures (1nM P=0.002; 10nM P=0.023; n=8 donors) and OC+OB co-cultures (1nM P=0.013; 10nM P=0.012; n=8 donors). We then tested the effects of GLP-1 on osteoblast activity in OC+OB co-cultures by measuring alkaline phosphatase (ALP). We found that GLP-1 increased ALP in OC+OB cultures (1nM, P=0.049; 10nM, P=0.019) and these effects were reversed by the GLP-1R antagonist exendin 9–39 (1nM, P=0.93, 10nM, P=0.64). However, in OB monocultures GLP-1 had no effects on ALP (1nM P=0.93, 10nM P=0.64) indicating a GLP-1-driven increase in osteoblast activity through osteoclast-osteoblast coupling. We then assessed the effect of GLP-1 on OC differentiation by assessing TRAcP activity. Although there was a trend towards increased TRAcP activity upon stimulation with GLP-1 on day 10 of osteoclastogenesis, this was not statistically significant (1nM P=0.12; n=8 donors; 10nM P=0.29, n=4 donors). Our studies indicated GLP-1 may have a direct effect on osteoclasts, and we therefore sought to characterise GLP-1-mediated signalling in these cells. We assessed the effect of GLP-1 on cAMP signalling using LANCE assays and assessed phosphorylation of ERK proteins by Western blot analysis in human OC cultures. OCs treated with 10nM GLP-1 for 30 minutes had increased cAMP signaling (P=0.004, n=12 bone slices from 2 donors) when compared to vehicle. Furthermore, 10nM GLP-1 induced rapid increases in phosphorylated ERK (P=0.03 following 2 minutes exposure, n=4 blots). In conclusion, our studies reveal that GLP-1 increases activity in primary mature human OCs, and OBs, via OCs. Our signaling studies in OCs indicate this is mediated by direct action of GLP-1 on human bone cells.

Download Full-text