|
1
|
Lei WS, Chen X, Zhao L, Daley T, Phillips B, Rickels MR, Kelly A, Kindler JM. Effect of GIP and GLP-1 infusion on bone resorption in glucose intolerant, pancreatic insufficient cystic fibrosis. J Clin Transl Endocrinol 2025; 40:100392. [PMID: 40275940 PMCID: PMC12019020 DOI: 10.1016/j.jcte.2025.100392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 03/22/2025] [Accepted: 04/04/2025] [Indexed: 04/26/2025] Open
Abstract
Context Diabetes and bone disease are common in cystic fibrosis (CF) and primarily occur alongside exocrine pancreatic insufficiency (PI). "Incretins," glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), augment insulin secretion and regulate bone metabolism. In CF, PI dampens the incretin response. Loss of the insulinotropic effect of GIP in CF was recently identified, but effects on bone are unknown. Objective Determine effects of incretins on bone resorption markers in adults with PI-CF. Design Secondary analysis of a mechanistic double-blinded randomized placebo-controlled crossover trial including adults ages 18-40 years with PI-CF (n = 25). Intervention Adults with PI-CF received either GIP (4 pmol/kg/min) or GLP-1 (1.5 pmol/kg/min) infusion, followed by double-blind randomization to either incretin or placebo infusion. Non-CF healthy controls received double-blind GIP (4 pmol/kg/min) or placebo. Serum C-terminal telopeptide (CTX), a bone resorption marker, was assessed during the infusion over 80 (GIP) or 60 (GLP-1) minutes. Main Outcome Measures CTX (mg/dL) concentrations. Results In PI-CF, CTX decreased during GIP infusion, but not during placebo (time-by-treatment interaction P < 0.01). GLP-1 did not affect CTX. In non-CF healthy controls, time-by-treatment interaction was not significant (P = 0.23), but CTX decreased during GIP (P = 0.02) but not placebo (P = 0.47). Conclusions GIP evokes a bone anti-resorptive effect in people with PI-CF. Since the incretin response is perturbed in PI-CF, and an infusion of GIP lowers bone resorption, the "gut-bone axis" in CF-related bone disease requires attention.
Collapse
Affiliation(s)
- Wang Shin Lei
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA
| | - XianYan Chen
- Department of Epidemiology & Biostatistics, The University of Georgia, Athens, GA, USA
| | - Lingyu Zhao
- Department of Statistics, The University of Georgia, Athens, GA, USA
| | - Tanicia Daley
- Department of Pediatrics, Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, GA, USA
| | - Bradley Phillips
- College of Pharmacy and Biomedical & Translational Sciences Institute, The University of Georgia, Athens, GA, USA
| | - Michael R. Rickels
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Joseph M. Kindler
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA
| |
Collapse
|
|
2
|
Tordrup EK, Gadgaard S, Windeløv J, Holst JJ, Gasbjerg LS, Hartmann B, Rosenkilde MM. Development of a long-acting unbiased GIP receptor agonist for studies of GIP's role in bone metabolism. Biochem Pharmacol 2025; 236:116893. [PMID: 40132763 DOI: 10.1016/j.bcp.2025.116893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/26/2025] [Accepted: 03/21/2025] [Indexed: 03/27/2025]
Abstract
The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates bone remodeling postprandially. Species variations complicate the development of long-acting agonists with similar effects on rodent and human GIP receptors (GIPR). We created a series of long-acting molecules suitable for rat studies based on human GIP, stabilized with Aib insertion in position 2, lipidations in the middle region (compounds 1-4: positions 14/16/17/20) or the C-terminus (compound 5: position 40), and elongation with an exendin-4 tail in the C-terminus (Cex). The compounds were tested in vitro on the human and rat GIPR for cAMP accumulation, beta-arrestin recruitment and internalization. Pharmacokinetic profiling in rats was completed for two compounds, and one was selected for bone remodeling studies in rats (measurements of C-terminal telopeptide (CTX) and procollagen type 1 N-propeptide). All five compounds retained the potency and efficacy of native (human and rat) GIP in cAMP accumulation and arrestin recruitment on human and rat GIPR with no differences in relative activities from native GIP. Only compound 3 induced internalization like species-matched GIP on respective receptors and was chosen for in vivo assessments in rats. Mean T1/2 was 9.1 h, and it decreased plasma levels of CTX compared to vehicle treatment following 1000 µg·kg-1 injections. In conclusion, the long-acting, unbiased compound 3 (hGIP(1-30-Cex)/Aib2/C16-diacid moiety in position 17), with retained activity for the human and rat GIPR, is suitable for bone remodeling studies in rats; hence, a useful tool compound for future research of GIP's therapeutic potential in bone-related diseases.
Collapse
Affiliation(s)
- Esther Karen Tordrup
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
| | | | - Johanne Windeløv
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Bainan Biotech ApS, Copenhagen, Denmark.
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
| | - Lærke Smidt Gasbjerg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
| |
Collapse
|
|
3
|
Ahmed F, Ahmad SS, Alam MM, Shaquiquzzaman M, Altamish M, Krishnan A, Vohora D, Najmi AK, Khan MA. Osteogenic effect of alogliptin in chemical-induced bone loss: a tri-modal in silico, in vitro, and in vivo analysis. J Pharm Pharmacol 2025; 77:668-684. [PMID: 39360980 DOI: 10.1093/jpp/rgae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 08/13/2024] [Indexed: 05/03/2025]
Abstract
OBJECTIVE To investigate the effects of Alogliptin in chemical-induced post-menopausal osteoporosis. METHODOLOGY The binding affinity of alogliptin with osteogenic proteins was analysed in silico. The effect of alogliptin on osteogenic proteins and mineralization of osteoblastic cells was evaluated in UMR-106 cells. Further, in vivo anti-osteoporotic activity of alogliptin was evaluated in postmenopausal osteoporosis. Various bone turnover markers were assayed in serum. This followed the analysis of microarchitecture of bone, histology, and immunohistochemistry (IHC) of bone tissue. RESULTS Docking scores showed that alogliptin has binding affinity for bone alkaline phosphatase (BALP), osteocalcin, and bone morphogenic protein (BMP-2). Alogliptin also enhanced mineralization of osteoblast cells, evidenced with increased ALP, osteocalcin, and BMP-2. Animal studies revealed significant elevation of bone formation markers, bone ALP, osteocalcin and BMP-2, and decreased bone resorption markers, receptor activator of NF-κβ (RANKL), cathepsin K (CTSK), tartrate resistant acid phosphatase (TRAcP5b) in VCD-induced post-menopausal osteoporosis. Micro computed tomography (μCT) analysis and histology of femur bone and lumbar vertebrae demonstrated decrease in trabecular separation and improved bone density. IHC of femur showed reduced DPP4 enzyme. CONCLUSIONS Alogliptin increased mineralization in osteoblast cells. It had beneficial effects also altered bone turnover markers, repaired the trabecular microstructure, improved bone mineral density, and exhibited bone forming capacity targeting DPP-4 enzyme in postmenopausal osteoporosis.
Collapse
Affiliation(s)
- Faraha Ahmed
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Syed Sufian Ahmad
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Mohammad Mumtaz Alam
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Mohammad Shaquiquzzaman
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Mohammad Altamish
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Anuja Krishnan
- Department of Molecular Medicine, School of Interdisciplinary Science and Technology, Jamia Hamdard, New Delhi 110062, India
| | - Divya Vohora
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Abul Kalam Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| |
Collapse
|
|
4
|
Muskiet MHA, Winter EM, Rensen PCN, Appelman-Dijkstra NM, de Jongh RT. The gut-bone axis: implications of gut hormone-based therapies for bone health. Lancet Diabetes Endocrinol 2025; 13:364-367. [PMID: 40194530 DOI: 10.1016/s2213-8587(25)00090-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Accepted: 03/24/2025] [Indexed: 04/09/2025]
Affiliation(s)
- Marcel H A Muskiet
- Diabetes Centre, Department of Internal Medicine, Amsterdam UMC, Amsterdam, Netherlands; Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam, Netherlands.
| | - Elizabeth M Winter
- Department of Internal Medicine, Division of Endocrinology, LUMC, Leiden, Netherlands; Centre for Bone Quality, Leiden University Medical Centre, Leiden, Netherlands
| | - Patrick C N Rensen
- Department of Internal Medicine, Division of Endocrinology, LUMC, Leiden, Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, Netherlands
| | - Natasha M Appelman-Dijkstra
- Department of Internal Medicine, Division of Endocrinology, LUMC, Leiden, Netherlands; Centre for Bone Quality, Leiden University Medical Centre, Leiden, Netherlands
| | - Renate T de Jongh
- Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam, Netherlands
| |
Collapse
|
|
5
|
Smith HA, Templeman I, Davis M, Slater T, Clayton DJ, Varley I, James LJ, Middleton B, Johnston JD, Karagounis LG, Tsintzas K, Thompson D, Gonzalez JT, Walhin JP, Betts JA. Characterizing 24-Hour Skeletal Muscle Gene Expression Alongside Metabolic and Endocrine Responses Under Diurnal Conditions. J Clin Endocrinol Metab 2025; 110:e1017-e1030. [PMID: 38779872 PMCID: PMC11913097 DOI: 10.1210/clinem/dgae350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 05/14/2024] [Accepted: 05/20/2024] [Indexed: 05/25/2024]
Abstract
CONTEXT Skeletal muscle plays a central role in the storage, synthesis, and breakdown of nutrients, yet little research has explored temporal responses of this human tissue, especially with concurrent measures of systemic biomarkers of metabolism. OBJECTIVE To characterize temporal profiles in skeletal muscle expression of genes involved in carbohydrate metabolism, lipid metabolism, circadian clocks, and autophagy and descriptively relate them to systemic metabolites and hormones during a controlled laboratory protocol. METHODS Ten healthy adults (9M/1F, [mean ± SD] age 30 ± 10 years; BMI 24.1 ± 2.7 kg·m-2) rested in the laboratory for 37 hours with all data collected during the final 24 hours (08:00-08:00 hours). Participants ingested hourly isocaloric liquid meal replacements alongside appetite assessments during waking before a sleep opportunity from 22:00 to 07:00 hours. Blood samples were collected hourly for endocrine and metabolite analyses, with muscle biopsies occurring every 4 hours from 12:00 to 08:00 hours the following day to quantify gene expression. RESULTS Plasma insulin displayed diurnal rhythmicity peaking at 18:04 hours. Expression of skeletal muscle genes involved in carbohydrate metabolism (Name, Acrophase [hours]: GLUT4, 14:40; PPARGC1A, 16:13; HK2, 18:24) and lipid metabolism (FABP3, 12:37; PDK4, 05:30; CPT1B, 12:58) displayed 24-hour rhythmicity that reflected the temporal rhythm of insulin. Equally, circulating glucose (00:19 hours), nonesterified fatty acids (04:56), glycerol (04:32), triglyceride (23:14), urea (00:46), C-terminal telopeptide (05:07), and cortisol (22:50) concentrations also all displayed diurnal rhythmicity. CONCLUSION Diurnal rhythms were present in human skeletal muscle gene expression as well systemic metabolites and hormones under controlled diurnal conditions. The temporal patterns of genes relating to carbohydrate and lipid metabolism alongside circulating insulin are consistent with diurnal rhythms being driven in part by the diurnal influence of cyclic feeding and fasting.
Collapse
Affiliation(s)
- Harry A Smith
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, UK, BA2 7AY
| | - Iain Templeman
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, UK, BA2 7AY
| | - Max Davis
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, UK, BA2 7AY
| | - Tommy Slater
- Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK, NG1 4FQ
| | - David J Clayton
- Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK, NG1 4FQ
| | - Ian Varley
- Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK, NG1 4FQ
| | - Lewis J James
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK, LE11 3TU
| | - Benita Middleton
- Section of Chronobiology, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK, GU2 7XH
| | - Jonathan D Johnston
- Section of Chronobiology, School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK, GU2 7XH
| | - Leonidas G Karagounis
- Institute of Social and Preventive Medicine, University of Bern, 3012 Bern, Switzerland
- Mary MacKillop Institute for Health Research (MMIHR), Australian Catholic University (ACU), Melbourne, VIC 3000, Australia
| | - Kostas Tsintzas
- MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK, NG7 2UH
| | - Dylan Thompson
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, UK, BA2 7AY
| | - Javier T Gonzalez
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, UK, BA2 7AY
| | - Jean-Philippe Walhin
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, UK, BA2 7AY
| | - James A Betts
- Centre for Nutrition, Exercise and Metabolism, Department for Health, University of Bath, Bath, UK, BA2 7AY
| |
Collapse
|
|
6
|
Nulty CD, Tang JCY, Dutton J, Dunn R, Fraser WD, Enright K, Stewart CE, Erskine RM. Hydrolyzed collagen supplementation prior to resistance exercise augments collagen synthesis in a dose-response manner in resistance-trained, middle-aged men. Am J Physiol Endocrinol Metab 2024; 327:E668-E677. [PMID: 39259166 DOI: 10.1152/ajpendo.00252.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 09/06/2024] [Accepted: 09/08/2024] [Indexed: 09/12/2024]
Abstract
Resistance exercise (RE) increases collagen synthesis in young and older men, whereas hydrolyzed collagen (HC) ingestion improves this response to RE in a dose-response manner in young men. However, the collagen synthesis response to RE with and without HC in middle-aged men is unknown. Eight resistance-trained men (age: 49 ± 8 yr; height: 1.78 ± 0.02 m; mass: 90 ± 4 kg) took part in this double-blind, crossover design study and undertook 4 × 10 repetitions of lower-limb RE at maximum load, after consuming 0 g, 15 g, or 30 g vitamin C-enriched HC. We analyzed venous blood samples for N-terminal propeptide of type 1 pro-collagen (PINP), β-isomerized C-terminal telopeptide of type 1 collagen (β-CTx), and 18 collagen amino acids throughout all three interventions. The serum PINP concentration × time area-under-the-curve (AUC) was higher following 30 g (169 ± 28 µg/mL × h) than 15 g (134 ± 23 µg/mL × h, P < 0.05) HC ingestion, and both 15 g and 30 g were higher than 0 g HC (96 ± 23 µg/mL × h, P < 0.05). RE with 0 g HC showed no change in serum PINP concentration. The AUCs for glycine, proline, hydroxyproline, alanine, arginine, lysine, serine, leucine, valine, and isoleucine were greater with 30 g than 15 g and 0 g HC ingestion (P < 0.05) and greater with 15 g than 0 g HC ingestion (P < 0.05). Plasma β-CTx concentration decreased after RE independently of HC dose. Our study suggests connective tissue anabolic resistance to RE in middle-aged men but ingesting 15 g HC rescues the collagen synthesis response and 30 g augments that response further. This dose response is associated with the increased bioavailability of collagen amino acids in the blood, which stimulate collagen synthesis.NEW & NOTEWORTHY This study is the first to document the dose-response effect of hydrolyzed collagen (HC) ingestion before resistance exercise (RE) on collagen turnover in middle-aged, resistance-trained men. Strikingly, RE alone did not increase collagen synthesis (suggesting connective tissue anabolic resistance), but ingesting 15 g HC rescued the collagen synthesis response and 30 g augmented that response further. These results were associated with the increased bioavailability of collagen amino acids in the blood, which stimulate collagen synthesis.
Collapse
Affiliation(s)
- Christopher D Nulty
- School of Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
- Department of Health and Sport Science, South East Technological University, Carlow, Ireland
| | - Jonathan C Y Tang
- Bioanalytical Facility, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
- Clinical Biochemistry, Department of Laboratory Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom
| | - John Dutton
- Bioanalytical Facility, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Rachel Dunn
- Bioanalytical Facility, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
- Clinical Biochemistry, Department of Laboratory Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom
| | - William D Fraser
- Bioanalytical Facility, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
- Clinical Biochemistry, Department of Laboratory Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom
- Department of Diabetes and Endocrinology, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, United Kingdom
| | - Kevin Enright
- School of Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
| | - Claire E Stewart
- School of Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
| | - Robert M Erskine
- School of Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
- Institute of Sport, Exercise and Health, University College London, London, United Kingdom
| |
Collapse
|
|
7
|
Paccou J, Compston JE. Bone health in adults with obesity before and after interventions to promote weight loss. Lancet Diabetes Endocrinol 2024; 12:748-760. [PMID: 39053479 DOI: 10.1016/s2213-8587(24)00163-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/27/2024]
Abstract
Obesity and its associated comorbidities constitute a serious and growing public health burden. Fractures affect a substantial proportion of people with obesity and result from reduced bone strength relative to increased mechanical loading, together with an increased risk of falls. Factors contributing to fractures in people with obesity include adverse effects of adipose tissue on bone and muscle and, in many people, the coexistence of type 2 diabetes. Strategies to reduce weight include calorie-restricted diets, exercise, bariatric surgery, and pharmacological interventions with GLP-1 receptor agonists. However, although weight loss in people with obesity has many health benefits, it can also have adverse skeletal effects, with increased bone loss and fracture risk. Priorities for future research include the development of effective approaches to reduce fracture risk in people with obesity and the investigation of the effects of GLP-1 receptor agonists on bone loss resulting from weight reduction.
Collapse
Affiliation(s)
- Julien Paccou
- Department of Rheumatology, Université de Lille, Centre Hospitalier Universitaire de Lille, Lille, France
| | | |
Collapse
|
|
8
|
Ярославцева МВ, Бондаренко ОН, Эль-Тарави ЯА, Магеррамова СТ, Пигарова ЕА, Ульянова ИН, Галстян ГР. [Etiopathogenetic features of bone metabolism in patients with diabetes mellitus and Charcot foot]. PROBLEMY ENDOKRINOLOGII 2024; 70:57-64. [PMID: 39302865 PMCID: PMC11551796 DOI: 10.14341/probl13362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/02/2023] [Accepted: 11/19/2023] [Indexed: 09/22/2024]
Abstract
Diabetic neuropathy is one of the most common diabetes mellitus complications associated with mediocalcinosis of the lower extremities, a significant decrease in feet bone mineral density, and a high incidence of cardiovascular disease. In most cases, calcium-phosphorus metabolism changes occur in patients with diabetic neuroarthropathy, or Charcot foot, when we can observe feet local osteoporosis, which in 90% of cases associated with a vessel's calcification of the lower extremities in the majority of diabetes population. A large number of studies presented literature have demonstrated that patients with Charcot foot can have accelerated bone metabolism and increased bone resorption. Patients with Charcot foot often have crucial abnormalities in the calcium-phosphorus parameters, bone metabolism, and levels of vitamin D and its metabolites. In addition, the duration of diabetes mellitus, the degree of its compensation widely affects the development of its micro- and macrovascular complications, which could also accelerate the development of mineral and bone disorders in these types of patients. Multifactorial pathogenesis of these disorders complicates the management of patients with a long and complicated course of diabetes mellitus. This review discusses the peculiarities of vitamin D metabolism, the importance of timely diagnosis in phosphorus-calcium disorders, and the specifics of therapy in these patients. Special attention is paid to the timely diagnosis of the Charcot's foots acute stage based on the bone marrow edema by MRI evaluation and the possibility of reducing the immobilization period.
Collapse
Affiliation(s)
| | | | | | | | - Е. А. Пигарова
- Национальный медицинский исследовательский центр эндокринологии
| | - И. Н. Ульянова
- Национальный медицинский исследовательский центр эндокринологии
| | - Г. Р. Галстян
- Национальный медицинский исследовательский центр эндокринологии
| |
Collapse
|
|
9
|
Krogh LM, Nissen A, Weischendorff S, Hartmann B, Andersen JL, Holst JJ, Sørensen K, Fridh MK, Mackey AL, Müller K. Bone remodeling in survivors of pediatric hematopoietic stem cell transplantation: Impact of heavy resistance training. Pediatr Blood Cancer 2024; 71:e31159. [PMID: 38953152 DOI: 10.1002/pbc.31159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/23/2024] [Accepted: 06/09/2024] [Indexed: 07/03/2024]
Abstract
BACKGROUND Early-onset osteoporosis is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT). It remains unknown if physical training can improve bone formation in these patients, as the transplantation procedure may cause sustained dysregulation of the bone-forming osteoblast progenitor cells. OBJECTIVE We aimed to explore the effect of resistance training on bone remodeling in long-term survivors of pediatric HSCT. PROCEDURE In this prospective, controlled intervention study, we included seven HSCT survivors and 15 age- and sex-matched healthy controls. The participants completed a 12-week heavy load, lower extremity resistance training intervention with three weekly sessions. We measured fasting serum levels of the bone formation marker "N-terminal propeptide of type I procollagen" (P1NP), and the bone resorption marker "C-terminal telopeptide of type I collagen" (CTX). The hypothesis was planned before data collection began. The trial was registered at Clinicaltrials.gov before including the first participant, with trial registration no. NCT04922970. RESULTS Resistance training led to significantly increased levels of fasting P1NP in both patients (from 57.62 to 114.99 ng/mL, p = .03) and controls (from 66.02 to 104.62 ng/mL, p < .001). No significant changes in fasting CTX levels were observed. CONCLUSIONS Despite previous high-dose cytotoxic therapy, long-term survivors of pediatric HSCT respond to resistance training with improvement of bone formation, comparable to that of healthy controls. This suggests that resistance training might be a promising non-pharmacological approach to prevent the early decline in bone mass, and should be considered as part of a follow-up program to counteract long-term sequela after pediatric HSCT.
Collapse
Affiliation(s)
- Lise Marie Krogh
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Anne Nissen
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Sarah Weischendorff
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesper Løvind Andersen
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery, Copenhagen University Hospital - Bispebjerg & Frederiksberg, Copenhagen, Denmark
- Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kaspar Sørensen
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Bone Marrow Transplantation and Immunodeficiency, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Martin Kaj Fridh
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Abigail Louise Mackey
- Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery, Copenhagen University Hospital - Bispebjerg & Frederiksberg, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Klaus Müller
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
10
|
Starup-Linde J, Westberg-Rasmussen S, Viggers R, Al-Mashhadi ZK, Handberg A, Vestergaard P, Gregersen S. Serum osteoglycin is stable during various glycemic challenges in healthy men. Endocrine 2024; 85:1117-1121. [PMID: 38549032 DOI: 10.1007/s12020-024-03789-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/17/2024] [Indexed: 08/11/2024]
Abstract
PURPOSE Osteoglycin is hypothesized to be metabolically active and may enhance insulin action. We hypothesized that osteoglycin levels increase during hyperglycemia as a physiological response to enhance the effects of insulin. METHODS Eight healthy males were included in a cross-over study consisting of three study days following an 8 h fast. First, we performed an oral glucose tolerance test (OGTT); second, an isoglycemic intravenous glucose infusion (IIGI); and third, a control period consisting of a three hour fast. We analyzed blood samples for circulating osteoglycin levels during the study days. Repeated measures ANOVA was performed to compare levels of s-osteoglycin between OGTT, IIGI, and the fasting control. RESULTS There were no differences in baseline osteoglycin levels among study days (p > 0.05). We observed no significant changes neither in absolute s-osteoglycin levels by time (p = 0.14) nor over time by study day (p = 0.99). Likewise, we observed no significant changes in percentage s-osteoglycin levels neither by time (p = 0.11) nor over time by study day (p = 0.89). CONCLUSION We found that s-osteoglycin levels were stable for three hours during OGTT, IIGI, and fasting in healthy males. Based on the present study, circulating s-osteoglycin levels may be measured independently of fasting or non-fasting conditions. Furthermore, circulating physiological levels of glucose and insulin did not affect s-osteoglycin levels.
Collapse
Affiliation(s)
- Jakob Starup-Linde
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Central Region Denmark, Aarhus N, 8200, Denmark.
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
| | - Sidse Westberg-Rasmussen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Central Region Denmark, Aarhus N, 8200, Denmark
| | - Rikke Viggers
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Zheer Kejlberg Al-Mashhadi
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Central Region Denmark, Aarhus N, 8200, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Aase Handberg
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Peter Vestergaard
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Søren Gregersen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Central Region Denmark, Aarhus N, 8200, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
11
|
Zaki MK, Abed MN, Alassaf FA. Antidiabetic Agents and Bone Quality: A Focus on Glycation End Products and Incretin Pathway Modulations. J Bone Metab 2024; 31:169-181. [PMID: 39307518 PMCID: PMC11416877 DOI: 10.11005/jbm.2024.31.3.169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/01/2024] [Accepted: 05/18/2024] [Indexed: 09/26/2024] Open
Abstract
Diabetes mellitus is associated with inadequate bone health and quality and heightened susceptibility to fractures, even in patients with normal or elevated bone mineral density. Elevated advanced glycation end-products (AGEs) and a suppressed incretin pathway are among the mechanisms through which diabetes affects the bone. Accordingly, the present review aimed to investigate the effects of antidiabetic medications on bone quality, primarily through AGEs and the incretin pathway. Google Scholar, Cochrane Library, and PubMed were used to examine related studies until February 2024. Antidiabetic medications influence AGEs and the incretin pathway directly or indirectly. Certain antidiabetic drugs including metformin, glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl-peptidase-4 (DDP-4) inhibitors, α-glucosidase inhibitors (AGIs), sodium-glucose co-transporter-2 inhibitors, and thiazolidinediones (TZDs), directly affect AGEs through multiple mechanisms. These mechanisms include decreasing the formation of AGEs and the expression of AGEs receptor (RAGE) in tissue and increasing serum soluble RAGE levels, resulting in the reduced action of AGEs. Similarly, metformin, GLP-1RA, DDP-4 inhibitors, AGIs, and TZDs may enhance incretin hormones directly by increasing their production or suppressing their metabolism. Additionally, these medications could influence AGEs and the incretin pathway indirectly by enhancing glycemic control. In contrast, sulfonylureas have not demonstrated any obvious effects on AGEs or the incretin pathway. Considering their favorable effects on AGEs and the incretin pathway, a suitable selection of antidiabetic drugs may facilitate more protective effects on the bone in diabetic patients.
Collapse
Affiliation(s)
- Muthanna K. Zaki
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul,
Iraq
| | - Mohammed N. Abed
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul,
Iraq
| | - Fawaz A. Alassaf
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul,
Iraq
| |
Collapse
|
|
12
|
Pechmann LM, Pinheiro FI, Andrade VFC, Moreira CA. The multiple actions of dipeptidyl peptidase 4 (DPP-4) and its pharmacological inhibition on bone metabolism: a review. Diabetol Metab Syndr 2024; 16:175. [PMID: 39054499 PMCID: PMC11270814 DOI: 10.1186/s13098-024-01412-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 07/10/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Dipeptidyl peptidase 4 (DPP-4) plays a crucial role in breaking down various substrates. It also has effects on the insulin signaling pathway, contributing to insulin resistance, and involvement in inflammatory processes like obesity and type 2 diabetes mellitus. Emerging effects of DPP-4 on bone metabolism include an inverse relationship between DPP-4 activity levels and bone mineral density, along with an increased risk of fractures. MAIN BODY The influence of DPP-4 on bone metabolism occurs through two axes. The entero-endocrine-osseous axis involves gastrointestinal substrates for DPP-4, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptides 1 (GLP-1) and 2 (GLP-2). Studies suggest that supraphysiological doses of exogenous GLP-2 has a significant inhibitory effect on bone resorption, however the specific mechanism by which GLP-2 influences bone metabolism remains unknown. Of these, GIP stands out for its role in bone formation. Other gastrointestinal DPP-4 substrates are pancreatic peptide YY and neuropeptide Y-both bind to the same receptors and appear to increase bone resorption and decrease bone formation. Adipokines (e.g., leptin and adiponectin) are regulated by DPP-4 and may influence bone remodeling and energy metabolism in a paracrine manner. The pancreatic-endocrine-osseous axis involves a potential link between DPP-4, bone, and energy metabolism through the receptor activator of nuclear factor kappa B ligand (RANKL), which induces DPP-4 expression in osteoclasts, leading to decreased GLP-1 levels and increased blood glucose levels. Inhibitors of DPP-4 participate in the pancreatic-endocrine-osseous axis by increasing endogenous GLP-1. In addition to their glycemic effects, DPP-4 inhibitors have the potential to decrease bone resorption, increase bone formation, and reduce the incidence of osteoporosis and fractures. Still, many questions on the interactions between DPP-4 and bone remain unanswered, particularly regarding the effects of DPP-4 inhibition on the skeleton of older individuals. CONCLUSION The elucidation of the intricate interactions and impact of DPP-4 on bone is paramount for a proper understanding of the body's mechanisms in regulating bone homeostasis and responses to internal stimuli. This understanding bears significant implications in the investigation of conditions like osteoporosis, in which disruptions to these signaling pathways occur. Further research is essential to uncover the full extent of DPP-4's effects on bone metabolism and energy regulation, paving the way for novel therapeutic interventions targeting these pathways, particularly in older individuals.
Collapse
Affiliation(s)
- L M Pechmann
- Universidade Federal do Paraná, Setor de Ciências da Saúde, Endocrine Division (SEMPR), Centro de Diabetes Curitiba, Academic Research Center Pro Renal Institute, Curitiba, Brazil.
| | - F I Pinheiro
- Biotechnology at Universidade Potiguar and Discipline of Ophthalmology at the Federal University of Rio Grande do Norte (UFRN), Natal, Brazil
| | - V F C Andrade
- Academic Research Center Pro Renal Institute, Endocrine Division, Hospital de Cínicas da Universidade Federal do Paraná (SEMPR), Curitiba, Brazil
| | - C A Moreira
- Academic Research Center Pro Renal Institute, Endocrine Division, Hospital de Clinicas da Universidade Federal do Paraná ( SEMPR), Curitiba, Brazil
| |
Collapse
|
|
13
|
Helsted MM, Schaltz NL, Gasbjerg LS, Christensen MB, Vilsbøll T, Knop FK. Safety of native glucose-dependent insulinotropic polypeptide in humans. Peptides 2024; 177:171214. [PMID: 38615716 DOI: 10.1016/j.peptides.2024.171214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/04/2024] [Accepted: 04/09/2024] [Indexed: 04/16/2024]
Abstract
In this systematic review, we assessed the safety and possible safety events of native glucose-dependent insulinotropic polypeptide (GIP)(1-42) in human studies with administration of synthetic human GIP. We searched the PubMed database for all trials investigating synthetic human GIP(1-42) administration. A total of 67 studies were included. Study duration ranged from 30 min to 6 days. In addition to healthy individuals, the studies included individuals with impaired glucose tolerance, type 2 diabetes, type 1 diabetes, chronic pancreatitis and secondary diabetes, latent autoimmune diabetes in adults, diabetes caused by a mutation in the hepatocyte nuclear factor 1-alpha gene, end-stage renal disease, chronic renal insufficiency, critical illness, hypoparathyroidism, or cystic fibrosis-related diabetes. Of the included studies, 78% did not mention safety events, 10% of the studies reported that no safety events were observed in relation to GIP administration, and 15% of the studies reported safety events in relation to GIP administration with most frequently reported event being a moderate and transient increased heart rate. Gastrointestinal safety events, and changes in blood pressure were also reported. Plasma concentration of active GIP(1-42) increased linearly with dose independent of participant phenotype. There was no significant correlation between achieved maximal concentration of GIP(1-42) and reported safety events. Clearance rates of GIP(1-42) were similar between participant groups. In conclusion, the available data indicate that GIP(1-42) in short-term (up to 6 days) infusion studies is generally well-tolerated. The long-term safety of continuous GIP(1-42) administration is unknown.
Collapse
Affiliation(s)
- Mads M Helsted
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Nina L Schaltz
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel B Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Herlev, Denmark.
| |
Collapse
|
|
14
|
Mabilleau G, Bouvard B. Gut hormone analogues and skeletal health in diabetes and obesity: Evidence from preclinical models. Peptides 2024; 177:171228. [PMID: 38657908 DOI: 10.1016/j.peptides.2024.171228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 04/26/2024]
Abstract
Diabetes mellitus and obesity are rapidly growing worldwide. Aside from metabolic disturbances, these two disorders also affect bone with a higher prevalence of bone fractures. In the last decade, a growing body of evidence suggested that several gut hormones, including ghrelin, gastrin, glucose-dependent insulinotropic polypeptide (GIP), glucagon, and glucagon-like peptide-1 and 2 (GLP-1 and GLP-2, respectively) may affect bone physiology. Several gut hormone analogues have been developed for the treatment of type 2 diabetes and obesity, and could represent a new alternative in the therapeutic arsenal against bone fragility. In the present review, a summary of the physiological roles of these gut hormones and their analogues is presented at the cellular level but also in several preclinical models of bone fragility disorders including type 2 diabetes mellitus, especially on bone mineral density, microarchitecture and bone material properties. The present review also summarizes the impact of GLP-1 receptor agonists approved for the treatment of type 2 diabetes mellitus and the more recent dual or triple analogue on bone physiology and strength.
Collapse
Affiliation(s)
- Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS, UMR 1229, SFR ICAT, Angers F-49000, France; CHU Angers, Département de Pathologie Cellulaire et Tissulaire, UF de Pathologie osseuse, Angers F-49933, France.
| | - Béatrice Bouvard
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS, UMR 1229, SFR ICAT, Angers F-49000, France; CHU Angers, Service de Rhumatologie, Angers F-49933, France
| |
Collapse
|
|
15
|
Skov-Jeppesen K, Christiansen CB, Hansen LS, Windeløv JA, Hedbäck N, Gasbjerg LS, Hindsø M, Svane MS, Madsbad S, Holst JJ, Rosenkilde MM, Hartmann B. Effects of Exogenous GIP and GLP-2 on Bone Turnover in Individuals With Type 2 Diabetes. J Clin Endocrinol Metab 2024; 109:1773-1780. [PMID: 38217866 PMCID: PMC11180509 DOI: 10.1210/clinem/dgae022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 12/11/2023] [Accepted: 01/09/2024] [Indexed: 01/15/2024]
Abstract
CONTEXT Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. OBJECTIVE The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. METHODS We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. RESULTS GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. CONCLUSION Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.
Collapse
Affiliation(s)
- Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Charlotte B Christiansen
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Laura S Hansen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Johanne A Windeløv
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Nora Hedbäck
- Department of Endocrinology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark
| | - Lærke S Gasbjerg
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Morten Hindsø
- Department of Endocrinology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark
| | - Maria S Svane
- Department of Endocrinology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
| |
Collapse
|
|
16
|
Bouvard B, Mabilleau G. Gut hormones and bone homeostasis: potential therapeutic implications. Nat Rev Endocrinol 2024:10.1038/s41574-024-01000-z. [PMID: 38858581 DOI: 10.1038/s41574-024-01000-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 06/12/2024]
Abstract
Bone resorption follows a circadian rhythm, with a marked reduction in circulating markers of resorption (such as carboxy-terminal telopeptide region of collagen type I in serum) in the postprandial period. Several gut hormones, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and GLP2, have been linked to this effect in humans and rodent models. These hormones are secreted from enteroendocrine cells in the gastrointestinal tract in response to a variety of stimuli and effect a wide range of physiological processes within and outside the gut. Single GLP1, dual GLP1-GIP or GLP1-glucagon and triple GLP1-GIP-glucagon receptor agonists have been developed for the treatment of type 2 diabetes mellitus and obesity. In addition, single GIP, GLP1 and GLP2 analogues have been investigated in preclinical studies as novel therapeutics to improve bone strength in bone fragility disorders. Dual GIP-GLP2 analogues have been developed that show therapeutic promise for bone fragility in preclinical studies and seem to exert considerable activity at the bone material level. This Review summarizes the evidence of the action of gut hormones on bone homeostasis and physiology.
Collapse
Affiliation(s)
- Béatrice Bouvard
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France
- CHU Angers, Service de Rhumatologie, Angers, France
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS UMR 1229, Angers, France.
- CHU Angers, Departement de Pathologie Cellulaire et Tissulaire, Angers, France.
| |
Collapse
|
|
17
|
Heckmann ND, Palmer R, Mayfield CK, Gucev G, Lieberman JR, Hong K. Glucagon-Like Peptide Receptor-1 Agonists Used for Medically-Supervised Weight Loss in Patients With Hip and Knee Osteoarthritis: Critical Considerations for the Arthroplasty Surgeon. Arthroplast Today 2024; 27:101327. [PMID: 39071832 PMCID: PMC11282421 DOI: 10.1016/j.artd.2024.101327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/08/2023] [Accepted: 01/27/2024] [Indexed: 07/30/2024] Open
Abstract
Patients with morbid obesity and concomitant hip or knee osteoarthritis represent a challenging patient demographic to treat as these patients often present earlier in life, have more severe symptoms, and have worse surgical outcomes following total hip and total knee arthroplasty. Previously, bariatric and metabolic surgeries represented one of the few weight loss interventions that morbidly obese patients could undergo prior to total joint arthroplasty. However, data regarding the reduction in complications with preoperative bariatric surgery remain mixed. Glucagon-like peptide receptor-1 (GLP-1) agonists have emerged as an effective treatment option for obesity in patients with and without diabetes mellitus. Furthermore, recent data suggest these medications may serve as potential anti-inflammatory and disease-modifying agents for numerous chronic conditions, including osteoarthritis. This review will discuss the GLP-1 agonists and GLP-1/glucose-dependent insulinotropic polypeptide dual agonists currently available, along with GLP-1/glucose-dependent insulinotropic polypeptide/glucagon triple agonists presently being developed to address the obesity epidemic. Furthermore, this review will address the potential problem of GLP-1-related delayed gastric emptying and its impact on the timing of elective total joint arthroplasty. The review aims to provide arthroplasty surgeons with a primer for implementing this class of medication in their current and future practice, including perioperative instructions and perioperative safety considerations when treating patients taking these medications.
Collapse
Affiliation(s)
- Nathanael D. Heckmann
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Ryan Palmer
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Cory K. Mayfield
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Gligor Gucev
- Department of Anesthesiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Jay R. Lieberman
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Kurt Hong
- Center for Clinical Nutrition, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| |
Collapse
|
|
18
|
Liu H, Xiao H, Lin S, Zhou H, Cheng Y, Xie B, Xu D. Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis. Front Pharmacol 2024; 15:1372399. [PMID: 38725663 PMCID: PMC11079205 DOI: 10.3389/fphar.2024.1372399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 03/25/2024] [Indexed: 05/12/2024] Open
Abstract
Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.
Collapse
Affiliation(s)
- Hongyu Liu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Huimin Xiao
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Sufen Lin
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Huan Zhou
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Yizhao Cheng
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| | - Baocheng Xie
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Department of Pharmacy, The 10th Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan, China
| | - Daohua Xu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, School of Pharmacy, Guangdong Medical University, Dongguan, China
- Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, China
| |
Collapse
|
|
19
|
Ali A, Flatt PR, Irwin N. Gut-Derived Peptide Hormone Analogues and Potential Treatment of Bone Disorders in Obesity and Diabetes Mellitus. Clin Med Insights Endocrinol Diabetes 2024; 17:11795514241238059. [PMID: 38486712 PMCID: PMC10938612 DOI: 10.1177/11795514241238059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/14/2024] [Indexed: 03/17/2024] Open
Abstract
Obesity and diabetes mellitus are prevalent metabolic disorders that have a detrimental impact on overall health. In this regard, there is now a clear link between these metabolic disorders and compromised bone health. Interestingly, both obesity and diabetes lead to elevated risk of bone fracture which is independent of effects on bone mineral density (BMD). In this regard, gastrointestinal (GIT)-derived peptide hormones and their related long-acting analogues, some of which are already clinically approved for diabetes and/or obesity, also seem to possess positive effects on bone remodelling and microarchitecture to reduce bone fracture risk. Specifically, the incretin peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as glucagon-like peptide-2 (GLP-2), exert key direct and/or indirect benefits on bone metabolism. This review aims to provide an initial appraisal of the relationship between obesity, diabetes and bone, with a focus on the positive impact of these GIT-derived peptide hormones for bone health in obesity/diabetes. Brief discussion of related peptides such as parathyroid hormone, leptin, calcitonin and growth hormone is also included. Taken together, drugs engineered to promote GIP, GLP-1 and GLP-2 receptor signalling may have potential to offer therapeutic promise for improving bone health in obesity and diabetes.
Collapse
Affiliation(s)
- Asif Ali
- Diabetes Research Centre, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK
| | - Peter R Flatt
- Diabetes Research Centre, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK
| | - Nigel Irwin
- Diabetes Research Centre, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK
| |
Collapse
|
|
20
|
Kim TY, Schafer AL. Bariatric surgery, vitamin D, and bone loss. FELDMAN AND PIKE'S VITAMIN D 2024:161-184. [DOI: 10.1016/b978-0-323-91338-6.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
21
|
Hartmann B, Longo M, Mathiesen DS, Hare KJ, Jørgensen NR, Esposito K, Deacon CF, Vilsbøll T, Holst JJ, Knop FK. Signs of a Glucose- and Insulin-Independent Gut-Bone Axis and Aberrant Bone Homeostasis in Type 1 Diabetes. J Clin Endocrinol Metab 2023; 109:e259-e265. [PMID: 37466204 DOI: 10.1210/clinem/dgad431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 06/15/2023] [Accepted: 07/17/2023] [Indexed: 07/20/2023]
Abstract
CONTEXT Gut hormones seem to play an important role in postprandial bone turnover, which also may be affected by postprandial plasma glucose excursions and insulin secretion. OBJECTIVE To investigate the effect of an oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI) on bone resorption and formation markers in individuals with type 1 diabetes and healthy controls. METHODS This observational case-control study, conducted at the Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark, included 9 individuals with C-peptide negative type 1 diabetes and 8 healthy controls matched for gender, age, and body mass index. Subjects underwent an OGTT and a subsequent IIGI. We analyzed changes in bone resorption assessed by measurements of carboxy-terminal type I collagen crosslinks (CTX) and in bone formation as assessed by procollagen type I N-terminal propeptide (PINP) concentrations. RESULTS Baseline CTX and PINP levels were similar in the 2 groups. Both groups exhibited significantly greater suppression of CTX during OGTT than IIGI. PINP levels were unaffected by OGTT and IIGI, respectively, in healthy controls. Participants with type 1 diabetes displayed impaired suppression of CTX-assessed bone resorption and inappropriate suppression of PINP-assessed bone formation during OGTT. CONCLUSION Our data suggest the existence of a gut-bone axis reducing bone resorption in response to oral glucose independently of plasma glucose excursions and insulin secretion. Subjects with type 1 diabetes showed impaired suppression of bone resorption and reduced bone formation during OGTT, which may allude to the reduced bone mineral density and increased fracture risk characterizing these individuals.
Collapse
Affiliation(s)
- Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Miriam Longo
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - David S Mathiesen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Kristine J Hare
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Obstetrics and Gynaecology, Hvidovre Hospital, University of Copenhagen, DK-2650 Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Niklas R Jørgensen
- Department of Clinical Biochemistry, Centre of Diagnostic Investigation, Rigshospitalet, University of Copenhagen, DK-2100 Glostrup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, DK-2750 Herlev, Denmark
| | - Katherine Esposito
- Department of Advanced Medical and Surgical Sciences, Division of Endocrinology and Metabolic Diseases, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Carolyn F Deacon
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, DK-2750 Herlev, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, DK-2750 Herlev, Denmark
| |
Collapse
|
|
22
|
Viggers R, Rasmussen NH, Vestergaard P. Effects of Incretin Therapy on Skeletal Health in Type 2 Diabetes-A Systematic Review. JBMR Plus 2023; 7:e10817. [PMID: 38025038 PMCID: PMC10652182 DOI: 10.1002/jbm4.10817] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 12/01/2023] Open
Abstract
Diabetes poses a significant risk to bone health, with Type 1 diabetes (T1D) having a more detrimental impact than Type 2 diabetes (T2D). The group of hormones known as incretins, which includes gastric inhibitory peptide (GIP) and glucagon-like peptide 1 (GLP-1), play a role in regulating bowel function and insulin secretion during feeding. GLP-1 receptor agonists (GLP-1 RAs) are emerging as the primary treatment choice in T2D, particularly when atherosclerotic cardiovascular disease is present. Dipeptidyl peptidase 4 inhibitors (DPP-4is), although less potent than GLP-1 RAs, can also be used. Additionally, GLP-1 RAs, either alone or in combination with GIP, may be employed to address overweight and obesity. Since feeding influences bone turnover, a relationship has been established between incretins and bone health. To explore this relationship, we conducted a systematic literature review following the PRISMA guidelines. While some studies on cells and animals have suggested positive effects of incretins on bone cells, turnover, and bone density, human studies have yielded either no or limited and conflicting results regarding their impact on bone mineral density (BMD) and fracture risk. The effect on fracture risk may vary depending on the choice of comparison drug and the duration of follow-up, which was often limited in several studies. Nevertheless, GLP-1 RAs may hold promise for people with T2D who have multiple fracture risk factors and poor metabolic control. Furthermore, a potential new area of interest is the use of GLP-1 RAs in fracture prevention among overweight and obese people. Based on this systematic review, existing evidence remains insufficient to support a positive or a superior effect on bone health to reduce fracture risk in people with T2D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Collapse
Affiliation(s)
- Rikke Viggers
- Steno Diabetes Center North DenmarkAalborgDenmark
- Department of EndocrinologyAalborg University HospitalAalborgDenmark
| | | | - Peter Vestergaard
- Steno Diabetes Center North DenmarkAalborgDenmark
- Department of EndocrinologyAalborg University HospitalAalborgDenmark
| |
Collapse
|
|
23
|
Hilkens L, Boerboom M, van Schijndel N, Bons J, van Loon LJC, van Dijk JW. Bone turnover following high-impact exercise is not modulated by collagen supplementation in young men: A randomized cross-over trial. Bone 2023; 170:116705. [PMID: 36804484 DOI: 10.1016/j.bone.2023.116705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 01/23/2023] [Accepted: 02/10/2023] [Indexed: 02/17/2023]
Abstract
INTRODUCTION We assessed whether collagen supplementation augments the effects of high-impact exercise on bone turnover and whether a higher exercise frequency results in a greater benefit for bone metabolism. METHODS In this randomized, cross-over trial, 14 healthy males (age 24 ± 4 y, BMI 22.0 ± 2.1 kg/m2) performed 5-min of high-impact exercise once (JUMP+PLA and JUMP+COL) or twice daily (JUMP2+COL2) during a 3-day intervention period, separated by a 10-day wash out period. One hour before every exercise bout participants ingested 20 g hydrolysed collagen (JUMP+COL and JUMP2+COL2) or a placebo control (JUMP+PLA). Blood markers of bone formation (P1NP) and resorption (CTXI) were assessed in the fasted state before the ingestion of the initial test drinks and 24, 48, and 72 h thereafter. In JUMP+PLA and JUMP+COL, additional blood samples were collected in the postprandial state at 1, 2, 3, 4, 5 and 13 h after ingestion of the test drink. RESULTS In the postprandial state, serum P1NP concentrations decreased marginally from 99 ± 37 to 93 ± 33 ng/mL in JUMP+COL, and from 97 ± 32 to 92 ± 31 ng/mL in JUMP+PLA, with P1NP levels having returned to baseline levels after 13 h (time-effect, P = 0.053). No differences in serum P1NP concentrations were observed between JUMP+PLA and JUMP+COL (time x treatment, P = 0.58). Serum CTX-I concentrations showed a ~ 50 % decline (time, P < 0.001) in the postprandial state in JUMP+COL (0.9 ± 0.3 to 0.4 ± 0.2 ng/mL) and JUMP+PLA (0.9 ± 0.3 to 0.4 ± 0.2 ng/mL), with no differences between treatments (time x treatment, P = 0.17). Fasted serum P1NP concentrations increased ~8 % by daily jumping exercise (time-effect, P < 0.01), with no differences between treatments (time x treatment, P = 0.71). Fasted serum CTX-I concentrations did not change over time (time-effect, P = 0.41) and did not differ between treatments (time x treatment, P = 0.58). CONCLUSIONS Five minutes of high-impact exercise performed daily stimulates bone formation during a 3-day intervention period. This was indicated by an increase in fasted serum P1NP concentrations, rather than an acute increase in post-exercise serum P1NP concentrations. Collagen supplementation or an increase in exercise frequency does not further increase serum P1NP concentrations. The bone resorption marker CTX-I was not affected by daily short-duration high-impact exercise with or without concurrent collagen supplementation.
Collapse
Affiliation(s)
- Luuk Hilkens
- School of Sport and Exercise, HAN University of Applied Sciences, Nijmegen, the Netherlands; Department of Human Biology, NUTRIM, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Marleen Boerboom
- School of Sport and Exercise, HAN University of Applied Sciences, Nijmegen, the Netherlands
| | - Nick van Schijndel
- School of Sport and Exercise, HAN University of Applied Sciences, Nijmegen, the Netherlands
| | - Judith Bons
- Central Diagnostic Laboratory, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Luc J C van Loon
- School of Sport and Exercise, HAN University of Applied Sciences, Nijmegen, the Netherlands; Department of Human Biology, NUTRIM, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Jan-Willem van Dijk
- School of Sport and Exercise, HAN University of Applied Sciences, Nijmegen, the Netherlands.
| |
Collapse
|
|
24
|
Dalsgaard NB, Gasbjerg LS, Helsted MM, Hansen LS, Hansen NL, Skov-Jeppesen K, Hartmann B, Holst JJ, Vilsbøll T, Knop FK. Acarbose diminishes postprandial suppression of bone resorption in patients with type 2 diabetes. Bone 2023; 170:116687. [PMID: 36754130 DOI: 10.1016/j.bone.2023.116687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 01/16/2023] [Accepted: 01/27/2023] [Indexed: 02/08/2023]
Abstract
AIMS The alpha-glucosidase inhibitor acarbose is an antidiabetic drug delaying assimilation of carbohydrates and, thus, increasing the amount of carbohydrates in the distal parts of the intestines, which in turn increases circulating levels of the gut-derived incretin hormone glucagon-like peptide 1 (GLP-1). As GLP-1 may suppress bone resorption, acarbose has been proposed to potentiate meal-induced suppression of bone resorption. We investigated the effect of acarbose treatment on postprandial bone resorption in patients with type 2 diabetes and used the GLP-1 receptor antagonist exendin(9-39)NH2 to disclose contributory effect of acarbose-induced GLP-1 secretion. METHODS In a randomised, placebo-controlled, double-blind, crossover study, 15 participants with metformin-treated type 2 diabetes (2 women/13 men, age 71 (57-85 years), BMI 29.7 (23.6-34.6 kg/m2), HbA1c 48 (40-74 mmol/mol)/6.5 (5.8-11.6 %) (median and range)) were subjected to two 14-day treatment periods with acarbose and placebo, respectively, separated by a six-week wash-out period. At the end of each period, circulating bone formation and resorption markers were assessed during two randomised 4-h liquid mixed meal tests (MMT) with infusions of exendin(9-39)NH2 and saline, respectively. Glucagon-like peptide 2 (GLP-2) was also assessed. RESULTS Compared to placebo, acarbose impaired the MMT-induced suppression of CTX as assessed by baseline-subtracted area under curve (P = 0.0037) and nadir of CTX (P = 0.0128). During acarbose treatment, exendin(9-39)NH2 infusion lowered nadir of CTX compared to saline (P = 0.0344). Neither parathyroid hormone or the bone formation marker procollagen 1 intact N-terminal propeptide were affected by acarbose or GLP-1 receptor antagonism. Acarbose treatment induced a greater postprandial GLP-2 response than placebo treatment (P = 0.0479) and exendin(9-39)NH2 infusion exacerbated this (P = 0.0002). CONCLUSIONS In patients with type 2 diabetes, treatment with acarbose reduced postprandial suppression of bone resorption. Acarbose-induced GLP-1 secretion may contribute to this phenomenon as the impairment was partially reversed by GLP-1 receptor antagonism. Also, acarbose-induced reductions in other factors reducing bone resorption, e.g. glucose-dependent insulinotropic polypeptide, may contribute.
Collapse
Affiliation(s)
- Niels B Dalsgaard
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mads M Helsted
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Laura S Hansen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Nina L Hansen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark.
| |
Collapse
|
|
25
|
Gadgaard S, Windeløv JA, Schiellerup SP, Holst JJ, Hartmann B, Rosenkilde MM. Long-acting agonists of human and rodent GLP-2 receptors for studies of the physiology and pharmacological potential of the GLP-2 system. Biomed Pharmacother 2023; 160:114383. [PMID: 36780786 DOI: 10.1016/j.biopha.2023.114383] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/01/2023] [Accepted: 02/07/2023] [Indexed: 02/13/2023] Open
Abstract
BACKGROUND AND PURPOSE Glucagon-like peptide-2 (GLP-2) is secreted postprandially from enteroendocrine Lcells and has anabolic action on gut and bone. Short-acting teduglutide is the only approved GLP-2 analog for the treatment of short-bowel syndrome (SBS). To improve the therapeutic effect, we created a series of lipidated GLP-2R agonists. EXPERIMENTAL APPROACH Six GLP-2 analogs were studied in vitro for cAMP accumulation, β-arrestin 1 and 2 recruitment, affinity, and internalization. The trophic actions on intestine and bone were examined in vivo in rodents. KEY RESULTS Lipidations at lysines introduced at position 12, 16, and 20 of hGLP-2(1-33) were well-tolerated with less than 2.2-fold impaired potency and full efficacy at the hGLP-2R in cAMP accumulation. In contrast, N- and C-terminal (His1 and Lys30) lipidations impaired potency by 4.2- and 45-fold and lowered efficacy to 77% and 85% of hGLP-2, respectively. All variants were similarly active on the rat and mouse GLP-2Rs and the three most active variants displayed increased selectivity for hGLP-2R over hGLP-1R activation, compared to native hGLP-2. Impact on arrestin recruitment and receptor internalization followed that of Gαs-coupling, except for lipidation in position 20, where internalization was more impaired, suggesting desensitization protection. A highly active variant (C16 at position 20) with low internalization and a half-life of 9.5 h in rats showed improved gut and bone tropism with increased weight of small intestine in mice and decreased CTX levels in rats. CONCLUSION AND IMPLICATION We present novel hGLP-2 agonists suitable for in vivo studies of the GLP-2 system to uncover its pharmacological potential.
Collapse
Affiliation(s)
- Sarina Gadgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Bainan Biotech, Copenhagen, Denmark
| | | | - Sine P Schiellerup
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Mette M Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
| |
Collapse
|
|
26
|
Lei WS, Rodrick EB, Belcher SL, Kelly A, Kindler JM. Bone resorption and incretin hormones following glucose ingestion in healthy emerging adults. J Clin Transl Endocrinol 2023; 31:100314. [PMID: 36845829 PMCID: PMC9950953 DOI: 10.1016/j.jcte.2023.100314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/28/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023] Open
Abstract
Background Studies in adults indicate that macronutrient ingestion yields an acute anti-resorptive effect on bone, reflected by decreases in C-terminal telopeptide (CTX), a biomarker of bone resorption, and that gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), facilitate this response. There remain knowledge gaps relating to other biomarkers of bone turnover, and whether gut-bone cross-talk is operative during the years surrounding peak bone strength attainment. This study first, describes changes in bone resorption during oral glucose tolerance testing (OGTT), and second, tests relationships between changes in incretins and bone biomarkers during OGTT and bone micro-structure. Methods We conducted a cross-sectional study in 10 healthy emerging adults ages 18-25 years. During a multi-sample 2-hour 75 g OGTT, glucose, insulin, GIP, GLP-1, CTX, bone-specific alkaline phosphatase (BSAP), osteocalcin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-β ligand (RANKL), sclerostin, and parathyroid hormone (PTH) were assayed at mins 0, 30, 60, and 120. Incremental areas under the curve (iAUC) were computed from mins 0-30 and mins 0-120. Tibia bone micro-structure was assessed using second generation high resolution peripheral quantitative computed tomography. Results During OGTT, glucose, insulin, GIP, and GLP-1 increased significantly. CTX at min 30, 60, and 120 was significantly lower than min 0, with a maximum decrease of about 53 % by min 120. Glucose-iAUC0-30 inversely correlated with CTX-iAUC0-120 (rho = -0.91, P < 0.001), and GLP-1-iAUC0-30 positively correlated with BSAP-iAUC0-120 (rho = 0.83, P = 0.005), RANKL-iAUC0-120 (rho = 0.86, P = 0.007), and cortical volumetric bone mineral density (rho = 0.93, P < 0.001). Conclusions Glucose ingestion yields an anti-resorptive effect on bone metabolism during the years surrounding peak bone strength. Cross-talk between the gut and bone during this pivotal life stage requires further attention.
Collapse
Affiliation(s)
- Wang Shin Lei
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA
| | - Eugene B. Rodrick
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA
| | - Staci L. Belcher
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA,Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA
| | - Joseph M. Kindler
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA,Corresponding author.
| |
Collapse
|
|
27
|
Maagensen H, Helsted MM, Gasbjerg LS, Vilsbøll T, Knop FK. The Gut-Bone Axis in Diabetes. Curr Osteoporos Rep 2023; 21:21-31. [PMID: 36441432 DOI: 10.1007/s11914-022-00767-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/03/2022] [Indexed: 11/29/2022]
Abstract
PURPOSE OF REVIEW To describe recent advances in the understanding of how gut-derived hormones regulate bone homeostasis in humans with emphasis on pathophysiological and therapeutic perspectives in diabetes. RECENT FINDINGS The gut-derived incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is important for postprandial suppression of bone resorption. The other incretin hormone, glucagon-like peptide 1 (GLP-1), as well as the intestinotrophic glucagon-like peptide 2 (GLP-2) has been shown to suppress bone resorption in pharmacological concentrations, but the role of the endogenous hormones in bone homeostasis is uncertain. For ambiguous reasons, both patients with type 1 and type 2 diabetes have increased fracture risk. In diabetes, the suppressive effect of endogenous GIP on bone resorption seems preserved, while the effect of GLP-2 remains unexplored both pharmacologically and physiologically. GLP-1 receptor agonists, used for the treatment of type 2 diabetes and obesity, may reduce bone loss, but results are inconsistent. GIP is an important physiological suppressor of postprandial bone resorption, while GLP-1 and GLP-2 may also exert bone-preserving effects when used pharmacologically. A better understanding of the actions of these gut hormones on bone homeostasis in patients with diabetes may lead to new strategies for the prevention and treatment of skeletal frailty related to diabetes.
Collapse
Affiliation(s)
- Henrik Maagensen
- Clinical Research, Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
| | - Mads M Helsted
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
| | - Lærke S Gasbjerg
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Clinical Research, Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Clinical Research, Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark.
- Center for Clinical Metabolic Research, Copenhagen University Hospital-Herlev and Gentofte, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
28
|
Gabe MBN, von Voss L, Hunt JE, Gadgaard S, Gasbjerg LS, Holst JJ, Kissow H, Hartmann B, Rosenkilde MM. Biased GLP-2 agonist with strong G protein-coupling but impaired arrestin recruitment and receptor desensitization enhances intestinal growth in mice. Br J Pharmacol 2023. [PMID: 36683195 DOI: 10.1111/bph.16040] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 12/04/2022] [Accepted: 01/15/2023] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND AND PURPOSE Glucagon-like peptide-2 (GLP-2) is secreted postprandially by enteroendocrine L-cells and stimulates growth of the gut and bone. One GLP-2 analogue is approved for short bowel syndrome (SBS). To improve therapeutic efficacy, we developed biased GLP-2 receptor (GLP-2R) agonists through N-terminal modifications. EXPERIMENTAL APPROACH Variants with Ala and Trp substitutions of the first seven positions of GLP-2(1-33) were studied in vitro for affinity, G protein activation (cAMP accumulation), recruitment of β-arrestin 1 and 2, and internalization of the human and mouse GLP-2R. The intestinotrophic actions of the most efficacious (cAMP) biased variant were examined in mice. KEY RESULTS Ala substitutions had more profound effects than Trp substitutions. For both, alterations at positions 1, 3 and 6 most severely impaired activity. β-arrestin recruitment was more affected than cAMP accumulation. Among Ala substitutions, [H1A], [D3A] and [F6A] impaired potency (EC50 ) for cAMP-accumulation >20-fold and efficacy (Emax ) to 48%-87%, and were unable to recruit arrestins. The Trp substitutions, [A2W], [D3W] and [G4W] were partial agonists (Emax of 46%-59%) with 1.7-12-fold decreased potencies in cAMP and diminished β-arrestin recruitment. The biased variants, [F6A], [F6W] and [S7W] induced less GLP-2R internalization compared with GLP-2, which induced internalization in a partly arrestin-independent manner. In mice, [S7W] enhanced gut trophic actions with increased weight of the small intestine, increased villus height and crypt depth compared with GLP-2. CONCLUSION AND IMPLICATIONS G protein-biased GLP-2R agonists with diminished receptor desensitization have superior intestinotrophic effects and may represent improved treatment of intestinal insufficiency including SBS.
Collapse
Affiliation(s)
- Maria Buur Nordskov Gabe
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Liv von Voss
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jenna Elizabeth Hunt
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sarina Gadgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Laerke Smidt Gasbjerg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hannelouise Kissow
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
29
|
Schini M, Vilaca T, Gossiel F, Salam S, Eastell R. Bone Turnover Markers: Basic Biology to Clinical Applications. Endocr Rev 2022; 44:417-473. [PMID: 36510335 PMCID: PMC10166271 DOI: 10.1210/endrev/bnac031] [Citation(s) in RCA: 132] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 11/26/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022]
Abstract
Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide; and commonly used resorption markers serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen and tartrate resistant acid phosphatase type 5b. BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable components (e.g., age, gender, ethnicity) and controllable components, particularly relating to collection conditions (e.g., fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics; and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget's disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder.
Collapse
Affiliation(s)
- Marian Schini
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.,Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Tatiane Vilaca
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Fatma Gossiel
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Syazrah Salam
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.,Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Richard Eastell
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| |
Collapse
|
|
30
|
Lei WS, Kilberg MJ, Zemel BS, Rubenstein RC, Harris C, Sheikh S, Kelly A, Kindler JM. Bone metabolism and incretin hormones following glucose ingestion in young adults with pancreatic insufficient cystic fibrosis. J Clin Transl Endocrinol 2022; 30:100304. [PMID: 36110921 PMCID: PMC9467887 DOI: 10.1016/j.jcte.2022.100304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/12/2022] [Accepted: 08/29/2022] [Indexed: 11/23/2022] Open
Abstract
Background Gut-derived incretin hormones, including glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), regulate post-prandial glucose metabolism by promoting insulin production. GIP, GLP-1, and insulin contribute to the acute bone anti-resorptive effect of macronutrient ingestion by modifying bone turnover. Cystic fibrosis (CF) is associated with exocrine pancreatic insufficiency (PI), which perturbs the incretin response. Cross-talk between the gut and bone ("gut-bone axis") has not yet been studied in PI-CF. The objectives of this study were to assess changes in biomarkers of bone metabolism during oral glucose tolerance testing (OGTT) and to test associations between incretins and biomarkers of bone metabolism in individuals with PI-CF. Methods We performed a secondary analysis of previously acquired blood specimens from multi-sample OGTT from individuals with PI-CF ages 14-30 years (n = 23). Changes in insulin, incretins, and biomarkers of bone resorption (C-terminal telopeptide of type 1 collagen [CTX]) and formation (procollagen type I N-terminal propeptide [P1NP]) during OGTT were computed. Results CTX decreased by 32% by min 120 of OGTT (P < 0.001), but P1NP was unchanged. Increases in GIP from 0 to 30 mins (rho = -0.48, P = 0.03) and decreases in GIP from 30 to 120 mins (rho = 0.62, P = 0.002) correlated with decreases in CTX from mins 0-120. Changes in GLP-1 and insulin were not correlated with changes in CTX, and changes in incretins and insulin were not correlated with changes in P1NP. Conclusions Intact GIP response was correlated with the bone anti-resorptive effect of glucose ingestion, represented by a decrease in CTX. Since incretin hormones might contribute to development of diabetes and bone disease in CF, the "gut-bone axis" warrants further attention in CF during the years surrounding peak bone mass attainment.
Collapse
Affiliation(s)
- Wang Shin Lei
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA
| | - Marissa J. Kilberg
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA
| | - Babette S. Zemel
- Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Ronald C. Rubenstein
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Clea Harris
- Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA
| | - Saba Sheikh
- Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA
- Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA
| | - Joseph M. Kindler
- Department of Nutritional Sciences, The University of Georgia, Athens, GA, USA
| |
Collapse
|
|
31
|
Gabe MBN, Gasbjerg LS, Gadgaard S, Lindquist P, Holst JJ, Rosenkilde MM. N-terminal alterations turn the gut hormone GLP-2 into an antagonist with gradual loss of GLP-2 receptor selectivity towards more GLP-1 receptor interaction. Br J Pharmacol 2022; 179:4473-4485. [PMID: 35523760 PMCID: PMC9541843 DOI: 10.1111/bph.15866] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 02/21/2022] [Accepted: 03/17/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE To fully elucidate the regulatory role of the GLP-2 system in the gut and the bones, potent and selective GLP-2 receptor (GLP-2R) antagonists are needed. Searching for antagonist activity, we performed systematic N-terminal truncations of human GLP-2(1-33). EXPERIMENTAL APPROACH COS-7 cells were transfected with the human GLP-2R and assessed for cAMP accumulation or competition binding using 125 I-GLP-2(1-33)[M10Y]. To examine selectivity, human GLP-1 or GIP receptor expressing COS-7 cells were assessed for cAMP accumulation. KEY RESULTS The affinity for the GLP-2R of the N-terminally truncated GLP-2 peptides decreased with reduced N-terminal peptide length (Ki 6.5-871 nM), while increasing antagonism appeared with inhibitory potencies (IC50 ) values from 79 to 204 nM for truncation up to GLP-2(4-33) and then declined. In contrast, truncation-dependent increases in intrinsic activity were observed from an Emax of only 20% for GLP-(2-33) up to 46% for GLP-2(6-33) at 1 μM, followed by a decline. GLP-2(9-33) had the highest intrinsic efficacy (Emax 65%) and no antagonistic properties. Moreover, with truncations up to GLP-2(8-33) a gradual loss in selectivity for the GLP-2R appeared with increasing GLP-1 receptor (GLP-1R) inhibition (up to 73% at 1 μM). Lipidation of the peptides improved antagonism (IC50 down to 7.9 nM) for both the GLP-2R and the GLP-1R. CONCLUSION AND IMPLICATIONS The N-terminus of GLP-2 is crucial for GLP-2R activity and selectivity. Our observations form the basis for the development of tool compounds for further characterization of the GLP-2 system.
Collapse
Affiliation(s)
- Maria Buur Nordskov Gabe
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Laerke Smidt Gasbjerg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Sarina Gadgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Peter Lindquist
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| |
Collapse
|
|
32
|
Schou A, Jørgensen NR, Maro VP, Kilonzo K, Ramaiya K, Sironga J, Jensen AK, Christensen DL, Schwarz P. The circadian rhythm of calcium and bone homeostasis in Maasai. Am J Hum Biol 2022; 34:e23756. [PMID: 35481615 PMCID: PMC9539595 DOI: 10.1002/ajhb.23756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 04/04/2022] [Accepted: 04/13/2022] [Indexed: 11/09/2022] Open
Abstract
OBJECTIVES Ethnic groups differ in prevalence of calcium-related diseases. Differences in the physiology and the endogenous circadian rhythm (CR) of calcium and bone homeostasis may play a role. Thus, we aimed to investigate details of CR pattern in calcium and bone homeostasis in East African Maasai. METHODS Ten clinically healthy adult Maasai men and women from Tanzania were examined. Blood samples were collected every 2nd hour for 24 h. Serum levels of total calcium, albumin, parathyroid hormone (PTH), 25(OH)D, creatinine, C-terminal telopeptide (CTX), bone-specific alkaline phosphatase (BSAP), procollagen type 1 N-terminal propeptide (P1NP), and osteocalcin were measured. Circadian patterns were derived from graphic curves of medians, and rhythmicity was assessed with Fourier analysis. RESULTS PTH-levels varied over the 24 h exhibiting a bimodal pattern. Nadir level corresponded to 65% of total 24-h mean. CTX and P1NP showed 24-h variations with a morning nadir and nocturnal peak with nadir levels corresponding to 23% and 79% of the 24-h mean, respectively. Albumin-corrected calcium level was held in a narrow range and alterations were corresponding to alterations in PTH. There was no distinct pattern in 24-h variations of 25(OH)D, creatinine, osteocalcin, or BSAP. CONCLUSIONS All participants showed pronounced 24-h variations in PTH and bone turnover markers CTX and P1NP. These findings support that Maasai participants included in this study have typical patterns of CR in calcium and bone homeostasis consistent with findings from other ethnic populations.
Collapse
Affiliation(s)
- Anne Schou
- Diabetes and Bone-Metabolic Research Unit, Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark.,Department of Public Health, Global Health Section, University of Copenhagen, Copenhagen, Denmark
| | - Niklas Rye Jørgensen
- Department of Clinical Biochemistry, Rigshospitalet Glostrup, Copenhagen, Denmark.,Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Venance Phillip Maro
- Department of Internal Medicine, Kilimanjaro Christian Medical University College, Moshi, Tanzania
| | - Kajiru Kilonzo
- Department of Internal Medicine, Kilimanjaro Christian Medical University College, Moshi, Tanzania
| | - Kaushik Ramaiya
- Department of Internal Medicine, Shree Hindu Mandal Hospital, Dar es Salaam, Tanzania
| | - Joseph Sironga
- Department of Internal Medicine, Kilimanjaro Christian Medical University College, Moshi, Tanzania.,Department of Internal Medicine, Monduli District Hospital, Monduli, Tanzania
| | - Andreas Kryger Jensen
- Department of Public Health, Global Health Section, University of Copenhagen, Copenhagen, Denmark.,Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Dirk Lund Christensen
- Department of Public Health, Global Health Section, University of Copenhagen, Copenhagen, Denmark.,Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter Schwarz
- Diabetes and Bone-Metabolic Research Unit, Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark.,Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
33
|
Gabe MBN, Skov-Jeppesen K, Gasbjerg LS, Schiellerup SP, Martinussen C, Gadgaard S, Boer GA, Oeke J, Torz LJ, Veedfald S, Svane MS, Bojsen-Møller KN, Madsbad S, Holst JJ, Hartmann B, Rosenkilde MM. GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. Pharmacol Res 2022; 176:106058. [PMID: 34995796 DOI: 10.1016/j.phrs.2022.106058] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 01/02/2022] [Accepted: 01/02/2022] [Indexed: 11/22/2022]
Abstract
The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are key regulators of postprandial bone turnover in humans. We hypothesized that GIP and GLP-2 co-administration would provide stronger effect on bone turnover than administration of the hormones separately, and tested this using subcutaneous injections of GIP and GLP-2 alone or in combination in humans. Guided by these findings, we designed series of GIPR-GLP-2R co-agonists as template for new osteoporosis treatment. The clinical experiment was a randomized cross-over design including 10 healthy men administered subcutaneous injections of GIP and GLP-2 alone or in combination. The GIPR-GLP-2R co-agonists were characterized in terms of binding and activation profiles on human and rodent GIP and GLP-2 receptors, and their pharmacokinetic (PK) profiles were improved by dipeptidyl peptidase-4 protection and site-directed lipidation. Co-administration of GIP and GLP-2 in humans resulted in an additive reduction in bone resorption superior to each hormone individually. The GIPR-GLP-2R co-agonists, designed by combining regions of importance for cognate receptor activation, obtained similar efficacies as the two native hormones and nanomolar potencies on both human receptors. The PK-improved co-agonists maintained receptor activity along with their prolonged half-lives. Finally, we found that the GIPR-GLP-2R co-agonists optimized toward the human receptors for bone remodeling are not feasible for use in rodent models. The successful development of potent and efficacious GIPR-GLP-2R co-agonists, combined with the improved effect on bone metabolism in humans by co-administration, support these co-agonists as a future osteoporosis treatment.
Collapse
Affiliation(s)
- Maria Buur Nordskov Gabe
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lærke Smidt Gasbjerg
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Sine Pasch Schiellerup
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Christoffer Martinussen
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
| | - Sarina Gadgaard
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Geke Aline Boer
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Jannika Oeke
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lola Julia Torz
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Simon Veedfald
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Maria Saur Svane
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Endocrinology, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
| | | | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
| |
Collapse
|
|
34
|
Starup-Linde J, Ornstrup MJ, Kjær TN, Lykkeboe S, Handberg A, Gregersen S, Harsløf T, Pedersen SB, Vestergaard P, Langdahl BL. Bone Density and Structure in Overweight Men With and Without Diabetes. Front Endocrinol (Lausanne) 2022; 13:837084. [PMID: 35360074 PMCID: PMC8960162 DOI: 10.3389/fendo.2022.837084] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/10/2022] [Indexed: 12/04/2022] Open
Abstract
OBJECTIVE Metabolic syndrome (MetS), type 1 diabetes (T1D), and type 2 diabetes, are associated with an increased risk of fractures; however, the impact of obesity on bone deficits in diabetes is unknown. We aimed to compare markers of bone structure, bone density, and bone turnover in non-diabetic overweight men with MetS and overweight men with T1D or T2D. METHODS AND RESEARCH DESIGN In this cross-sectional study we included participants from two previously described study cohorts consisting of participants with diabetes and participants with MetS. Participants underwent dual-energy X-ray absorptiometry measuring areal bone mineral density (aBMD) at the hip and lumbar spine, High Resolution peripheral Quantitative (HRpQCT) scan of the tibia and radius and measurement of circulating bone turnover markers. We compared groups with unpaired t test and performed multiple linear regression with adjustment for age, body mass index, and smoking. RESULTS We included 33 participants with T1D, 25 participants with T2D, and 34 participants with MetS. Bone turnover markers levels were comparable between T1D and MetS. aBMD at the hip was lower in T1D compared to MetS, also after adjustment. P1NP and Osteocalcin levels were lower among individuals with T2D compared to MetS, whereas aBMD were similar between the groups after multiple adjustments. We observed no difference in volumetric BMD at the tibia or radius between MetS and T1D and T2D, respectively. Participants with T2D had a higher trabecular number and lower trabecular separation compared to individuals with MetS at the tibia, which remained signficant after multiple adjustments. CONCLUSION In conclusion, we observed no clinically important differences in bone density or structure between men with T2D, T1D, or MetS. However, men with T2D displayed lower bone turnover compared to MetS highlighting that T2D per se and not obesity, is associated with low bone turnover.
Collapse
Affiliation(s)
- Jakob Starup-Linde
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center North Jutland, Aalborg University Hospital, Aalborg, Denmark
- *Correspondence: Jakob Starup-Linde,
| | - Marie Juul Ornstrup
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Thomas Nordstrøm Kjær
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Simon Lykkeboe
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Aase Handberg
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - Søren Gregersen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Torben Harsløf
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Steen Bønløkke Pedersen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Vestergaard
- Steno Diabetes Center North Jutland, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Bente Lomholt Langdahl
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
35
|
Fuglsang-Nielsen R, Rakvaag E, Vestergaard P, Hermansen K, Gregersen S, Starup-Linde J. The Effects of 12-Weeks Whey Protein Supplements on Markers of Bone Turnover in Adults With Abdominal Obesity - A Post Hoc Analysis. Front Endocrinol (Lausanne) 2022; 13:832897. [PMID: 35422766 PMCID: PMC9001834 DOI: 10.3389/fendo.2022.832897] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND While osteoporosis is characterized by skeletal fragility due to increased bone turnover and low bone mineral density (BMD), subjects with abdominal obesity and type-2 diabetes have increased risk of bone fractures despite low bone turnover and increased BMD. Diets with increased protein content are reported to increase bone turnover in healthy adults and may be a point of interest in preserving bone strength in subjects with abdominal obesity and/or type-2 diabetes. METHODS We examined the effect of 12-weeks dietary intervention on bone turnover in 64 adults with abdominal obesity using data from the MERITS trial. The trial was a randomized, controlled, double blinded study in which participants were allocated to receive either 60 g/d of whey protein hydrolysate or maltodextrin in combination with either high (30 g/d) or low dietary fiber intake (10 g/d). Primarily, we assessed changes in plasma markers of bone turnover Procollagen type 1 N-terminal propeptide (p1NP), C-terminal telopeptide type-1 collagen (CTX), and parathyroid hormone (PTH) within the four intervention groups. In addition, we measured u-calcium and u-carbamide excretion, 25(OH)D, and BMD by whole body DXA scans. Finally, we compared changes in insulin resistance (Homeostasis-model assessment of insulin resistance, HOMA-IR) with changes in bone turnover markers.The trial was registered at www.clinicaltrials.gov as NCT02931630. RESULTS Sixty-four subjects were included in the study. We did not find any effect of twelve weeks of high protein or high fiber intake on plasma levels of P1NP or CTX. There was a nonsignificant positive association between protein intake and PTH levels (p=0.06). U-calcium and u-carbamide increased in both protein groups. There was a positive association between change in HOMA-IR and PTH (p=0.042), while changes in P1NP and CTX did not associate to changes in HOMA-IR. CONCLUSION Twelve weeks of increased whey protein intake in subjects with abdominal obesity did not affect markers of bone turnover significantly, although tended to increase PTH levels. Dietary fiber intake did not affect bone turnover. We report a positive association between change in HOMA-IR and PTH supporting a hypothesis of insulin resistance as a potential key factor in the expanding field of bone fragility in T2D subjects.
Collapse
Affiliation(s)
- Rasmus Fuglsang-Nielsen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- *Correspondence: Rasmus Fuglsang-Nielsen,
| | - Elin Rakvaag
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Vestergaard
- Steno Diabetes Center North Jutland, Aalborg University Hospital, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Kjeld Hermansen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Søren Gregersen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Jakob Starup-Linde
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
36
|
Abstract
Bone fragility fractures remain an important worldwide health and economic problem due to increased morbidity and mortality. The current methods for predicting fractures are largely based on the measurement of bone mineral density and the utilization of mathematical risk calculators based on clinical risk factors for bone fragility. Despite these approaches, many bone fractures remain undiagnosed. Therefore, current research is focused on the identification of new factors such as bone turnover markers (BTM) for risk calculation. BTM are a group of proteins and peptides released during bone remodeling that can be found in serum or urine. They derive from bone resorptive and formative processes mediated by osteoclasts and osteoblasts, respectively. Potential use of BTM in monitoring these phenomenon and therefore bone fracture risk is limited by physiologic and pathophysiologic factors that influence BTM. These limitations in predicting fractures explain why their inclusion in clinical guidelines remains limited despite the large number of studies examining BTM.
Collapse
Affiliation(s)
- Lisa Di Medio
- Department of Surgery and Translational Medicine, University Hospital of Florence, Florence, Italy.
| | - Maria Luisa Brandi
- Department of Surgery and Translational Medicine, University Hospital of Florence, Florence, Italy
| |
Collapse
|
|
37
|
Sharma DK, Anderson PH, Morris HA, Clifton PM. Acute CTX-1 Suppression With Milk Calcium or Calcium Carbonate is Independent of Visceral Fat in A Randomized Crossover Study in Lean and Overweight Postmenopausal Women. J Nutr 2021; 152:1006-1014. [PMID: 36967157 DOI: 10.1093/jn/nxab384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/24/2021] [Accepted: 11/01/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Postmenopausal women with higher visceral adipose tissue (VAT) present with suppressed bone resorption (lower c-terminal cross-linking telopeptide of type I collagen, CTX-1) and turnover (lower osteocalcin) but whether this blunts the effect of calcium is unknown. OBJECTIVE The primary outcome of this study was the effect of VAT on changes in CTX-1 after intake of two forms of calcium. Secondary outcomes included changes in parathyroid hormone (PTH), serum calcium, phosphorus, and alkaline phosphatase (ALP). DESIGN Randomized open three period crossover trial conducted between 2017-2019 at the University of South Australia among 77 lean and overweight postmenopausal women (53-79 y) with body mass index (BMI) less than 25 kg/m2 and greater than 27 kg/m2, respectively. Participants received a single dose of milk (1000 mg calcium), calcium carbonate tablet (1000 mg calcium), and fruit juice (no calcium) in random order with a seven-day washout period. Blood samples were collected at baseline and hourly for 5h. Data was analysed by repeated measures analysis of variance (ANOVA) of log-transformed data. RESULTS At baseline, women with higher VAT had significantly lower CTX-1 and higher PTH (44% lower and 30% higher, respectively between Q4 and Q1, P < 0.0001). VAT had no influence on the acute changes in CTX-1 or PTH with calcium or juice. A suppression of 44% in CTX-1 was seen with calcium carbonate and milk and a suppression of 18% with juice. PTH was suppressed more with calcium carbonate (47%) compared to milk (22%). Milk calcium reduced PTH and CTX-1 at 2-hour while calcium carbonate reduced PTH in 1 hour. The suppression in CTX-1 was slower with lowest levels at 4-5 hour. CONCLUSIONS 1000 mg calcium obtained from milk or from calcium carbonate is effective in acutely suppressing bone resorption in postmenopausal women irrespective of visceral fat.This trial is registered with the Australian New Zealand Clinical Trials Registry http://www.ANZCTR.org.au/ACTRN12617000779370.aspx (ACTRN 12617000779370).
Collapse
Affiliation(s)
- Deepti K Sharma
- Clinical and Health Sciences Academic Unit, University of South Australia, Adelaide, Australia.,Department of Orthopaedics and Trauma, Royal Adelaide Hospital
| | - Paul H Anderson
- Clinical and Health Sciences Academic Unit, University of South Australia, Adelaide, Australia
| | - Howard A Morris
- Clinical and Health Sciences Academic Unit, University of South Australia, Adelaide, Australia
| | - Peter M Clifton
- Clinical and Health Sciences Academic Unit, University of South Australia, Adelaide, Australia
| |
Collapse
|
|
38
|
Skov-Jeppesen K, Veedfald S, Madsbad S, Holst JJ, Rosenkilde MM, Hartmann B. Subcutaneous GIP and GLP-2 inhibit nightly bone resorption in postmenopausal women: A preliminary study. Bone 2021; 152:116065. [PMID: 34153529 DOI: 10.1016/j.bone.2021.116065] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/10/2021] [Accepted: 06/14/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted in response to food ingestion, and they have been suggested to regulate bone turnover. In humans, exogenous GIP and GLP-2 acutely inhibit bone resorption as measured by circulating levels of carboxy-terminal type 1 collagen crosslinks (CTX). OBJECTIVE The objective was to study the individual and combined acute effects of GIP and GLP-2 on bone turnover in postmenopausal women during nighttime - a period of increased bone resorption. METHODS Using a randomized, placebo-controlled, double-blinded, crossover design, each participant (n = 9) received on four separate study days: GIP, GLP-2, GIP + GLP-2, and placebo (saline) as subcutaneous injections at bedtime. Main outcomes were levels of CTX and procollagen type 1 N-terminal propeptide (P1NP). RESULTS Compared with placebo, GIP and GLP-2 alone significantly inhibited bone resorption (measured by CTX). GIP rapidly reduced CTX levels in the period from 45 to 120 min after injection, while GLP-2 had a more delayed effect with reduced CTX levels in the period from 120 to 240 min after injection. Combining GIP and GLP-2 showed complementary effects resulting in a sustained inhibition of CTX with reduced levels from 45 to 240 min after injection. Furthermore, GIP acutely increased bone formation (measured by P1NP). CONCLUSION Both GIP and GLP-2 reduced CTX during the night and had complementary effects when combined.
Collapse
Affiliation(s)
- Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Simon Veedfald
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Department of Endocrinology, Hvidovre University Hospital, Kettegaard Alle 30, 2650 Hvidovre, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre University Hospital, Kettegaard Alle 30, 2650 Hvidovre, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
| |
Collapse
|
|
39
|
Zheng Q, Kernozek T, Daoud-Gray A, Borer KT. Anabolic Bone Stimulus Requires a Pre-Exercise Meal and 45-Minute Walking Impulse of Suprathreshold Speed-Enhanced Momentum to Prevent or Mitigate Postmenopausal Osteoporosis within Circadian Constraints. Nutrients 2021; 13:nu13113727. [PMID: 34835982 PMCID: PMC8620686 DOI: 10.3390/nu13113727] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 10/05/2021] [Accepted: 10/18/2021] [Indexed: 01/22/2023] Open
Abstract
Osteoporosis currently afflicts 8 million postmenopausal women in the US, increasing the risk of bone fractures and morbidity, and reducing overall quality of life. We sought to define moderate exercise protocols that can prevent postmenopausal osteoporosis. Our previous findings singled out higher walking speed and pre-exercise meals as necessary for suppression of bone resorption and increasing of markers of bone formation. Since both studies were amenable to alternate biomechanical, nutritional, and circadian interpretations, we sought to determine the relative importance of higher speed, momentum, speed-enhanced load, duration of impulse, and meal timing on osteogenic response. We hypothesized that: (1) 20 min of exercise one hour after eating is sufficient to suppress bone resorption as much as a 40-min impulse and that two 20 min exercise bouts separated by 7 h would double the anabolic effect; (2) early morning exercise performed after eating will be as effective as mid-day exercise for anabolic outcome; and (3) the 08:00 h 40-min. exercise uphill would be as osteogenic as the 40-min exercise downhill. Healthy postmenopausal women, 8 each, were assigned to a no-exercise condition (SED) or to 40- or 20-min exercise bouts, spaced 7 h apart, for walking uphill (40 Up and 20 Up) or downhill (40 Down and 20 Down) to produce differences in biomechanical variables. Exercise was initiated at 08:00 h one hour after eating in 40-min groups, and also 7 h later, two hours after the midday meal, in 20-min groups. Measurements were made of CICP (c-terminal peptide of type I collagen), osteocalcin (OC), and bone-specific alkaline phosphatase (BALP), markers of bone formation, and of the bone resorptive marker CTX (c-terminal telopeptide of type 1 collagen). The osteogenic ratios CICP/CTX, OC/CTX, and BALP/CTX were calculated. Only the 40-min downhill exercise of suprathreshold speed-enhanced momentum, increased the three osteogenic ratios, demonstrating the necessity of a 40-min, and inadequacy of a 20-min, exercise impulse. The failure of anabolic outcome in 40-min uphill exercise was attributed to a sustained elevation of PTH concentration, as its high morning elevation enhances the CTX circadian rhythm. We conclude that postmenopausal osteoporosis can be prevented or mitigated in sedentary women by 45 min of morning exercise of suprathreshold speed-enhanced increased momentum performed shortly after a meal while walking on level ground, or by 40-min downhill, but not 40-min uphill, exercise to avoid circadian PTH oversecretion. The principal stimulus for the anabolic effect is exercise, but the prerequisite for a pre-exercise meal demonstrates the requirement for nutrient facilitation.
Collapse
Affiliation(s)
- Qingyun Zheng
- School of Kinesiology, The University of Michigan, Ann Arbor, MI 48109, USA; (A.D.-G.); (K.T.B.)
- School of Physical Education, Henan University, Kaifeng 475004, China
- Correspondence: ; Tel.: +86-138-4915-1204
| | - Thomas Kernozek
- Physical Therapy Program, Department of Health Professions, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA;
| | - Adam Daoud-Gray
- School of Kinesiology, The University of Michigan, Ann Arbor, MI 48109, USA; (A.D.-G.); (K.T.B.)
| | - Katarina T. Borer
- School of Kinesiology, The University of Michigan, Ann Arbor, MI 48109, USA; (A.D.-G.); (K.T.B.)
| |
Collapse
|
|
40
|
Associations between Postprandial Gut Hormones and Markers of Bone Remodeling. Nutrients 2021; 13:nu13093197. [PMID: 34579074 PMCID: PMC8467604 DOI: 10.3390/nu13093197] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/06/2021] [Accepted: 09/10/2021] [Indexed: 01/31/2023] Open
Abstract
Gut-derived hormones have been suggested to play a role in bone homeostasis following food intake, although the associations are highly complex and not fully understood. In a randomized, two-day cross-over study on 14 healthy individuals, we performed postprandial time-course studies to examine the associations of the bone remodeling markers carboxyl-terminal collagen type I crosslinks (CTX) and procollagen type 1 N-terminal propeptide (P1NP) with the gut hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) using two different meal types-a standardized mixed meal (498 kcal) or a granola bar (260 kcal). Plasma concentrations of total GIP, total GLP-1, total PYY, CTX, and P1NP were measured up to 240 min after meal intake, and the incremental area under the curve (iAUC) for each marker was calculated. The iAUC of CTX and P1NP were used to assess associations with the iAUC of GIP, GLP-1, and PYY in linear mixed effect models adjusted for meal type. CTX was positively associated with GIP and GLP-1, and it was inversely associated with PYY (all p < 0.001). No associations of P1NP with GIP or GLP-1 and PYY were found. In conclusion, the postprandial responses of the gut hormones GIP, GLP-1, and PYY are associated with the bone resorption marker CTX, supporting a link between gut hormones and bone homeostasis following food intake.
Collapse
|
|
41
|
Proia P, Amato A, Drid P, Korovljev D, Vasto S, Baldassano S. The Impact of Diet and Physical Activity on Bone Health in Children and Adolescents. Front Endocrinol (Lausanne) 2021; 12:704647. [PMID: 34589054 PMCID: PMC8473684 DOI: 10.3389/fendo.2021.704647] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 08/13/2021] [Indexed: 12/15/2022] Open
Abstract
There is growing recognition of the role of diet and physical activity in modulating bone mineral density, bone mineral content, and remodeling, which in turn can impact bone health later in life. Adequate nutrient composition could influence bone health and help to maximize peak bone mass. Therefore, children's nutrition may have lifelong consequences. Also, physical activity, adequate in volume or intensity, may have positive consequences on bone mineral content and density and may preserve bone loss in adulthood. Most of the literature that exists for children, about diet and physical activity on bone health, has been translated from studies conducted in adults. Thus, there are still many unanswered questions about what type of diet and physical activity may positively influence skeletal development. This review focuses on bone requirements in terms of nutrients and physical activity in childhood and adolescence to promote bone health. It explores the contemporary scientific literature that analyzes the impact of diet together with the typology and timing of physical activity that could be more appropriate depending on whether they are children and adolescents to assure an optimal skeleton formation. A description of the role of parathyroid hormone (PTH) and gut hormones (gastric inhibitory peptide (GIP), glucagon-like peptide (GLP)-1, and GLP-2) as potential candidates in this interaction to promote bone health is also presented.
Collapse
Affiliation(s)
- Patrizia Proia
- Department of Psychological, Pedagogical and Educational Sciences, Sport and Exercise Sciences Research Unit, University of Palermo, Palermo, Italy
| | - Alessandra Amato
- Department of Psychological, Pedagogical and Educational Sciences, Sport and Exercise Sciences Research Unit, University of Palermo, Palermo, Italy
| | - Patrik Drid
- Faculty of Sport and Physical Education, University of Novi Sad, Novi Sad, Serbia
| | - Darinka Korovljev
- Faculty of Sport and Physical Education, University of Novi Sad, Novi Sad, Serbia
| | - Sonya Vasto
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Sara Baldassano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| |
Collapse
|
|
42
|
Skov‐Jeppesen K, Hepp N, Oeke J, Hansen MS, Jafari A, Svane MS, Balenga N, Olson JA, Frost M, Kassem M, Madsbad S, Beck Jensen J, Holst JJ, Rosenkilde MM, Hartmann B. The Antiresorptive Effect of GIP, But Not GLP-2, Is Preserved in Patients With Hypoparathyroidism-A Randomized Crossover Study. J Bone Miner Res 2021; 36:1448-1458. [PMID: 33852173 PMCID: PMC8338760 DOI: 10.1002/jbmr.4308] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/17/2021] [Accepted: 04/08/2021] [Indexed: 01/20/2023]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP- and GLP-2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed-meal test (n = 7) followed by a peptide injection test (n = 4) using a randomized crossover design. We observed that the meal- and GIP- but not the GLP-2-induced changes in bone turnover markers were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP-2 receptor (GLP-2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP-2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP-2R were expressed in parathyroid tissue. Our findings suggest that the GIP-induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP-2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP-2R in the parathyroid gland. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Collapse
Affiliation(s)
- Kirsa Skov‐Jeppesen
- Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
| | - Nicola Hepp
- Department of EndocrinologyHvidovre University HospitalHvidovreDenmark
| | - Jannika Oeke
- Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Morten Steen Hansen
- Molecular Endocrinology Unit (KMEB), Department of EndocrinologyOdense University HospitalOdenseDenmark
| | - Abbas Jafari
- Department of Cellular and Molecular Medicine, Novo Nordisk Foundation Center for Stem Cell Biology (Danstem)University of CopenhagenCopenhagenDenmark
| | - Maria Saur Svane
- Department of EndocrinologyHvidovre University HospitalHvidovreDenmark
| | - Nariman Balenga
- Division of General and Oncologic Surgery, Department of Surgery, Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of Maryland School of MedicineBaltimoreMDUSA
| | - John A Olson
- Division of General and Oncologic Surgery, Department of Surgery, Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of Maryland School of MedicineBaltimoreMDUSA
| | - Morten Frost
- Molecular Endocrinology Unit (KMEB), Department of EndocrinologyOdense University HospitalOdenseDenmark
| | - Moustapha Kassem
- Molecular Endocrinology Unit (KMEB), Department of EndocrinologyOdense University HospitalOdenseDenmark
- Department of Cellular and Molecular Medicine, Novo Nordisk Foundation Center for Stem Cell Biology (Danstem)University of CopenhagenCopenhagenDenmark
| | - Sten Madsbad
- Department of EndocrinologyHvidovre University HospitalHvidovreDenmark
| | - Jens‐Erik Beck Jensen
- Department of EndocrinologyHvidovre University HospitalHvidovreDenmark
- Department of Clinical MedicineUniversity of CopenhagenCopenhagenDenmark
| | - Jens Juul Holst
- Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
| | | | - Bolette Hartmann
- Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
| |
Collapse
|
|
43
|
Hansen MS, Frost M. Alliances of the gut and bone axis. Semin Cell Dev Biol 2021; 123:74-81. [PMID: 34303607 DOI: 10.1016/j.semcdb.2021.06.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/27/2021] [Accepted: 06/28/2021] [Indexed: 12/12/2022]
Abstract
Gut hormones secreted from enteroendocrine cells following nutrient ingestion modulate metabolic processes including glucose homeostasis and food intake, and several of these gut hormones are involved in the regulation of the energy demanding process of bone remodelling. Here, we review the gut hormones considered or known to be involved in the gut-bone crosstalk and their role in orchestrating adaptions of bone formation and resorption as demonstrated in cellular and physiological experiments and clinical trials. Understanding the physiology and pathophysiology of the gut-bone axis may identify adverse effects of investigational drugs aimed to treat metabolic diseases such as type 2 diabetes and obesity and new therapeutic candidates for the treatment of bone diseases.
Collapse
Affiliation(s)
- Morten Steen Hansen
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark
| | - Morten Frost
- Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark.
| |
Collapse
|
|
44
|
Kreitman A, Schneider SH, Hao L, Schlussel Y, Bello NT, Shapses SA. Reduced postprandial bone resorption and greater rise in GLP-1 in overweight and obese individuals after an α-glucosidase inhibitor: a double-blinded randomized crossover trial. Osteoporos Int 2021; 32:1379-1386. [PMID: 33432459 DOI: 10.1007/s00198-020-05791-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022]
Abstract
UNLABELLED When taken with a meal, α-glucosidase inhibitors (α-GI) reduce the rise in postprandial glucose and increase glucagon-like peptide-1 (GLP-1), and this may lower bone turnover. In this study, a salacinol-type α-GI increased GLP-1 and markedly reduced postprandial bone resorption compared to placebo, suggesting it could have implications for bone health. INTRODUCTION Animal and clinical trials indicate that α-glucosidase inhibitors attenuate postprandial glycemic indices and increase secretion of GLP-1. In addition, GLP-1 acts on bone by inhibiting resorption. The goal in this study was to determine if a salacinol α-GI alters postprandial bone turnover and can be explained by changes in serum GLP-1. METHODS In this double-blind, placebo-controlled crossover study, healthy overweight/obese adults (body mass index 29.0 ± 3.8 kg/m2; 21-59 years; n = 21) received a fixed breakfast and, in random order, were administered Salacia chinensis (SC; 500 mg) or placebo. A fasting blood sample was taken before and at regular intervals for 3 h after the meal. Serum was measured for bone turnover markers, C-terminal telopeptide of type I collagen (CTX) and osteocalcin, and for glycemic indices and gut peptides. RESULTS Compared to placebo, SC attenuated the bone resorption marker, CTX, at 60, 90, and 120 min (p < 0.05) after the meal, and decreased osteocalcin, at 180 min (p < 0.05). As expected, SC attenuated the postprandial rise in glucose compared with placebo, whereas GLP-1 was increased at 60 min (p < 0.05) with SC. Serum GLP-1 explained 41% of the variance for change in postprandial CTX (p < 0.05). CONCLUSION This study indicates that attenuating postprandial glycemic indices, with an α-GI, markedly decreases postprandial bone resorption and can be explained by the rise in GLP-1. Future studies should determine whether longer term α-GI use benefits bone health.
Collapse
Affiliation(s)
- A Kreitman
- Department of Nutritional Sciences, Rutgers University, 59 Dudley RD, New Brunswick, NJ, 08901, USA
| | - S H Schneider
- Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Rutgers-Robert Wood Johnson University Hospital, New Brunswick, NJ, 08901, USA
- NJ-Institute of Food, Nutrition and Health, New Brunswick, NJ, 08901, USA
| | - L Hao
- Department of Nutritional Sciences, Rutgers University, 59 Dudley RD, New Brunswick, NJ, 08901, USA
- NJ-Institute of Food, Nutrition and Health, New Brunswick, NJ, 08901, USA
| | - Y Schlussel
- Department of Nutritional Sciences, Rutgers University, 59 Dudley RD, New Brunswick, NJ, 08901, USA
| | - N T Bello
- NJ-Institute of Food, Nutrition and Health, New Brunswick, NJ, 08901, USA
- Department of Animal Sciences, Rutgers University, New Brunswick, NJ, 08901, USA
| | - S A Shapses
- Department of Nutritional Sciences, Rutgers University, 59 Dudley RD, New Brunswick, NJ, 08901, USA.
- Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, Rutgers-Robert Wood Johnson University Hospital, New Brunswick, NJ, 08901, USA.
- NJ-Institute of Food, Nutrition and Health, New Brunswick, NJ, 08901, USA.
| |
Collapse
|
|
45
|
Kitaura H, Ogawa S, Ohori F, Noguchi T, Marahleh A, Nara Y, Pramusita A, Kinjo R, Ma J, Kanou K, Mizoguchi I. Effects of Incretin-Related Diabetes Drugs on Bone Formation and Bone Resorption. Int J Mol Sci 2021; 22:ijms22126578. [PMID: 34205264 PMCID: PMC8234693 DOI: 10.3390/ijms22126578] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Patients with type 2 diabetes have an increased risk of fracture compared to the general population. Glucose absorption is accelerated by incretin hormones, which induce insulin secretion from the pancreas. The level of the incretin hormone, glucagon-like peptide-1 (GLP-1), shows an immediate postprandial increase, and the circulating level of intact GLP-1 is reduced rapidly by dipeptidyl peptidase-4 (DPP-4)-mediated inactivation. Therefore, GLP-1 receptor agonists and DPP-4 inhibitors are effective in the treatment of type 2 diabetes. However, these incretin-related diabetic agents have been reported to affect bone metabolism, including bone formation and resorption. These agents enhance the expression of bone markers, and have been applied to improve bone quality and bone density. In addition, they have been reported to suppress chronic inflammation and reduce the levels of inflammatory cytokine expression. Previously, we reported that these incretin-related agents inhibited both the expression of inflammatory cytokines and inflammation-induced bone resorption. This review presents an overview of current knowledge regarding the effects of incretin-related diabetes drugs on osteoblast differentiation and bone formation as well as osteoclast differentiation and bone resorption. The mechanisms by which incretin-related diabetes drugs regulate bone formation and bone resorption are also discussed.
Collapse
|
|
46
|
Bjørnshave A, Lykkeboe S, Hartmann B, Holst JJ, Hermansen K, Starup-Linde J. Effects of a whey protein pre-meal on bone turnover in participants with and without type 2 diabetes-A post hoc analysis of a randomised, controlled, crossover trial. Diabet Med 2021; 38:e14471. [PMID: 33259643 DOI: 10.1111/dme.14471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/23/2020] [Accepted: 11/27/2020] [Indexed: 12/28/2022]
Abstract
AIMS Whey protein may improve bone turnover and have anti-osteoporotic effects. The aim of the present randomised, controlled, crossover trial was to evaluate the effects of a whey protein pre-meal on bone turnover in people with type 2 diabetes and controls. METHODS Two groups, matched on sex, age and body mass index, comprising 12 participants with and 12 participants without type 2 diabetes were randomly given a pre-meal of whey protein (20 g) or water, which was consumed 15 min before a fat-rich meal or a fat-rich meal supplemented with 20 g whey protein. During a 360-min period, postprandial responses in bone turnover were examined. RESULTS Osteocalcin, P-procollagen type 1 amino terminal propeptide (P1NP), C-terminal cross-linked telopeptide of type-I collagen (CTX) and parathyroid hormone (PTH) were lower at baseline and PTH, osteocalcin and P1NP were lower during the entire postprandial phase in participants with type 2 diabetes than in participants without type 2 diabetes. We observed similar postprandial responses in bone turnover markers between persons with and without type 2 diabetes. We observed no effect of the whey protein or the water pre-meal on bone turnover markers. The changes were unrelated to secretion of hormones of the gut-bone axis. CONCLUSION Osteocalcin, P1NP, CTX and PTH all decreased following meal ingestion. We observed no convincing effect of a whey protein pre-meal on bone turnover. However, these results confirm that people with type 2 diabetes have low bone turnover and that the decreased bone formation markers are also extend into the postprandial responses.
Collapse
Affiliation(s)
- Ann Bjørnshave
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C, Denmark
- Danish Diabetes Academy, Odense, Denmark
| | - Simon Lykkeboe
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Bolette Hartmann
- NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kjeld Hermansen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C, Denmark
| | - Jakob Starup-Linde
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C, Denmark
| |
Collapse
|
|
47
|
Lafferty RA, O’Harte FPM, Irwin N, Gault VA, Flatt PR. Proglucagon-Derived Peptides as Therapeutics. Front Endocrinol (Lausanne) 2021; 12:689678. [PMID: 34093449 PMCID: PMC8171296 DOI: 10.3389/fendo.2021.689678] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022] Open
Abstract
Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.
Collapse
Affiliation(s)
| | | | | | - Victor A. Gault
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | | |
Collapse
|
|
48
|
Amato A, Proia P, Caldara GF, Alongi A, Ferrantelli V, Baldassano S. Analysis of Body Perception, Preworkout Meal Habits and Bone Resorption in Child Gymnasts. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18042184. [PMID: 33672264 PMCID: PMC7926894 DOI: 10.3390/ijerph18042184] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 12/13/2022]
Abstract
The beneficial effects of physical activity on body image perception and bone are debated among artistic gymnasts. Gymnasts seem to be at greater risk of developing body dissatisfaction, eating disorders and osteoporosis due to inadequate nutrition and attention to the appearance of the body. The objective of this work was to investigate the association between the artistic gymnast and a more favorable body image compared to their sedentary peers and if a preworkout high-carbohydrate meal (HCM; 300 kcal, 88% carbohydrates, 9% protein, 3% fat) or high-protein meal (HPM; 300 kcal, 55% carbohydrates, 31% protein, 13% fat) is able to attenuate bone resorption in young rhythmic gymnasts. Twenty-eight preadolescent female gymnasts were examined. Self-esteem tests were used to analyze body image perception. Preworkout eating habits were examined by short food frequency questions (FFQ) validated for children. The biomarker of the bone resorption C-terminal telopeptide region of collagen type 1 (CTX) was measured in the urine (fasting, postmeal and postworkout). Gymnasts reported higher satisfaction with their body appearance compared to sedentary peers. Of the gymnasts, 30% did not have a preworkout meal regularly, and the timing of the consumption was variable. Bone resorption was decreased by the HCM, consumed 90 min before the training, with respect to the HPM. The study suggests that playing artistic gymnastics is associated with a positive body self-perception in a child. The variability in preworkout meal frequency and timing need attention to prevent inadequate eating habits in light of the ability of the HCM to reduce acute bone resorption.
Collapse
Affiliation(s)
- Alessandra Amato
- Department of Psychological, Pedagogical and Educational Sciences, Sport and Exercise Sciences Research Unit, University of Palermo, 90128 Palermo, Italy; (A.A.); (P.P.)
| | - Patrizia Proia
- Department of Psychological, Pedagogical and Educational Sciences, Sport and Exercise Sciences Research Unit, University of Palermo, 90128 Palermo, Italy; (A.A.); (P.P.)
| | - Gaetano Felice Caldara
- Istituto Zooprofilattico Sperimentale della Sicilia, 90129 Palermo, Italy; (G.F.C.); (A.A.); (V.F.)
- Department of Sciences for Health Promotion and Mother and Child Care “G. D’Alessandro”, University of Palermo, 90127 Palermo, Italy
| | - Angelina Alongi
- Istituto Zooprofilattico Sperimentale della Sicilia, 90129 Palermo, Italy; (G.F.C.); (A.A.); (V.F.)
| | - Vincenzo Ferrantelli
- Istituto Zooprofilattico Sperimentale della Sicilia, 90129 Palermo, Italy; (G.F.C.); (A.A.); (V.F.)
| | - Sara Baldassano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90128 Palermo, Italy
- Correspondence:
| |
Collapse
|
|
49
|
Abildgaard J, Ploug T, Pedersen AT, Eiken P, Pedersen BK, Holst JJ, Hartmann B, Lindegaard B. Preserved postprandial suppression of bone turnover markers, despite increased fasting levels, in postmenopausal women. Bone 2021; 143:115612. [PMID: 32853851 DOI: 10.1016/j.bone.2020.115612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/12/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023]
Abstract
CONTEXT Menopause leads to an increased bone turnover associated with a high risk of fractures. Bone turnover is inhibited by meal intake, to some extent mediated by gut hormones, and interventions based on these endocrine changes may have potential in future prevention of osteoporosis. OBJECTIVE To investigate whether postmenopausal women exhibit postprandial suppression of bone turnover markers to the same extent as premenopausal women, despite higher fasting levels. Furthermore, to assess whether menopausal differences in bone turnover markers are related to postmenopausal changes in plasma gut hormone levels. METHODS A cross-sectional study of 21 premenopausal, 9 perimenopausal, and 24 postmenopausal women between 45 and 60 years of age. Serum/plasma levels of bone turnover markers and gut hormones were investigated during a 120 min oral glucose tolerance test. Bone turnover markers included N-terminal propeptide of type-I procollagen (PINP, bone formation marker) and carboxyterminal collagen I crosslinks (CTX-I, bone resorption marker). Gut hormone secretion was evaluated from responses of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP). RESULTS Fasting levels of s-CTX-I were increased in peri- and postmenopausal women compared to premenopausal women (p = 0.001). Despite higher fasting levels, the relative postprandial s-CTX-I suppression was comparable across menopausal status (p = 0.14). Fasting levels of s-PINP were also increased in postmenopausal women compared to premenopausal women (p < 0.001) with comparable and modest s-PINP suppression over menopause (p = 0.13). Postprandial plasma GLP-1 (p = 0.006) and GLP-2 (p = 0.01) were significantly increased in postmenopausal women compared to premenopausal women while GIP responses were slightly increased in the perimenopausal group (p = 0.02) but comparable between pre- and postmenopausal women. None of the postprandial gut hormone increases predicted postprandial bone turnover suppression in these women. CONCLUSIONS Glucose-induced suppression of bone turnover markers is preserved in postmenopausal women, despite significantly higher fasting values, indicating that CTX-I lowering treatments based on these postprandial mechanisms might be a feasible strategy to prevent postmenopausal osteoporosis.
Collapse
Affiliation(s)
- Julie Abildgaard
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark; Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Denmark.
| | - Thorkil Ploug
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Anette Tønnes Pedersen
- Department of Gynaecology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Pia Eiken
- Department of Nephrology and Endocrinology, Nordsjællands Hospital, Hillerød, Denmark
| | - Bente Klarlund Pedersen
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Birgitte Lindegaard
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark; Department of Pulmonary and Infectious Diseases, Nordsjællands Hospital, Hillerød, Denmark.
| |
Collapse
|
|
50
|
Mieczkowska A, Bouvard B, Legrand E, Mabilleau G. [Gly²]-GLP-2, But Not Glucagon or [D-Ala²]-GLP-1, Controls Collagen Crosslinking in Murine Osteoblast Cultures. Front Endocrinol (Lausanne) 2021; 12:721506. [PMID: 34421828 PMCID: PMC8371440 DOI: 10.3389/fendo.2021.721506] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/16/2021] [Indexed: 11/23/2022] Open
Abstract
Bone tissue is organized at the molecular level to resist fracture with the minimum of bone material. This implies that several modifications of the extracellular matrix, including enzymatic collagen crosslinking, take place. We previously highlighted the role of several gut hormones in enhancing collagen maturity and bone strength. The present study investigated the effect of proglucagon-derived peptides on osteoblast-mediated collagen post-processing. Briefly, MC3T3-E1 murine osteoblasts were cultured in the presence of glucagon (GCG), [D-Ala²]-glucagon-like peptide-1 ([D-Ala²]-GLP-1), and [Gly²]-glucagon-like peptide-2 ([Gly²]-GLP-2). Gut hormone receptor expression at the mRNA and protein levels were investigated by qPCR and Western blot. Extent of collagen postprocessing was examined by Fourier transform infrared microspectroscopy. GCG and GLP-1 receptors were not evidenced in osteoblast cells at the mRNA and protein levels. However, it is not clear whether the known GLP-2 receptor is expressed. Nevertheless, administration of [Gly²]-GLP-2, but not GCG or [D-Ala²]-GLP-1, led to a dose-dependent increase in collagen maturity and an acceleration of collagen post-processing. This mechanism was dependent on adenylyl cyclase activation. In conclusion, the present study highlighted a direct effect of [Gly²]-GLP-2 to enhance collagen post-processing and crosslinking maturation in murine osteoblast cultures. Whether this effect is translatable to human osteoblasts remains to be elucidated.
Collapse
Affiliation(s)
| | - Beatrice Bouvard
- Univ Angers, GEROM, SFR ICAT, Angers, France
- CHU Angers, Rheumatology Department, Angers, France
| | - Erick Legrand
- Univ Angers, GEROM, SFR ICAT, Angers, France
- CHU Angers, Rheumatology Department, Angers, France
| | - Guillaume Mabilleau
- Univ Angers, GEROM, SFR ICAT, Angers, France
- CHU Angers, Bone Pathology Unit, Angers, France
- *Correspondence: Guillaume Mabilleau,
| |
Collapse
|