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Psachna S, Chondrogianni ME, Stathopoulos K, Polymeris A, Chatzigeorgiou A, Chronopoulos E, Tournis S, Kassi E. The effect of antidiabetic drugs on bone metabolism: a concise review. Endocrine 2025; 87:907-919. [PMID: 39402366 DOI: 10.1007/s12020-024-04070-1] [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: 04/29/2024] [Accepted: 10/06/2024] [Indexed: 01/06/2025]
Abstract
Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, which derives from either insufficient insulin production [type 1 diabetes mellitus (T1DM)] or both impaired insulin sensitivity along with inadequate insulin production [type 2 diabetes mellitus (T2DM)] and affects millions of people worldwide. In addition to the adverse effects of DM on classical target organs and tissues, skeletal health can also be adversely affected. There is considerable evidence linking DM with osteoporosis. The fracture risk in patients with DM differs upon the type of diabetes, and it appears to be related to the type of anti-diabetic treatment. Antidiabetic drugs may have various effects on bone health. Most of them have neutral or even favorable effects on bone metabolism with the exception of thiazolidinediones (TZDs). Some studies suggest that TZDs may have negative impact on bone health by decreasing bone formation and increasing the fracture risk. There are also limited studies linking the use of canagliflozin, a Sodium-glucose contransporter-2 inhibitor (SGLT2i), with increased fracture risk. On the other hand, therapies that are based on incretin effect, like Dipeptidyl peptidase-4 inhibitors (DPP-4i) and Glucagon-like peptide-1 receptor agonizts (GLP-1RAs) might have positive effects on bone health by promoting bone formation. Herein we review the impact of antidiabetic drugs on bone health, highlighting the potential benefits and risks associated with these medications in an attempt to contribute to the development of personalized treatment strategies for individuals with DM.
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Affiliation(s)
- Stavroula Psachna
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Department of Endocrinology, Metabolism and Diabetes Mellitus, Attica General Hospital "Sismanoglio-Amalia Fleming", Athens, Greece
| | - Maria Eleni Chondrogianni
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, Medical Scool, National and Kapodistrian University of Athens, Athens, Greece
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Stathopoulos
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonis Polymeris
- Department of Endocrinology, Metabolism and Diabetes Mellitus, Attica General Hospital "Sismanoglio-Amalia Fleming", Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Efstathios Chronopoulos
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Symeon Tournis
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Laboratory for Research of the Musculoskeletal System, KAT Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, Medical Scool, National and Kapodistrian University of Athens, Athens, Greece.
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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Chen L, Xu T, Wang J, Wang Z, Pan Y, Kong L. Siwu tablet attenuates high fructose-induced glomerular podocyte senescence in rats through increasing Nup155 to promote INO80 mRNA nuclear export. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118878. [PMID: 39362331 DOI: 10.1016/j.jep.2024.118878] [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: 06/05/2024] [Revised: 08/23/2024] [Accepted: 09/30/2024] [Indexed: 10/05/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Siwu tablet (SWT), derived from a traditional Chinese medicinal formula named Siwu decoction, is widely used for blood deficiency syndrome. Siwu decoction and its derived formulas have been proven to improve renal anemia and prevent senescence. Whether SWT prevents glomerular podocyte senescence and the underlying molecular mechanism remains unknow. AIM OF THE STUDY To elucidate the protective effect and possible mechanism of SWT on glomerular podocyte senescence. MATERIAL AND METHODS Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to characterize components of SWT. Male Sprague-Dawley rats were given 10% fructose drinking water for 16 weeks. SWT (810 and 1620 mg/kg) was administered orally for the last 8 weeks. The assays of senescence-associated beta-galactosidase (SA-β-gal) staining, immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot as well as enzyme linked immunosorbent assay were performed to evaluate rat glomerular podocyte senescence. The mRNA and protein levels of nucleoporin 155 (Nup155) and inositol requiring mutant 80 (INO80) in rat glomeruli were detected by qRT-PCR, Western blot and immunofluorescence. Foot processes and nuclear pore complexes (NPCs) of rat glomerular podocytes were visualized by transmission electron microscopy. RESULTS One hundred and fifty-nine components were preliminarily identified in SWT. The results of animal experiments showed that SWT decreased the activity of SA-β-gal, protein levels of p16, p21, p53 and phosphorylated histone H2AX (γ-H2AX), and mRNA levels of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in glomeruli of high fructose-fed rats. As expected, SWT increased renal cortex erythropoietin mRNA expression and serum erythropoietin concentration in this animal model. SWT reduced urine albumin-to-creatinine ratio and serum levels of uric acid, creatinine and blood urea nitrogen, and recovered glomerular structure injury in high fructose-fed rats. It up-regulated mRNA and protein levels of Nup155 and the number of podocyte NPCs, and subsequently reinforced mRNA nuclear export and protein expression of INO80 in rat glomeruli under high fructose stimulation. CONCLUSIONS SWT ameliorates glomerular podocyte senescence in high fructose-fed rats possibly by increasing Nup155 to promote INO80 mRNA nuclear export.
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Affiliation(s)
- Li Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China.
| | - Tangdi Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China.
| | - Jiahao Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China.
| | - Zixuan Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China.
| | - Ying Pan
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China.
| | - Lingdong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing, PR China.
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Bauer DC, Black DM, Dell R, Fan B, Smith CD, Ernst MT, Jurik AG, Frøkjær JB, Boesen M, Vittinghoff E, Abrahamsen B. Bisphosphonate Use and Risk of Atypical Femoral Fractures: A Danish Case-Cohort Study With Blinded Radiographic Review. J Clin Endocrinol Metab 2024; 109:e2141-e2150. [PMID: 38198798 PMCID: PMC11479699 DOI: 10.1210/clinem/dgae023] [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: 08/24/2023] [Revised: 10/20/2023] [Accepted: 01/09/2024] [Indexed: 01/12/2024]
Abstract
CONTEXT Prolonged bisphosphonate (BP) treatment for osteoporosis prevents hip and other fractures but causes atypical femoral fractures (AFF). OBJECTIVE To establish the relationship between patterns of BP use and the risk of AFF and hip fractures. Other potential risk factors for AFF were also examined. METHODS This population-based case-cohort study utilized data from the Danish National Healthcare system, including longitudinal records of medication use, healthcare utilization, and x-ray images. Among all 1.9 million Danish adults ≥50, those with subtrochanteric or femoral shaft fractures between 2010 and 2015 (n = 4973) were identified and compared to a random sample (n = 37 021). Bisphosphonate use was collected from 1995-2015. Fracture radiographs (n = 4769) were reviewed by blinded study radiologists to identify AFFs (n = 189) using established criteria. Traditional hip fractures in the random sample (n = 691) were identified by ICD-10. RESULTS Compared to <1 year of BP use, 5 to 7 years of use was associated with a 7-fold increase in AFF (adjusted HR = 7.29 [CI: 3.07, 17.30]); the risk of AFF fell quickly after discontinuation. The 5-year number needed to harm for one AFF was 1424, while the 5-year number needed to treat to prevent one hip fracture was 56. Glucocorticoid and proton pump inhibitor use were independently associated with increased AFF risk. Thirty-one percent of those with AFF had no BP exposure. CONCLUSION The risk of AFF increases with duration of BP use but the beneficial effects of BP therapy in adults ≥50 dramatically exceed this increased risk. Nearly one-third of those with AFF have no BP exposure.
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Affiliation(s)
- Douglas C Bauer
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Dennis M Black
- Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Rick Dell
- Kaiser Permanente Southern California, Downey, CA 90242, USA
| | - Bo Fan
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA
| | | | - Martin T Ernst
- Department of Public Health, University of Southern Denmark, Odense 5000, Denmark
| | - Anne G Jurik
- Department of Radiology, Aarhus University, Aarhus 8200, Denmark
| | - Jens B Frøkjær
- Departments of Radiology and Clinical Medicine, Aalborg University Hospital, Aalborg 9100, Denmark
| | - Mikael Boesen
- Department of Radiology, Copenhagen University Hospital, Bispebjerg and Frederiksberg 2400, Denmark
| | - Eric Vittinghoff
- Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Bo Abrahamsen
- Department of Public Health, University of Southern Denmark, Odense 5000, Denmark
- Department of Clinical Research, Odense Patient Data Explorative Network, University of Southern Denmark, Odense 5000, Denmark
- Department of Medicine, Holbæk Hospital, Holbæk 4300, Denmark
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Wanionok NE, Molinuevo MS, Fernández JM, Lucas B, Cortizo AM, Castillo EJ, Jiron JM, Claudia S, Leon S, Aguirre JI, McCarthy AD. Skeletal Effects of a Prolonged Oral Metformin Treatment in Adult Wistar Rats. Exp Clin Endocrinol Diabetes 2024; 132:547-556. [PMID: 38740375 DOI: 10.1055/a-2324-8661] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
INTRODUCTION We previously showed that a 3-week oral metformin (MET) treatment enhances the osteogenic potential of bone marrow stromal cells (BMSCs) and improves several bone histomorphometric parameters in Wistar rats with metabolic syndrome (MetS). However, the skeletal effects of extended periods of MET need to be completely elucidated. Hence, in this study, the impact of a prolonged (3-month) MET treatment was investigated on bone architecture, histomorphometric and biomechanics variables, and osteogenic potential of BMSCs in Wistar rats with or without MetS. MATERIALS AND METHODS Young male Wistar rats (n=36) were randomized into four groups (n=9) that received either 20% fructose (F), MET (MET), F plus MET treatments (FMET), or drinking water alone (Veh). Rats were euthanized, blood was collected, and bones were dissected and processed for peripheral quantitative computed tomography (pQCT) analysis, static and dynamic histomorphometry, and bone biomechanics. In addition, BMSCs were isolated to determine their osteogenic potential. RESULTS MET affected trabecular and cortical bone, altering bone architecture and biomechanics. Furthermore, MET increased the pro-resorptive profile of BMSCs. In addition, fructose-induced MetS practically did not affect the the structural or mechanical variables of the skeleton. CONCLUSION A 3-month treatment with MET (with or without MetS) affects bone architecture and biomechanical variables in Wistar rats.
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Affiliation(s)
- Nahuel E Wanionok
- Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Argentina
| | - María S Molinuevo
- Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Argentina
| | - Juan M Fernández
- Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Argentina
| | - Besada Lucas
- Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Argentina
| | - Ana M Cortizo
- Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Argentina
| | - Evelyn J Castillo
- Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA
| | - Jessica M Jiron
- Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA
| | - Sedlinsky Claudia
- Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Argentina
| | - Schurman Leon
- Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Argentina
| | - José I Aguirre
- Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA
| | - Antonio D McCarthy
- Laboratorio de Investigaciones en Osteopatías y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Argentina
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Leungsuwan DS, Chandran M. Bone Fragility in Diabetes and its Management: A Narrative Review. Drugs 2024; 84:1111-1134. [PMID: 39103693 DOI: 10.1007/s40265-024-02078-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 08/07/2024]
Abstract
Bone fragility is a serious yet under-recognised complication of diabetes mellitus (DM) that is associated with significant morbidity and mortality. Multiple complex pathophysiological mechanisms mediating bone fragility amongst DM patients have been proposed and identified. Fracture risk in both type 1 diabetes (T1D) and type 2 diabetes (T2D) continues to be understated and underestimated by conventional risk assessment tools, posing an additional challenge to the identification of at-risk patients who may benefit from earlier intervention or preventive strategies. Over the years, an increasing body of evidence has demonstrated the efficacy of osteo-pharmacological agents in managing skeletal fragility in DM. This review seeks to elaborate on the risk of bone fragility in DM, the underlying pathogenesis and skeletal alterations, the approach to fracture risk assessment in DM, management strategies and therapeutic options.
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Affiliation(s)
| | - Manju Chandran
- Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, 20 College Road, ACADEMIA, Singapore, 169856, Singapore.
- DUKE NUS Medical School, Singapore, Singapore.
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Sheu A, White CP, Center JR. Bone metabolism in diabetes: a clinician's guide to understanding the bone-glucose interplay. Diabetologia 2024; 67:1493-1506. [PMID: 38761257 PMCID: PMC11343884 DOI: 10.1007/s00125-024-06172-x] [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: 02/06/2024] [Accepted: 04/10/2024] [Indexed: 05/20/2024]
Abstract
Skeletal fragility is an increasingly recognised, but poorly understood, complication of both type 1 and type 2 diabetes. Fracture risk varies according to skeletal site and diabetes-related characteristics. Post-fracture outcomes, including mortality risk, are worse in those with diabetes, placing these people at significant risk. Each fracture therefore represents a sentinel event that warrants targeted management. However, diabetes is a very heterogeneous condition with complex interactions between multiple co-existing, and highly correlated, factors that preclude a clear assessment of the independent clinical markers and pathophysiological drivers for diabetic osteopathy. Additionally, fracture risk calculators and routinely used clinical bone measurements generally underestimate fracture risk in people with diabetes. In the absence of dedicated prospective studies including detailed bone and metabolic characteristics, optimal management centres around selecting treatments that minimise skeletal and metabolic harm. This review summarises the clinical landscape of diabetic osteopathy and outlines the interplay between metabolic and skeletal health. The underlying pathophysiology of skeletal fragility in diabetes and a rationale for considering a diabetes-based paradigm in assessing and managing diabetic bone disease will be discussed.
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Affiliation(s)
- Angela Sheu
- Skeletal Diseases Program, Garvan Institute of Medical Research, Sydney, Australia.
- Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia.
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia.
| | - Christopher P White
- Clinical School, Prince of Wales Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia
- Department of Endocrinology and Metabolism, Prince of Wales Hospital, Sydney, Australia
| | - Jacqueline R Center
- Skeletal Diseases Program, Garvan Institute of Medical Research, Sydney, Australia
- Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia
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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.
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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
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Forner P, Sheu A. Bone Health in Patients With Type 2 Diabetes. J Endocr Soc 2024; 8:bvae112. [PMID: 38887632 PMCID: PMC11181004 DOI: 10.1210/jendso/bvae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Indexed: 06/20/2024] Open
Abstract
The association between type 2 diabetes mellitus (T2DM) and skeletal fragility is complex, with effects on bone at the cellular, molecular, and biomechanical levels. As a result, people with T2DM, compared to those without, are at increased risk of fracture, despite often having preserved bone mineral density (BMD) on dual-energy x-ray absorptiometry (DXA). Maladaptive skeletal loading and changes in bone architecture (particularly cortical porosity and low cortical volumes, the hallmark of diabetic osteopathy) are not apparent on routine DXA. Alternative imaging modalities, including quantitative computed tomography and trabecular bone score, allow for noninvasive visualization of cortical and trabecular compartments and may be useful in identifying those at risk for fractures. Current fracture risk calculators underestimate fracture risk in T2DM, partly due to their reliance on BMD. As a result, individuals with T2DM, who are at high risk of fracture, may be overlooked for commencement of osteoporosis therapy. Rather, management of skeletal health in T2DM should include consideration of treatment initiation at lower BMD thresholds, the use of adjusted fracture risk calculators, and consideration of metabolic and nonskeletal risk factors. Antidiabetic medications have differing effects on the skeleton and treatment choice should consider the bone impacts in those at risk for fracture. T2DM poses a unique challenge when it comes to assessing bone health and fracture risk. This article discusses the clinical burden and presentation of skeletal disease in T2DM. Two clinical cases are presented to illustrate a clinical approach in assessing and managing fracture risk in these patients.
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Affiliation(s)
- Patrice Forner
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales Sydney, Sydney, NSW 2010, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, NSW 2010, Australia
| | - Angela Sheu
- Clinical School, Faculty of Medicine, St Vincent's Hospital, University of New South Wales Sydney, Sydney, NSW 2010, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, NSW 2010, Australia
- Skeletal Diseases Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2035, Australia
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Sheng R, Li Y, Wu Y, Liu C, Wang W, Han X, Li Y, Lei L, Jiang X, Zhang Y, Zhang Y, Li S, Hong B, Liu C, Xu Y, Si S. A pan-PPAR agonist E17241 ameliorates hyperglycemia and diabetic dyslipidemia in KKAy mice via up-regulating ABCA1 in islet, liver, and white adipose tissue. Biomed Pharmacother 2024; 172:116220. [PMID: 38308968 DOI: 10.1016/j.biopha.2024.116220] [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: 09/13/2023] [Revised: 01/18/2024] [Accepted: 01/25/2024] [Indexed: 02/05/2024] Open
Abstract
OBJECTIVE Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disease. Peroxisome proliferator-activated receptors (PPARs) play crucial roles in regulating glucolipid metabolism. Previous studies showed that E17241 could ameliorate atherosclerosis and lower fasting blood glucose levels in ApoE-/- mice. In this work, we investigated the role of E17241 in glycolipid metabolism in diabetic KKAy mice. APPROACH AND RESULTS We confirmed that E17241 is a powerful pan-PPAR agonist with a potent agonistic activity on PPARγ, a high activity on PPARα, and a moderate activity on PPARδ. E17241 also significantly increased the protein expression of ATP-binding cassette transporter 1 (ABCA1), a crucial downstream target gene for PPARs. E17241 clearly lowered plasma glucose levels, improved OGTT and ITT, decreased islet cholesterol content, improved β-cell function, and promoted insulin secretion in KKAy mice. Moreover, E17241 could significantly lower plasma total cholesterol and triglyceride levels, reduce liver lipid deposition, and improve the adipocyte hypertrophy and the inflammatory response in epididymal white adipose tissue. Further mechanistic studies indicated that E17241 boosts cholesterol efflux and insulin secretion in an ABCA1 dependent manner. RNA-seq and qRT-PCR analysis demonstrated that E17241 induced different expression of PPAR target genes in liver and adipose tissue differently from the PPARγ agonist rosiglitazone. In addition, E17241 treatment was also demonstrated to have an exhilarating cardiorenal benefits. CONCLUSIONS Our results demonstrate that E17241 regulates glucolipid metabolism in KKAy diabetic mice while having cardiorenal benefits without inducing weight gain. It is a promising drug candidate for the treatment of T2DM.
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Affiliation(s)
- Ren Sheng
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Yining Li
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Yexiang Wu
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Chang Liu
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Weizhi Wang
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Xiaowan Han
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, CAMS & PUMC, Beijing 100050, China
| | - Yinghong Li
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Lijuan Lei
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Xinhai Jiang
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Yuyan Zhang
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Yuhao Zhang
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Shunwang Li
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Bin Hong
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China
| | - Chao Liu
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China.
| | - Yanni Xu
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China.
| | - Shuyi Si
- NHC Key Laboratory of Biotechnology for Microbial Drugs, National Center for Screening Novel Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Tiantan Xili 1#, Beijing 100050, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, CAMS & PUMC, Beijing 100050, China.
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10
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Wang X, Wang Y, Hou J, Liu H, Zeng R, Li X, Han M, Li Q, Ji L, Pan D, Jia W, Zhong W, Xu T. Plasma proteome profiling reveals the therapeutic effects of the PPAR pan-agonist chiglitazar on insulin sensitivity, lipid metabolism, and inflammation in type 2 diabetes. Sci Rep 2024; 14:638. [PMID: 38182717 PMCID: PMC10770401 DOI: 10.1038/s41598-024-51210-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 01/02/2024] [Indexed: 01/07/2024] Open
Abstract
Chiglitazar is a novel peroxisome proliferator-activated receptor (PPAR) pan-agonist, which passed phase III clinical trials and was newly approved in China for use as an adjunct to diet and exercise in glycemic control in adult patients with Type 2 Diabetes (T2D). To explore the circulating protein signatures associated with the administration of chiglitazar in T2D patients, we conducted a comparative longitudinal study using plasma proteome profiling. Of the 157 T2D patients included in the study, we administered chiglitazar to a specific group, while the controls were given either placebo or sitagliptin. The plasma proteomes were profiled at baseline and 12 and 24 weeks post-treatment using data-independent acquisition mass spectrometry (DIA-MS). Our study indicated that 13 proteins were associated with chiglitazar treatment in T2D patients, including 10 up-regulated proteins (SHBG, TF, APOA2, APOD, GSN, MBL2, CFD, PGLYRP2, A2M, and APOA1) and 3 down-regulated proteins (PRG4, FETUB, and C2) after treatment, which were implicated in the regulation of insulin sensitivity, lipid metabolism, and inflammation response. Our study provides insight into the response of chiglitazar treatment from a proteome perspective and demonstrates the multi-faceted effects of chiglitazar in T2D patients, which will help the clinical application of chiglitazar and further study of its action mechanism.
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Affiliation(s)
- Xingyue Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
| | - You Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Junjie Hou
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Hongyang Liu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Rong Zeng
- CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
| | - Xiangyu Li
- Guangzhou National Laboratory, Guangzhou, China
| | - Mei Han
- Guangzhou National Laboratory, Guangzhou, China
| | - Qingrun Li
- CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Desi Pan
- Shenzhen Chipscreen Biosciences Co., Ltd, Shenzhen, China
| | - Weiping Jia
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wen Zhong
- Guangzhou National Laboratory, Guangzhou, China.
| | - Tao Xu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
- Guangzhou National Laboratory, Guangzhou, China.
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
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11
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Zhao X, Ahn D, Nam G, Kwon J, Song S, Kang MJ, Ahn H, Chung SJ. Identification of Crocetin as a Dual Agonist of GPR40 and GPR120 Responsible for the Antidiabetic Effect of Saffron. Nutrients 2023; 15:4774. [PMID: 38004168 PMCID: PMC10675071 DOI: 10.3390/nu15224774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/04/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Crocin, a glycoside of crocetin, has been known as the principal component responsible for saffron's antidiabetic, anticancer, and anti-inflammatory effects. Crocetin, originating from the hydrolytic cleavage of crocin in biological systems, was subjected to ligand-based virtual screening in this investigation. Subsequent biochemical analysis unveiled crocetin, not crocin, as a novel dual GPR40 and GPR120 agonist, demonstrating a marked preference for GPR40 and GPR120 over peroxisome proliferator-activated receptors (PPAR)γ. This compound notably enhanced insulin and GLP-1 secretion from pancreatic β-cells and intestinal neuroendocrine cells, respectively, presenting a dual mechanism of action in glucose-lowering effects. Docking simulations showed that crocetin emulates the binding characteristics of natural ligands through hydrogen bonds and hydrophobic interactions, whereas crocin's hindered fit within the binding pocket is attributed to steric constraints. Collectively, for the first time, this study unveils crocetin as the true active component of saffron, functioning as a GPR40/120 agonist with potential implications in antidiabetic interventions.
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Affiliation(s)
- Xiaodi Zhao
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; (X.Z.); (G.N.); (J.K.); (S.S.); (M.J.K.); (H.A.)
| | - Dohee Ahn
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea;
| | - Gibeom Nam
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; (X.Z.); (G.N.); (J.K.); (S.S.); (M.J.K.); (H.A.)
| | - Jihee Kwon
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; (X.Z.); (G.N.); (J.K.); (S.S.); (M.J.K.); (H.A.)
| | - Songyi Song
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; (X.Z.); (G.N.); (J.K.); (S.S.); (M.J.K.); (H.A.)
| | - Min Ji Kang
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; (X.Z.); (G.N.); (J.K.); (S.S.); (M.J.K.); (H.A.)
| | - Hyejin Ahn
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; (X.Z.); (G.N.); (J.K.); (S.S.); (M.J.K.); (H.A.)
| | - Sang J. Chung
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea; (X.Z.); (G.N.); (J.K.); (S.S.); (M.J.K.); (H.A.)
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea;
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12
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Zhang N, Guo L, Yu Y, Chen S, Gao L, Hou X, Tian F, Wu S. New-onset stroke on the risk of hip fracture: the Kailuan cohort study in China. BMC Public Health 2023; 23:925. [PMID: 37217860 DOI: 10.1186/s12889-023-15787-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 04/29/2023] [Indexed: 05/24/2023] Open
Abstract
PURPOSE Stroke is a documented risk factor for hip fracture(HF). However, no data is currently available on this issue in mainland China, we therefore assessed the risk of hip fracture after new-onset stroke using a cohort study. METHODS This study included 165,670 participants without a history of stroke at baseline from the Kailuan study. All participants were followed biennially until December 31, 2021. During follow-up, a total of 8,496 new-onset stroke cases were identified. For each case subject, four control subjects was randomly selected, matched for age (± 1 years) and sex. The final analysis comprised 42,455 pair-matched cases and controls. A multivariate Cox proportional hazard regression model was used to estimate the effect of new-onset stroke on the risk of hip fracture. RESULTS During an average follow-up of 8.87 (3.94) years, a total of 231 hip fracture cases occurred, 78 cases in the stroke group and 153 cases in the control group, with incidence rates of 1.12 and 0.50 per 1000 person-years, respectively. The cumulative incidence of the stroke group was higher than that of the controls (P < 0.01). The adjusted hazard ratio (95% confidence interval) of hip fractures in the stroke group was 2.35 (1.77 to 3.12) (P < 0.001) to controls. After stratifying by gender, age, and body mass index, the higher risk was revealed in female (HR 3.10, 95 CI: 2.18 to 6.14, P < 0.001), age < 60 years old (HR 4.12, 95% CI: 2.18 to 7.78, P < 0.001), and non-obesity (BMI<28 kg/m2) (HR 1.74, 95% CI:1.31 to 2.31, P < 0.001) subgroup. CONCLUSIONS Stroke significantly increases the risk of hip fracture, strategy for protecting stroke patients from falls and hip fractures should be emphasized in poststroke long-term management, particularly the female, age < 60 years old, and non-obese patients.
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Affiliation(s)
- Nan Zhang
- Department of orthopedics, Kailuan General Hospital, Tangshan, Hebei, China
| | - Lu Guo
- the School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China
| | - Yaohui Yu
- the School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China
| | - Shuohua Chen
- Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei, China
| | - Lishu Gao
- Department of Endocrinology, Tangshan People's Hospital, Tangshan, Hebei, China
| | - Xiaoli Hou
- the School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China
| | - Faming Tian
- the School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China.
| | - Shouling Wu
- Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei, China.
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Bahardoust M, Yarali M, Donyadideh G, Rahimi E, Naderi D, Tehrani FM, Delpisheh A. The use of metformin, sulfonylurea compounds and insulin and the risk of hip fractures in diabetic patients: a systematic review and meta-analysis of observational studies. BMC Musculoskelet Disord 2023; 24:367. [PMID: 37161384 PMCID: PMC10170842 DOI: 10.1186/s12891-023-06493-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 05/04/2023] [Indexed: 05/11/2023] Open
Abstract
BACKGROUND Hip fracture is a major health problem that occurs more often in the elderly, especially in diabetic patients. Some studies have been conducted regarding the effect of anti- diabetic drugs on fractures. But so far, no meta-analysis study has been conducted to investigate the effect of diabetic drugs on hip fractures. Therefore, this study investigated the relationship between anti-diabetic drugs (Metformin, Sulfonylurea, and insulin) with hip fractures. METHODS In this systematic review and meta analysis study, PubMed, Scopus, Google Scholar, and Web of Science databases were searched with specific keywords to find relevant studies. Two researchers included related studies after screening based on the title and full text. Cochran's Q and I2 tests were used to assess heterogeneity between studies. Publication bias between studies was evaluated for each drug using Egger's test. A 95% confidence interval was used for effect size significance. Overall, 49 studies, including 6,631,297 participants, were reviewed. RESULTS The results showed that metformin significantly reduced the risk of hip fracture (HR: 0.833, 95% CI: 0.759, 0.914, P:0.001). Consumption of sulfonylurea compounds was significantly associated with an increased risk of hip fracture. (HR: 1.175, 95% CI:1.068,1.293, P:0.001), The risk of hip fracture in patients receiving insulin was significantly higher than in diabetic patients who did not receive insulin. (HR:1.366, 95% CI:1.226,1.522, P:0.001). CONCLUSION The results of this study showed that taking metformin reduces the risk of hip fracture, and insulin and Sulfonylurea increase the risk of hip fracture.
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Affiliation(s)
- Mansour Bahardoust
- Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Yarali
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Elham Rahimi
- Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Delaram Naderi
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Ali Delpisheh
- Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Safety Promotion and Injury Prevention Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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14
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Lopez N, Cohen SM, Emanuele M. Type 2 Diabetes and Bone Disease. Clin Rev Bone Miner Metab 2023; 21:21-31. [DOI: 10.1007/s12018-023-09288-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/10/2023] [Indexed: 01/05/2025]
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Araújo IMD, Moreira MLM, Paula FJAD. Diabetes and bone. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2022; 66:633-641. [PMID: 36382752 PMCID: PMC10118819 DOI: 10.20945/2359-3997000000552] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Globally, one in 11 adults has diabetes mellitus of which 90% have type 2 diabetes. The numbers for osteoporosis are no less staggering: 1 in 3 women has a fracture after menopause, and the same is true for 1 in 5 men after the age of 50 years. Aging is associated with several physiological changes that cause insulin resistance and impaired insulin secretion, which in turn lead to hyperglycemia. The negative balance between bone resorption and formation is a natural process that appears after the fourth decade of life and lasts for the following decades, eroding the bone structure and increasing the risk of fractures. Not incidentally, it has been acknowledged that diabetes mellitus, regardless of whether type 1 or 2, is associated with an increased risk of fracture. The nuances that differentiate bone damage in the two main forms of diabetes are part of the intrinsic heterogeneity of diabetes, which is enhanced when associated with a condition as complex as osteoporosis. This narrative review addresses the main parameters related to the increased risk of fractures in individuals with diabetes, and the mutual factors affecting the treatment of diabetes mellitus and osteoporosis.
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16
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Tsai WH, Kong SK, Lin CL, Cheng KH, Cheng YT, Chien MN, Lee CC, Tsai MC. Risk of fracture caused by anti-diabetic drugs in individuals with type 2 diabetes: A network meta-analysis. Diabetes Res Clin Pract 2022; 192:110082. [PMID: 36122867 DOI: 10.1016/j.diabres.2022.110082] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 08/28/2022] [Accepted: 09/10/2022] [Indexed: 11/23/2022]
Abstract
AIMS Diabetes is associated with increased risk of fracture. This study aims to evaluate the correlation between anti-diabetic agents and fracture risk in patients with type 2 diabetes. METHODS Literature research was conducted using PubMed, Embase, and ClinicalTrials.gov. Search-term included "type 2 diabetes," "fracture," "randomized controlled trial," and seven kinds of anti-diabetic agents. Random-effect models established fractures in the follow-up period as the primary outcome. A network meta-analysis was performed to compare available treatments within a single Bayesian analytical framework. RESULTS A total of 191,361 patients were included in 161 studies, with 2916 fractures. DPP-4i (risk ratio [RR] 1.76 [95 % confidence interval (CI) 1.21-2.55]), SGLT-2i (RR 1.5 [95 % CI 1.05-2.16]) and placebo (RR 1.44 [95 % CI 1.04-1.98]) increased fracture risk when compared to GLP1-RA. GLP1-RA (RR 0.5 [95 % CI 0.31-0.79]) and SU (RR 0.56 [95 % CI 0.41-0.77]) provided greater protection against fracture than TZD. DPP-4i increased fracture risk when compared to SU (RR 1.55 [95 % CI 1.08-2.22]), and was comparable in effect to TZD. CONCLUSIONS GLP1-RA offered better protection against fracture than placebo. Insulin and SU had effects comparable with GLP1-RA. SU offered greater protection against fractures than TZD and DPP-4i. SGLT-2i increased risk of fracture when compared to GLP1-RA.
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Affiliation(s)
- Wen-Hsuan Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC
| | - Siang-Ke Kong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC
| | - Chu-Lin Lin
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Kai-Hsuan Cheng
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Yi-Ting Cheng
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Ming-Nan Chien
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Chun-Chuan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC
| | - Ming-Chieh Tsai
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, ROC; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan, ROC; Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan, ROC.
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17
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The Role of Transcription Factor PPAR-γ in the Pathogenesis of Psoriasis, Skin Cells, and Immune Cells. Int J Mol Sci 2022; 23:ijms23179708. [PMID: 36077103 PMCID: PMC9456565 DOI: 10.3390/ijms23179708] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/22/2022] Open
Abstract
The peroxisome proliferator-activated receptor PPAR-γ is one of three PPAR nuclear receptors that act as ligand-activated transcription factors. In immune cells, the skin, and other organs, PPAR-γ regulates lipid, glucose, and amino acid metabolism. The receptor translates nutritional, pharmacological, and metabolic stimuli into the changes in gene expression. The activation of PPAR-γ promotes cell differentiation, reduces the proliferation rate, and modulates the immune response. In the skin, PPARs also contribute to the functioning of the skin barrier. Since we know that the route from identification to the registration of drugs is long and expensive, PPAR-γ agonists already approved for other diseases may also represent a high interest for psoriasis. In this review, we discuss the role of PPAR-γ in the activation, differentiation, and proliferation of skin and immune cells affected by psoriasis and in contributing to the pathogenesis of the disease. We also evaluate whether the agonists of PPAR-γ may become one of the therapeutic options to suppress the inflammatory response in lesional psoriatic skin and decrease the influence of comorbidities associated with psoriasis.
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18
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Sheu A, Greenfield JR, White CP, Center JR. Assessment and treatment of osteoporosis and fractures in type 2 diabetes. Trends Endocrinol Metab 2022; 33:333-344. [PMID: 35307247 DOI: 10.1016/j.tem.2022.02.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/01/2022] [Accepted: 02/22/2022] [Indexed: 01/10/2023]
Abstract
There is substantial, and growing, evidence that type 2 diabetes (T2D) is associated with skeletal fragility, despite often preserved bone mineral density. As post-fracture outcomes, including mortality, are worse in people with T2D, bone management should be carefully considered in this highly vulnerable group. However, current fracture risk calculators inadequately predict fracture risk in T2D, and dedicated randomised controlled trials identifying optimal management in patients with T2D are lacking, raising questions about the ideal assessment and treatment of bone health in these people. We synthesise the current literature on evaluating bone measurements in T2D and summarise the evidence for safety and efficacy of both T2D and anti-osteoporosis medications in relation to bone health in these patients.
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Affiliation(s)
- Angela Sheu
- Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia; Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia.
| | - Jerry R Greenfield
- Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia; Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, Australia
| | - Christopher P White
- Clinical School, Prince of Wales Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Metabolism, Prince of Wales Hospital, Sydney, Australia
| | - Jacqueline R Center
- Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia; Clinical School, St Vincent's Hospital, Faculty of Medicine, University of New South Wales Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, St Vincent's Hospital, Sydney, Australia
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19
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Papaetis GS. Pioglitazone, Bladder Cancer and the Presumption of Innocence. Curr Drug Saf 2022; 17:294-318. [PMID: 35249505 DOI: 10.2174/1574886317666220304124756] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 12/01/2021] [Accepted: 12/21/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Thiazolidinediones are potent exogenous agonists of PPAR-γ, which augment the effects of insulin to its cellular targets and mainly at the level of adipose tissue. Pioglitazone, the main thiazolidinedione in clinical practice, has shown cardiovascular and renal benefits in patients with type 2 diabetes, durable reduction of glycated hemoglobulin levels, important improvements of several components of the metabolic syndrome and beneficial effects of non-alcoholic fatty liver disease. OBJECTIVE Despite all of its established advantages, the controversy for an increased risk of developing bladder cancer, combined with the advent of newer drug classes that achieved major cardiorenal effects have significantly limited its use spreading a persistent shadow of doubt for its future role. METHODS Pubmed, Google and Scope databases have been thoroughly searched and relevant studies were selected. RESULTS This paper explores thoroughly both in vitro and in vivo (animal models and humans) studies that investigated the possible association of pioglitazone with bladder cancer. CONCLUSION Currently the association of pioglitazone with bladder cancer cannot be based on solid evidence. This evidence cannot justify its low clinical administration, especially in the present era of individualised treatment strategies. Definite clarification of this issue is imperative and urgently anticipated from future high quality and rigorous pharmacoepidemiologic research, keeping in mind its unique mechanism of action and its significant pleiotropic effects.
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Affiliation(s)
- Georgios S Papaetis
- Internal Medicine and Diabetes Clinic, Eleftherios Venizelos Avenue 62, Paphos, Cyprus.
- CDA College, 73 Democratias Avenue, Paphos, Cyprus
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20
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Hofbauer LC, Busse B, Eastell R, Ferrari S, Frost M, Müller R, Burden AM, Rivadeneira F, Napoli N, Rauner M. Bone fragility in diabetes: novel concepts and clinical implications. Lancet Diabetes Endocrinol 2022; 10:207-220. [PMID: 35101185 DOI: 10.1016/s2213-8587(21)00347-8] [Citation(s) in RCA: 205] [Impact Index Per Article: 68.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/09/2021] [Accepted: 12/09/2021] [Indexed: 12/12/2022]
Abstract
Increased fracture risk represents an emerging and severe complication of diabetes. The resulting prolonged immobility and hospitalisations can lead to substantial morbidity and mortality. In type 1 diabetes, bone mass and bone strength are reduced, resulting in up to a five-times greater risk of fractures throughout life. In type 2 diabetes, fracture risk is increased despite a normal bone mass. Conventional dual-energy x-ray absorptiometry might underestimate fracture risk, but can be improved by applying specific adjustments. Bone fragility in diabetes can result from cellular abnormalities, matrix interactions, immune and vascular changes, and musculoskeletal maladaptation to chronic hyperglycaemia. This Review summarises how the bone microenvironment responds to type 1 and type 2 diabetes, and the mechanisms underlying fragility fractures. We describe the value of novel imaging technologies and the clinical utility of biomarkers, and discuss current and future therapeutic approaches that protect bone health in people with diabetes.
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Affiliation(s)
- Lorenz C Hofbauer
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III, and Center for Healthy Aging, University Medical Center, Technische Universität Dresden, Dresden, Germany.
| | - Björn Busse
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Richard Eastell
- Department of Oncology and Metabolism, Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK
| | - Serge Ferrari
- Service and Laboratory of Bone Diseases, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland
| | - Morten Frost
- Molecular Endocrinology Laboratory and Steno Diabetes Centre Odense, Odense University Hospital, Odense, Denmark
| | - Ralph Müller
- Institute of Biomechanics, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Andrea M Burden
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | | | - Nicola Napoli
- RU of Endocrinology and Diabetes, Campus Bio-Medico University of Rome and Fondazione Policlinico Campus Bio-Medico, Rome, Italy; Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, MO, USA
| | - Martina Rauner
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III, and Center for Healthy Aging, University Medical Center, Technische Universität Dresden, Dresden, Germany
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Wang Y, Yu L, Ye Z, Lin R, Sun AR, Liu L, Wei J, Deng F, Zhong X, Cui L, Li L, Liu Y. Association of metformin use with fracture risk in type 2 diabetes: A systematic review and meta-analysis of observational studies. Front Endocrinol (Lausanne) 2022; 13:1038603. [PMID: 36714564 PMCID: PMC9874692 DOI: 10.3389/fendo.2022.1038603] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
AIMS Increasing evidence suggests that metformin can affect bone metabolism beyond its hypoglycemic effects in diabetic patients. However, the effects of metformin on fracture risk in type 2 diabetes mellitus (T2DM) patients remain unclear. A systematic review and meta-analysis were performed in this study to evaluate the association between metformin application and fracture risk in T2DM patients based on previous studies published until June 2021. METHODS A systematic search was performed to collect publications on metformin application in T2DM patients based on PubMed, Embase, Cochran, and Web of Science databases. Meta-analysis was performed by using a random-effects model to estimate the summary relative risks (RRs) with 95% confidence intervals (CIs). Subgroup analyses based on cohort/case-control and ethnicity and sensitivity analyses were also performed. RESULTS Eleven studies were included in the meta-analysis. Results demonstrated metformin use was not significantly associated with a decreased risk of fracture (RR, 0.91; 95% CI, 0.81-1.02; I2 = 96.8%). Moreover, metformin use also demonstrated similar results in subgroup analyses of seven cohort studies and four case-control studies, respectively (RR, 0.90; 95% CI, 0.76-1.07; I2 = 98.0%; RR, 0.96; 96% CI, 0.89-1.03; I2 = 53.7%). Sensitivity analysis revealed that there was no publication bias. CONCLUSION There was no significant correlation between fracture risk and metformin application in T2DM patients. Due to a limited number of existing studies, further research is needed to make a definite conclusion for clinical consensus.
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Affiliation(s)
- Yining Wang
- Zhanjiang Key Laboratory of Orthopaedic Technology and Trauma Treatment, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, China
- Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang, China
| | - Liming Yu
- Department of Stomatology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhiqiang Ye
- Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang, China
| | - Rui Lin
- Zhanjiang Key Laboratory of Orthopaedic Technology and Trauma Treatment, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, China
- Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang, China
| | - Antonia RuJia Sun
- Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, Queensland, Australia
- Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, Guangdong, China
| | - Lingna Liu
- Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang, China
- Marine Medical Research Institute of Zhanjiang, Zhanjiang, China
| | - Jinsong Wei
- Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Feifu Deng
- Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xiangxin Zhong
- Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Liao Cui
- Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang, China
- *Correspondence: Yanzhi Liu, ; Li Li, ; Liao Cui,
| | - Li Li
- Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang, China
- *Correspondence: Yanzhi Liu, ; Li Li, ; Liao Cui,
| | - Yanzhi Liu
- Zhanjiang Key Laboratory of Orthopaedic Technology and Trauma Treatment, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, China
- Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang, China
- Marine Medical Research Institute of Zhanjiang, Zhanjiang, China
- *Correspondence: Yanzhi Liu, ; Li Li, ; Liao Cui,
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Kirk AB, Michelsen-Correa S, Rosen C, Martin CF, Blumberg B. PFAS and Potential Adverse Effects on Bone and Adipose Tissue Through Interactions With PPARγ. Endocrinology 2021; 162:6364127. [PMID: 34480479 PMCID: PMC9034324 DOI: 10.1210/endocr/bqab194] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Indexed: 01/06/2023]
Abstract
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a widely dispersed, broad class of synthetic chemicals with diverse biological effects, including effects on adipose and bone differentiation. PFAS most commonly occur as mixtures and only rarely, if ever, as single environmental contaminants. This poses significant regulatory questions and a pronounced need for chemical risk assessments, analytical methods, and technological solutions to reduce the risk to public and environmental health. The effects of PFAS on biological systems may be complex. Each may have several molecular targets initiating multiple biochemical events leading to a number of different adverse outcomes. An exposure to mixtures or coexposures of PFAS complicates the picture further. This review illustrates how PFAS target peroxisome proliferator-activated receptors. Additionally, we describe how such activation leads to changes in cell differentiation and bone development that contributes to metabolic disorder and bone weakness. This discussion sheds light on the importance of seemingly modest outcomes observed in test animals and highlights why the most sensitive end points identified in some chemical risk assessments are significant from a public health perspective.
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Affiliation(s)
- Andrea B Kirk
- Correspondence: Andrea Kirk, PhD, US EPA Headquarters, William Jefferson Clinton Bldg, 1200 Pennsylvania Ave NW, Mail Code 5201P, Washington, DC 20460, USA.
| | - Stephani Michelsen-Correa
- EPA Office of Chemical Safety and Pollution Prevention, Biopesticides and Pollution Prevention Division, Washington, District of Columbia 20460, USA
| | - Cliff Rosen
- Tufts University School of Medicine, Boston, Massachusetts 02111, USA
| | | | - Bruce Blumberg
- University of California, Irvine, Irvine, California 92697, USA
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23
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Yang L, Ge Q, Ye Z, Wang L, Wang L, Mashrah MA, Pathak JL. Sulfonylureas for Treatment of Periodontitis-Diabetes Comorbidity-Related Complications: Killing Two Birds With One Stone. Front Pharmacol 2021; 12:728458. [PMID: 34539410 PMCID: PMC8440798 DOI: 10.3389/fphar.2021.728458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/19/2021] [Indexed: 12/28/2022] Open
Abstract
Periodontitis is one of the most prevalent oral inflammatory diseases leading to teeth loss and oral health problems in adults. Periodontitis mainly affects periodontal tissue by affecting the host immune system and bone homeostasis. Moreover, periodontitis is associated with various systemic diseases. Diabetes is a metabolic disease with systemic effects. Both periodontitis and diabetes are common inflammatory diseases, and comorbidity of two diseases is linked to exacerbation of the pathophysiology of both diseases. Since bacterial dysbiosis is mainly responsible for periodontitis, antibiotics are widely used drugs to treat periodontitis in clinics. However, the outcomes of antibiotic treatments in periodontitis are not satisfactory. Therefore, the application of anti-inflammatory drugs in combination with antibiotics could be a treatment option for periodontitis-diabetes comorbidity. Anti-diabetic drugs usually have anti-inflammatory properties and have shown beneficial effects on periodontitis. Sulfonylureas, insulin secretagogues, are the earliest and most widely used oral hypoglycemic drugs used for type-2 diabetes. Studies have found that sulfonylurea drugs can play a certain role in the mitigation of periodontitis and inflammation. This article reviews the effects of sulfonylurea drugs on the mitigation of periodontitis-diabetes comorbidity-related inflammation, bone loss, and vascular growth as well as the involved molecular mechanisms. We discuss the possibility of a new application of sulfonylureas (old drug) to treat periodontitis-diabetes comorbidity.
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Affiliation(s)
- Luxi Yang
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qing Ge
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhitong Ye
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lijing Wang
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China.,School of Life Sciences and Biopharmaceutics, Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China
| | - Liping Wang
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mubarak Ahmed Mashrah
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Janak L Pathak
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
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24
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Tao Y, E M, Shi J, Zhang Z. Sulfonylureas use and fractures risk in elderly patients with type 2 diabetes mellitus: a meta-analysis study. Aging Clin Exp Res 2021; 33:2133-2139. [PMID: 33104983 DOI: 10.1007/s40520-020-01736-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 10/03/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Sulfonylureas are widely used in patients with type 2 diabetes; meanwhile, the increasing fractures risks especially in the old are gradually taken into consideration. This meta-analysis aimed at investigating whether sulfonylureas could influence the risk of fractures in type 2 diabetes (T2DM) in the elder patients (≥ 65 years old). METHODS We searched the PubMed and other databases to screen eligible studies. Two authors independently extracted data according to the selection criteria for each study. The Newcastle-Ottawa scale was used to evaluate the quality. Subgroups and sensitivity analyses were performed and publication bias was assessed. RESULT A total of 7 studies involving 464,121 individuals were included in our meta-analysis. The pooled risk ratio for developing fracture in sulfonylurea users with type 2 diabetes (≥ 65 years old) was 1.26 (95% CI 1.15-1.39). Sensitivity analyses confirmed the stability of the results and there was no publication bias. CONCLUSIONS Sulfonylureas could add the risk of fractures among the old with type 2 diabetes. Initial sulfonylureas therapy in both men and women should be done prudently.
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Affiliation(s)
- Yujia Tao
- Department of Cardiology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Meng E
- Yangzhou Center for Disease Control and Prevention, Yang Zhou, China
| | - Jingjing Shi
- Department of Diagnostic Radiology, The University of Hong Kong, Hong Kong, China
| | - Zhen Zhang
- Department of Endocrinology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
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Chiodini I, Gaudio A, Palermo A, Napoli N, Vescini F, Falchetti A, Merlotti D, Eller-Vainicher C, Carnevale V, Scillitani A, Pugliese G, Rendina D, Salcuni A, Bertoldo F, Gonnelli S, Nuti R, Toscano V, Triggiani V, Cenci S, Gennari L. Management of bone fragility in type 2 diabetes: Perspective from an interdisciplinary expert panel. Nutr Metab Cardiovasc Dis 2021; 31:2210-2233. [PMID: 34059385 DOI: 10.1016/j.numecd.2021.04.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/11/2021] [Accepted: 04/15/2021] [Indexed: 12/22/2022]
Abstract
AIM Bone fragility is increasingly recognized as a relevant complication of type 2 diabetes (T2D) and diabetic patients with fragility fractures have higher mortality rates than non diabetic individuals or diabetic patients without fractures. However, current diagnostic approaches for fracture risk stratification, such as bone mineral density measurement or the use of risk assessment algorithms, largely underestimate fracture risk in T2D patients. A multidisciplinary expert panel was established in order to in order to formulate clinical consensus recommendations on bone health assessment and management of fracture risk in patients with T2D. DATA SYNTHESIS The following key questions were addressed: a) which are the risk factors for bone fragility in T2D?, b) which diagnostic procedures can be currently used to stratify fracture risk in T2D patients?, c) which are the effects of antidiabetic treatments on bone?, and d) how to prevent and treat bone fragility in T2D patients? Based on the available data members of this panel suggest that the stratification of fracture risk in patients with diabetes should firstly rely on the presence of a previous fragility fracture and on the individual risk profile, with the inclusion of T2D-specific risk factors (namely T2D duration above 10 yrs, presence of chronic T2D complications, use of insulin or thiazolidinediones and persistent HbA1c levels above 8% for at least 1 year). Two independent diagnostic approaches were then suggested in the presence or the absence of a prevalent fragility fracture, respectively. CONCLUSIONS Clinical trials in T2D patients at risk for fragility fractures are needed to determine the efficacy and safety of available antiresorptive and anabolic agents in this specific setting.
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Affiliation(s)
- Iacopo Chiodini
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Medical Science and Community Health, University of Milan, Milan, Italy
| | - Agostino Gaudio
- Department of Clinical and Experimental Medicine, University of Catania, University Hospital "G. Rodolico" Catania, Italy
| | - Andrea Palermo
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy
| | - Nicola Napoli
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy
| | - Fabio Vescini
- Endocrinology and Metabolism Unit, University-Hospital S. M. Misericordia of Udine, Italy
| | - Alberto Falchetti
- Unit for Bone Metabolism Diseases and Diabetes and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy; EndOsMet, Villa Donatello Private Hospital, Florence, Italy
| | - Daniela Merlotti
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | | | - Vincenzo Carnevale
- Unit of Internal Medicine, "Casa Sollievo della Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, (FG), Italy
| | - Alfredo Scillitani
- Unit of Endocrinology, "Casa Sollievo della Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, (FG), Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, and Diabetes Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Domenico Rendina
- Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Antonio Salcuni
- Endocrinology Unit, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Francesco Bertoldo
- Department of Medicine, University of Verona, Policlinico GB Rossi, Verona, Italy
| | - Stefano Gonnelli
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy
| | - Ranuccio Nuti
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy
| | - Vincenzo Toscano
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy
| | - Vincenzo Triggiani
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases. University of Bari "Aldo Moro", Bari, Italy
| | - Simone Cenci
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | - Luigi Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy.
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Shaik AR, Singh P, Shaik C, Kohli S, Vohora D, Ferrari SL. Metformin: Is It the Well Wisher of Bone Beyond Glycemic Control in Diabetes Mellitus? Calcif Tissue Int 2021; 108:693-707. [PMID: 33797562 DOI: 10.1007/s00223-021-00805-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 01/05/2021] [Indexed: 12/18/2022]
Abstract
Both diabetes mellitus and osteoporosis constitute a notable burden in terms of quality of life and healthcare costs. Diabetes mellitus affecting the skeletal system has been gaining attention in recent years and is now getting recognized as yet another complication of the disease, known as diabetic bone disease. As this condition with weaker bone strength increases fracture risk and reduces the quality of life, so much attention is being paid to investigate the molecular pathways through which both diabetes and its therapy are affecting bone metabolism. Out of many therapeutic agents currently available for managing diabetes mellitus, metformin is one of the most widely accepted first choices worldwide. The purpose of this review is to describe the effects of biguanide-metformin on bone metabolism in type 2 diabetes mellitus including its plausible mechanisms of action on the skeleton. In vitro studies suggest that metformin directly stimulates osteoblasts differentiation and may inhibit osteoclastogenesis by increasing osteoprotegerin expression, both through activation of the AMPK signaling pathway. Several studies in both preclinical and clinical settings report the favorable effects of metformin on bone microarchitecture, bone mineral density, bone turnover markers, and fracture risk. However, animal studies were not specific in terms of the diabetic models used and clinical studies were associated with several confounders. The review highlights some of these limitations and provide future recommendations for research in this area which is necessary to better understand the role of metformin on skeletal outcomes in diabetes.
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Affiliation(s)
- Abdul Rahaman Shaik
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India
| | - Prabhjeet Singh
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India
| | - Chandini Shaik
- Department of Pharmaceutical Analysis, University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur, Andhra Pradesh, 522510, India
| | - Sunil Kohli
- Department of Medicine, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India
| | - Divya Vohora
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India.
| | - Serge Livio Ferrari
- Service and Laboratory of Bone Diseases, Department of Medicine, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland
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Napoli N, Incalzi RA, De Gennaro G, Marcocci C, Marfella R, Papalia R, Purrello F, Ruggiero C, Tarantino U, Tramontana F, Conte C. Bone fragility in patients with diabetes mellitus: A consensus statement from the working group of the Italian Diabetes Society (SID), Italian Society of Endocrinology (SIE), Italian Society of Gerontology and Geriatrics (SIGG), Italian Society of Orthopaedics and Traumatology (SIOT). Nutr Metab Cardiovasc Dis 2021; 31:1375-1390. [PMID: 33812734 DOI: 10.1016/j.numecd.2021.01.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 02/08/2023]
Abstract
Bone fragility is one of the possible complications of diabetes, either type 1 (T1D) or type 2 (T2D). Bone fragility can affect patients of different age and with different disease severity depending on type of diabetes, disease duration and the presence of other complications. Fracture risk assessment should be started at different stages in the natural history of the disease depending on the type of diabetes and other risk factors. The risk of fracture in T1D is higher than in T2D, imposing a much earlier screening and therapeutic intervention that should also take into account a patient's life expectancy, diabetes complications etc. The therapeutic armamentarium for T2D has been enriched with drugs that may influence bone metabolism, and clinicians should be aware of these effects. Considering the complexity of diabetes and osteoporosis and the range of variables that influence treatment choices in a given individual, the Working Group on bone fragility in patients with diabetes mellitus has identified and issued recommendations based on the variables that should guide screening of bone fragility and management of diabetes and bone fragility: (A)ge, (B)MD, (C)omplications, (D)uration of disease, & (F)ractures (ABCD&F). Consideration of these parameters may help clinicians identify the best time for screening, the appropriate glycaemic target and anti-osteoporosis drug for patients with diabetes at risk of or with bone fragility.
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Affiliation(s)
- Nicola Napoli
- Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy; Division of Bone and Mineral Diseases, Washington University in St. Louis, St. Louis, MO, USA.
| | - Raffaele A Incalzi
- Unit of Geriatrics, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy.
| | - Giovanni De Gennaro
- Diabetes Center, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Claudio Marcocci
- Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Rocco Papalia
- Unit of Orthopedic and Trauma Surgery, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, University of Catania, 95100 Catania, Italy; Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy
| | - Carmelinda Ruggiero
- Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy
| | - Umberto Tarantino
- Department of Clinical Sciences and Translational Medicine, Faculty of Medicine and Surgery, "Tor Vergata" University of Rome, Rome, Italy; Department of Orthopaedics and Traumatology, "Policlinico Tor Vergata" Foundation, Rome, Italy
| | - Flavia Tramontana
- Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Caterina Conte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy; Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan, Italy
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Trends in diabetes medication use in Australia, Canada, England, and Scotland: a repeated cross-sectional analysis in primary care. Br J Gen Pract 2021; 71:e209-e218. [PMID: 33619050 PMCID: PMC7906622 DOI: 10.3399/bjgp20x714089] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/24/2020] [Indexed: 01/14/2023] Open
Abstract
Background Several new classes of glucose-lowering medications have been introduced in the past two decades. Some, such as sodium-glucose cotransporter 2 inhibitors (SGLT2s), have evidence of improved cardiovascular outcomes, while others, such as dipeptidyl peptidase-4 inhibitors (DPP4s), do not. It is therefore important to identify their uptake in order to find ways to support the use of more effective treatments. Aim To analyse the uptake of these new classes among patients with type 2 diabetes. Design and setting This was a retrospective repeated cross-sectional analysis in primary care. Rates of medication uptake in Australia, Canada, England, and Scotland were compared. Method Primary care Electronic Medical Data on prescriptions (Canada, UK) and dispensing data (Australia) from 2012 to 2017 were used. Individuals aged ≥40 years on at least one glucose-lowering drug class in each year of interest were included, excluding those on insulin only. Proportions of patients in each nation, for each year, on each class of medication, and on combinations of classes were determined. Results Data from 238 619 patients were included in 2017. The proportion of patients on sulfonylureas (SUs) decreased in three out of four nations, while metformin decreased in Canada. Use of combinations of metformin and new drug classes increased in all nations, replacing combinations involving SUs. In 2017, more patients were on DPP4s (between 19.1% and 27.6%) than on SGLT2s (between 10.1% and 15.3%). Conclusion New drugs are displacing SUs. However, despite evidence of better outcomes, the adoption of SGLT2s lagged behind DPP4s.
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Ryhänen EM, Schalin-Jäntti C, Matikainen N. Prolonged Hypophosphatemia and Intensive Care After Curative Surgery of Tumor Induced Osteomalacia: A Case Report. Front Endocrinol (Lausanne) 2021; 12:686135. [PMID: 34149623 PMCID: PMC8209372 DOI: 10.3389/fendo.2021.686135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 05/19/2021] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION Rare FGF23-producing mesenchymal tumors lead to paraneoplastic tumor-induced osteomalacia (TIO) presenting with phosphate wasting, hypophosphatemia, chronic hypomineralization of the bone, fragility fractures and muscle weakness. Diagnosis of TIO requires exclusion of other etiologies and careful search for a mesenchymal tumor that often is very small and can appear anywhere in the body. Surgical removal of the tumor is the only definitive treatment of TIO. Surgical complications due to chronic hypophosphatemia are not well recognized. CASE DESCRIPTION The current case describes severe fragility fractures in a 58-year-old woman, who lost her ability to walk and was bedridden for two years. First, the initial diagnostic laboratory work-up did not include serum phosphorus measurements, second, the suspicion of adverse effects of pioglitazone as an underlying cause delayed correct diagnosis for at least two years. After biochemical discovery of hyperphosphaturic hypophosphatemia at a tertiary referral centre, a FGF23-producing tumor of the mandible was discovered on physical examination, and then surgically removed. Postoperatively, severe hypophosphatemia and muscle weakness prolonged the need for ventilation support, intensive care and phosphate supplementation. After two years of rehabilitation, the patient was able to walk short distances. The tumor has not recurred, and serum phosphate concentration has remained within normal limits during 3.5 years of follow-up. CONCLUSIONS The case report illustrates knowledge gaps in the diagnostic work-up of rare causes of low bone mass and fragility fractures. Compared to other low phosphate conditions, surgical recovery from TIO-induced hypophosphatemia warrants special attention. Increased alkaline phosphatase concentration may indicate impaired postsurgical recovery due to prolonged hypophosphatemia, underlining the need for proactive perioperative correction of hypophosphatemia.
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30
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Zhao Y, Xie L, Ou N, Wu J, Zhang H, Zhou S, Liu Y, Chen J, Wang L, Wang L, Wang J, Shao F. Tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534, a potent G protein-coupled receptor 40 (GPR40) agonist, at single- and multiple-ascending oral doses in healthy Chinese subjects. Xenobiotica 2020; 51:297-306. [PMID: 33331206 DOI: 10.1080/00498254.2020.1864510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
SHR0534 is being developed for type-2 diabetes mellitus. Herein the tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534 in healthy Chinese subjects were assessed in a phase-I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study. Forty subjects were randomized 4:1 to receive SHR0534 at the dose of 10, 25, 50 or 100 mg, or placebo, and another eleven subjects were allocated to either the 5 mg group or the placebo group at an 8:3 ratio. All subjects received a single dose on day 1, followed by a 9-day washout and once-daily administrations for 14 consecutive days. Serial samples were collected, and vital signs, electrocardiograms, laboratory tests, urinalysis and adverse events (AEs) were recorded. All doses of SHR0534 were safe and well tolerated with infrequent, generally mild-to-moderate AEs and no serious AEs in the study. SHR0534 was absorbed with a T max of approximately 4 hours, and systemic exposure increased with dose. Accumulation was minimal (2- to 3-fold) and steady state was reached after seven days of dosing. For pharmacodynamics, no significant hypoglycaemic effects were seen in healthy adults. Good pharmacokinetics and safety were demonstrated but no obvious effect was found.
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Affiliation(s)
- Yuqing Zhao
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Lijun Xie
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Ning Ou
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jie Wu
- Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, China
| | - Hongwen Zhang
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Sufeng Zhou
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Yun Liu
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Juan Chen
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Lu Wang
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Libin Wang
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jingjing Wang
- Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, China
| | - Feng Shao
- Phase I Clinical Trial Unit, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China.,Pharmacy College, Nanjing Medical University, Nanjing, China
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Lim K, Haider A, Adams C, Sleigh A, Savage DB. Lipodistrophy: a paradigm for understanding the consequences of "overloading" adipose tissue. Physiol Rev 2020; 101:907-993. [PMID: 33356916 DOI: 10.1152/physrev.00032.2020] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Lipodystrophies have been recognized since at least the nineteenth century and, despite their rarity, tended to attract considerable medical attention because of the severity and somewhat paradoxical nature of the associated metabolic disease that so closely mimics that of obesity. Within the last 20 yr most of the monogenic subtypes have been characterized, facilitating family genetic screening and earlier disease detection as well as providing important insights into adipocyte biology and the systemic consequences of impaired adipocyte function. Even more recently, compelling genetic studies have suggested that subtle partial lipodystrophy is likely to be a major factor in prevalent insulin-resistant type 2 diabetes mellitus (T2DM), justifying the longstanding interest in these disorders. This progress has also underpinned novel approaches to treatment that, in at least some patients, can be of considerable therapeutic benefit.
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Affiliation(s)
- Koini Lim
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Afreen Haider
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Claire Adams
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Alison Sleigh
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - David B Savage
- Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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Abstract
G Protein-coupled receptor 120 (GPR120; fatty acid receptor 4, FFAR4) and PPARγ agonists both lead to anti-inflammatory and insulin sensitizing effects despite signalling through distinct pathways. We recently reported the overarching idea that these two pathways are interactive. Specifically, treatment of obese mice with the PPARγ agonist rosiglitazone (a thiazolidinedione, TZD) in combination with the GPR120 agonist compound A synergistically improves glucose tolerance and insulin sensitivity. We have deconvoluted the mechanisms underlying this feed-forward effect in the study. Taken together, our study shows that low dose TZD administration, in combination with GPR120 agonists, produces additive beneficial effects on glucose tolerance and insulin sensitivity without the undesirable adverse effects of TZD. Our study suggests potential value of combination PPARγ and GPR120 agonists to treat metabolic disease.
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Affiliation(s)
- Vivian A. Paschoal
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Da Young Oh
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Lin H, Shi F, Jiang S, Wang Y, Zou J, Ying Y, Huang D, Luo L, Yan X, Luo Z. Metformin attenuates trauma-induced heterotopic ossification via inhibition of Bone Morphogenetic Protein signalling. J Cell Mol Med 2020; 24:14491-14501. [PMID: 33169942 PMCID: PMC7754007 DOI: 10.1111/jcmm.16076] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 10/04/2020] [Accepted: 10/25/2020] [Indexed: 11/06/2022] Open
Abstract
AMP‐activated protein kinase (AMPK) is an intracellular sensor of energy homoeostasis that is activated under energy stress and suppressed in energy surplus. AMPK activation leads to inhibition of anabolic processes that consume ATP. Osteogenic differentiation is a process that highly demands ATP during which AMPK is inhibited. The bone morphogenetic proteins (BMPs) signalling pathway plays an essential role in osteogenic differentiation. The present study examines the inhibitory effect of metformin on BMP signalling, osteogenic differentiation and trauma‐induced heterotopic ossification. Our results showed that metformin inhibited Smad1/5 phosphorylation induced by BMP6 in osteoblast MC3T3‐E1 cells, concurrent with up‐regulation of Smad6, and this effect was attenuated by knockdown of Smad6. Furthermore, we found that metformin suppressed ALP activity and mineralization of the cells, an event that was attenuated by the dominant negative mutant of AMPK and mimicked by its constitutively active mutant. Finally, administration of metformin prevented the trauma‐induced heterotopic ossification in mice. In conjuncture, AMPK activity and Smad6 and Smurf1 expression were enhanced by metformin treatment in the muscle of injured area, concurrently with the reduction of ALK2. Collectively, our study suggests that metformin prevents heterotopic ossification via activation of AMPK and subsequent up‐regulation of Smad6. Therefore, metformin could be a potential therapeutic drug for heterotopic ossification induced by traumatic injury.
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Affiliation(s)
- Hui Lin
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology and Department of Pathophysiology, School of Basic Medical Sciences, Queen Mary School, Nanchang University, Nanchang, China
| | - Fuli Shi
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology and Department of Pathophysiology, School of Basic Medical Sciences, Queen Mary School, Nanchang University, Nanchang, China
| | - Shanshan Jiang
- Institute of Hematological Research, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Yuanyuan Wang
- Clinical Systems Biology Laboratory, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Junrong Zou
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology and Department of Pathophysiology, School of Basic Medical Sciences, Queen Mary School, Nanchang University, Nanchang, China
| | - Ying Ying
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology and Department of Pathophysiology, School of Basic Medical Sciences, Queen Mary School, Nanchang University, Nanchang, China
| | - Deqiang Huang
- Research Institute of Digestive Diseases, The First Affiliated Hospital, Nanchang University, Nanchang, China
| | - Lingyu Luo
- Research Institute of Digestive Diseases, The First Affiliated Hospital, Nanchang University, Nanchang, China
| | - Xiaohua Yan
- Institute of Basic Biomedical Sciences and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
| | - Zhijun Luo
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology and Department of Pathophysiology, School of Basic Medical Sciences, Queen Mary School, Nanchang University, Nanchang, China
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Abstract
INTRODUCTION Preclinical, clinical, and population-based studies have provided evidence that anti-diabetic drugs affect bone metabolism and may affect the risk of fracture in diabetic patients. AREAS COVERED An overview of the skeletal effects of anti-diabetic drugs used in type 2 diabetes is provided. Searches on AdisInsight, PubMed, and Medline databases were conducted up to 1st July 2020. The latest evidence from randomized clinical trials and population-based studies on the skeletal safety of the most recent drugs (DPP-4i, GLP-1RA, and SGLT-2i) is provided. EXPERT OPINION Diabetic patients present with a higher risk of fracture for a given bone mineral density suggesting a role of bone quality in the etiology of diabetic fracture. Bone quality is difficult to assess in human clinical practice and the use of preclinical models provides valuable information on diabetic bone alterations. As several links have been established between bone and energy homeostasis, it is interesting to study the safety of anti-diabetic drugs on the skeleton. So far, evidence for the newest molecules suggests a neutral fracture risk, but further studies, especially in different types of patient populations (patients at risk or with history of cardiovascular disease, renal impairment, neuropathy) are required to fully appreciate this matter.
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Affiliation(s)
- Guillaume Mabilleau
- Groupe Etude Remodelage Osseux et biomatériaux, GEROM, UPRES EA 4658, UNIV Angers, SFR ICAT 4208, Institut de Biologie en Santé , Angers, France
- Service Commun d'Imagerie et Analyses Microscopiques, SCIAM, UNIV Angers, SFR ICAT 4208, Institut de Biologie en Santé , Angers, France
- Bone pathology unit, Angers University hospital , Angers Cedex, France
| | - Béatrice Bouvard
- Groupe Etude Remodelage Osseux et biomatériaux, GEROM, UPRES EA 4658, UNIV Angers, SFR ICAT 4208, Institut de Biologie en Santé , Angers, France
- Rheumatology department, Angers University Hospital , Angers Cedex, France
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Donnelly LA, Dennis JM, Coleman RL, Sattar N, Hattersley AT, Holman RR, Pearson ER. Risk of Anemia With Metformin Use in Type 2 Diabetes: A MASTERMIND Study. Diabetes Care 2020; 43:2493-2499. [PMID: 32801130 PMCID: PMC7510037 DOI: 10.2337/dc20-1104] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 07/13/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To evaluate the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data. RESEARCH DESIGN AND METHODS Anemia was defined as a hemoglobin measure of <11 g/dL. In the RCTs A Diabetes Outcome Progression Trial (ADOPT; n = 3,967) and UK Prospective Diabetes Study (UKPDS; n = 1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters. In the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population (n = 3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk. RESULTS In ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones. In UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin. In ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years. In UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments. At years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia. CONCLUSIONS Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B12 deficiency alone.
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Affiliation(s)
- Louise A Donnelly
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee, U.K
| | - John M Dennis
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, U.K
| | - Ruth L Coleman
- Institute of Cardiovascular and Medicine Sciences, University of Glasgow, Glasgow, U.K
| | - Naveed Sattar
- Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K
| | - Andrew T Hattersley
- Institute of Biomedical & Clinical Science, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, U.K
| | - Rury R Holman
- Institute of Cardiovascular and Medicine Sciences, University of Glasgow, Glasgow, U.K
| | - Ewan R Pearson
- Population Health & Genomics, School of Medicine, University of Dundee, Dundee, U.K.
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Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N. Japanese Clinical Practice Guideline for Diabetes 2019. Diabetol Int 2020; 11:165-223. [PMID: 32802702 PMCID: PMC7387396 DOI: 10.1007/s13340-020-00439-5] [Citation(s) in RCA: 280] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Indexed: 01/09/2023]
Affiliation(s)
- Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Atsushi Goto
- Department of Health Data Science, Graduate School of Data Science, Yokohama City University, Yokohama, Japan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and Endocrinology, Kumamoto University Hospital, Kumamoto, Japan
| | - Mitsuhiko Noda
- Department of Diabetes, Metabolism and Endocrinology, Ichikawa Hospital, International University of Health and Welfare, Ichikawa, Japan
| | - Hiroshi Noto
- Division of Endocrinology and Metabolism, St. Luke’s International Hospital, Tokyo, Japan
| | - Hideki Origasa
- Department of Biostatistics and Clinical Epidemiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Haruhiko Osawa
- Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan
| | - Akihiko Taguchi
- Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Yukio Tanizawa
- Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Kazuyuki Tobe
- First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, Osawa H, Taguchi A, Tanizawa Y, Tobe K, Yoshioka N. Japanese Clinical Practice Guideline for Diabetes 2019. J Diabetes Investig 2020; 11:1020-1076. [PMID: 33021749 PMCID: PMC7378414 DOI: 10.1111/jdi.13306] [Citation(s) in RCA: 197] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 05/24/2020] [Indexed: 01/09/2023] Open
Affiliation(s)
- Eiichi Araki
- Department of Metabolic MedicineFaculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Atsushi Goto
- Department of Health Data ScienceGraduate School of Data ScienceYokohama City UniversityYokohamaJapan
| | - Tatsuya Kondo
- Department of Diabetes, Metabolism and EndocrinologyKumamoto University HospitalKumamotoJapan
| | - Mitsuhiko Noda
- Department of Diabetes, Metabolism and EndocrinologyIchikawa HospitalInternational University of Health and WelfareIchikawaJapan
| | - Hiroshi Noto
- Division of Endocrinology and MetabolismSt. Luke's International HospitalTokyoJapan
| | - Hideki Origasa
- Department of Biostatistics and Clinical EpidemiologyGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
| | - Haruhiko Osawa
- Department of Diabetes and Molecular GeneticsEhime University Graduate School of MedicineToonJapan
| | - Akihiko Taguchi
- Department of Endocrinology, Metabolism, Hematological Science and TherapeuticsGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Yukio Tanizawa
- Department of Endocrinology, Metabolism, Hematological Science and TherapeuticsGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Kazuyuki Tobe
- First Department of Internal MedicineGraduate School of Medicine and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
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Paschou SA, Anagnostis P, Pavlou DI, Vryonidou A, Goulis DG, Lambrinoudaki I. Diabetes in Menopause: Risks and Management. Curr Vasc Pharmacol 2020; 17:556-563. [PMID: 29938620 DOI: 10.2174/1570161116666180625124405] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 06/05/2018] [Accepted: 06/16/2018] [Indexed: 12/14/2022]
Abstract
The aim of this review is to present, critically appraise and qualitatively synthesize current evidence on the risk of type 2 diabetes mellitus (T2DM) development during menopause, the management of climacteric symptoms in women with T2DM and the management of T2DM in postmenopausal women. Menopause represents the end of reproductive life in women, as a result of ovarian aging. It is characterized by substantial decrease in the endogenous oestrogen concentrations and it is accompanied by alterations in body weight, adipose tissue distribution and energy expenditure, as well as insulin secretion, insulin sensitivity and activity that can predispose to the development of T2DM, independently of, and additively to, aging. Many women in midlife experience climacteric symptoms, including hot flushes and night sweats, resulting in an indication to receive Hormone Replacement Treatment (HRT). HRT has a favourable effect on glucose homeostasis both in women without and with T2DM. The latter was considered in the past as a cardiovascular disease (CVD) equivalent, which would suggest that women with the disease should not receive HRT. However, nowadays evidence exists to support an individualized approach of women based on their CVD risk, as some women with T2DM may be excellent candidates for HRT. Regarding T2DM management for women in menopause, lifestyle intervention, including diet and exercise, constitutes its cornerstone. However, most of these women will eventually require pharmacologic therapy. The most suitable agents should be selected according to their metabolic, cardiovascular and bone effects, taking into consideration the specific characteristics and comorbidities of each postmenopausal woman.
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Affiliation(s)
- Stavroula A Paschou
- Division of Endocrinology and Diabetes, "Aghia Sophia" Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Anagnostis
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitra I Pavlou
- Forth Department of Internal Medicine, Hippokration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andromachi Vryonidou
- Department of Endocrinology and Diabetes, Hellenic Red Cross Hospital, Athens, Greece
| | - Dimitrios G Goulis
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Irene Lambrinoudaki
- Division of Endocrinology and Diabetes, Second Department of Obstetrics and Gynecology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Paschoal VA, Walenta E, Talukdar S, Pessentheiner AR, Osborn O, Hah N, Chi TJ, Tye GL, Armando AM, Evans RM, Chi NW, Quehenberger O, Olefsky JM, Oh DY. Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity. Cell Metab 2020; 31:1173-1188.e5. [PMID: 32413335 PMCID: PMC7337476 DOI: 10.1016/j.cmet.2020.04.020] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/06/2020] [Accepted: 04/27/2020] [Indexed: 12/14/2022]
Abstract
G protein-coupled receptor 120 (GPR120) and PPARγ agonists each have insulin sensitizing effects. But whether these two pathways functionally interact and can be leveraged together to markedly improve insulin resistance has not been explored. Here, we show that treatment with the PPARγ agonist rosiglitazone (Rosi) plus the GPR120 agonist Compound A leads to additive effects to improve glucose tolerance and insulin sensitivity, but at lower doses of Rosi, thus avoiding its known side effects. Mechanistically, we show that GPR120 is a PPARγ target gene in adipocytes, while GPR120 augments PPARγ activity by inducing the endogenous ligand 15d-PGJ2 and by blocking ERK-mediated inhibition of PPARγ. Further, we used macrophage- (MKO) or adipocyte-specific GPR120 KO (AKO) mice to show that GRP120 has anti-inflammatory effects via macrophages while working with PPARγ in adipocytes to increase insulin sensitivity. These results raise the prospect of a safer way to increase insulin sensitization in the clinic.
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Affiliation(s)
- Vivian A Paschoal
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Evelyn Walenta
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Saswata Talukdar
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Merck & Co., Inc., SSF, 630 Gateway Boulevard, South San Francisco, CA 94080, USA
| | - Ariane R Pessentheiner
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Olivia Osborn
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Nasun Hah
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Tyler J Chi
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - George L Tye
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH 44106, USA
| | - Aaron M Armando
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Nai-Wen Chi
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; VA San Diego Healthcare System, San Diego, CA, USA
| | - Oswald Quehenberger
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jerrold M Olefsky
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
| | - Da Young Oh
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
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40
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Oh TK, Song IA. Metformin therapy and hip fracture risk among patients with type II diabetes mellitus: A population-based cohort study. Bone 2020; 135:115325. [PMID: 32201359 DOI: 10.1016/j.bone.2020.115325] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 03/14/2020] [Accepted: 03/16/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND This study aimed to investigate the potential association of exposure to metformin therapy with the risk of hip fracture in adult patients with type II diabetes. We included patients with diabetes who were registered in the 2010 sample cohort database of the National Health Insurance Service in South Korea. METHODS The patients who had been prescribed continuous oral metformin therapy for a 1-year period in 2010 were defined as the metformin group, while those who were not prescribed metformin during the same period were classified as the control group. The primary endpoint of this study was the development of hip fracture between January 2011 and December 2015. RESULTS A total of 64,878 patients (31,300 patients in the metformin group and 32,439 patients in the control group) were included in this study. Among those, 1655 patients (2.6%) had experienced a hip fracture. After a propensity score matching, a total of 37,378 patients (18,689 patients in each group) were included in the analysis. Using a time-dependent Cox regression analysis on the propensity score-matched cohort, the exposure to metformin was not significantly associated with the development of hip fracture compared to the control group (hazard ratio: 1.00, 95% confidence interval: 0.86 to 1.16; P = 0.985). Similar results were observed using sensitivity analysis of a multivariable time-dependent Cox regression model of the entire cohort (hazard ratio: 0.78, 95% confidence interval: 0.36 to 1.69; P = 0.525). CONCLUSIONS This population-based cohort study in South Korea showed that there was no significant association between the exposure to metformin therapy and hip fracture in patients with type II diabetes mellitus.
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Affiliation(s)
- Tak Kyu Oh
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - In-Ae Song
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
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Eller-Vainicher C, Cairoli E, Grassi G, Grassi F, Catalano A, Merlotti D, Falchetti A, Gaudio A, Chiodini I, Gennari L. Pathophysiology and Management of Type 2 Diabetes Mellitus Bone Fragility. J Diabetes Res 2020; 2020:7608964. [PMID: 32566682 PMCID: PMC7262667 DOI: 10.1155/2020/7608964] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 04/29/2020] [Accepted: 05/04/2020] [Indexed: 12/14/2022] Open
Abstract
Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of bone fragility fractures compared to nondiabetic subjects. This increased fracture risk may occur despite normal or even increased values of bone mineral density (BMD), and poor bone quality is suggested to contribute to skeletal fragility in this population. These concepts explain why the only evaluation of BMD could not be considered an adequate tool for evaluating the risk of fracture in the individual T2DM patient. Unfortunately, nowadays, the bone quality could not be reliably evaluated in the routine clinical practice. On the other hand, getting further insight on the pathogenesis of T2DM-related bone fragility could consent to ameliorate both the detection of the patients at risk for fracture and their appropriate treatment. The pathophysiological mechanisms underlying the increased risk of fragility fractures in a T2DM population are complex. Indeed, in T2DM, bone health is negatively affected by several factors, such as inflammatory cytokines, muscle-derived hormones, incretins, hydrogen sulfide (H2S) production and cortisol secretion, peripheral activation, and sensitivity. All these factors may alter bone formation and resorption, collagen formation, and bone marrow adiposity, ultimately leading to reduced bone strength. Additional factors such as hypoglycemia and the consequent increased propensity for falls and the direct effects on bone and mineral metabolism of certain antidiabetic medications may contribute to the increased fracture risk in this population. The purpose of this review is to summarize the literature evidence that faces the pathophysiological mechanisms underlying bone fragility in T2DM patients.
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Affiliation(s)
- C. Eller-Vainicher
- Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - E. Cairoli
- Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, Italy
- Dept. of Clinical Sciences & Community Health, University of Milan, Milan, Italy
| | - G. Grassi
- Unit of Endocrinology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Dept. of Clinical Sciences & Community Health, University of Milan, Milan, Italy
| | - F. Grassi
- Ramses Lab, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - A. Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - D. Merlotti
- Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
| | - A. Falchetti
- Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, Italy
| | - A. Gaudio
- Department of Clinical and Experimental Medicine, University of Catania, University Hospital ‘G. Rodolico', Catania, Italy
| | - I. Chiodini
- Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, Italy
- Dept. of Clinical Sciences & Community Health, University of Milan, Milan, Italy
| | - L. Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
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Xu H, Wang Z, Li X, Fan M, Bao C, Yang R, Song F, Xu W, Qi X. Osteoporosis and Osteopenia Among Patients With Type 2 Diabetes Aged ≥50: Role of Sex and Clinical Characteristics. J Clin Densitom 2020; 23:29-36. [PMID: 31101413 DOI: 10.1016/j.jocd.2019.04.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 04/13/2019] [Accepted: 04/17/2019] [Indexed: 10/27/2022]
Abstract
INTRODUCTION/BACKGROUND Although some studies have explored the association of adiposity and life habits (such as smoking) with osteoporosis and osteopenia among type 2 diabetes mellitus (T2DM) patients, the association between diabetic clinical characteristics (especially hypoglycemic drug use) and osteoporosis/osteopenia remains unclear. This study aimed to investigate the relationship of clinical characteristics with osteoporosis and osteopenia among T2DM patients by sex. METHODS A total of 1222 T2DM patients aged ≥50 were included in the present study. Information on demographic, anthropometric and clinical characteristics was collected from medical records. Bone mineral density was assessed by dual-energy X-ray absorptiometry densitometer. Multiple adjusted logistic regression analyses were performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of osteoporosis and osteopenia related to clinical characteristics. RESULTS Of all participants, the prevalence of osteoporosis and osteopenia was 9.2% and 41.3%, respectively, and they were higher in females (14.7% and 48.5%) than in males (2.8% and 33%). After adjustment for potential confounders, the results showed that overweight (OR = 0.59; 95% CI, 0.42-0.81) and obesity (OR = 0.35; 95% CI, 0.24-0.50) were related to decreased odds of osteoporosis and osteopenia in both male and female T2DM patients, poor glycemic control (OR = 1.63; 95% CI, 1.08-2.47) was associated with increased odds of osteoporosis and osteopenia in males, and metformin treatment (OR = 0.65; 95% CI, 0.43-0.99) was associated with decreased odds of osteoporosis and osteopenia in females. CONCLUSIONS Better glycemic management and rational choice of antidiabetic medication might be promising to prevent osteoporosis in T2DM patients. Further longitudinal studies are warranted to explore the association between antidiabetic treatment and osteoporosis.
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Affiliation(s)
- Hui Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Zhida Wang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Xuerui Li
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Meijuan Fan
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Cuiping Bao
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Rongrong Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Fei Song
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Weili Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China; Aging Research Center (ARC), Department Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
| | - Xiuying Qi
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China.
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Chan CB, Ahuja P, Ye K. Developing Insulin and BDNF Mimetics for Diabetes Therapy. Curr Top Med Chem 2019; 19:2188-2204. [PMID: 31660832 DOI: 10.2174/1568026619666191010160643] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 08/29/2019] [Accepted: 09/05/2019] [Indexed: 01/06/2023]
Abstract
Diabetes is a global public health concern nowadays. The majority of diabetes mellitus (DM) patients belong to type 2 diabetes mellitus (T2DM), which is highly associated with obesity. The general principle of current therapeutic strategies for patients with T2DM mainly focuses on restoring cellular insulin response by potentiating the insulin-induced signaling pathway. In late-stage T2DM, impaired insulin production requires the patients to receive insulin replacement therapy for maintaining their glucose homeostasis. T2DM patients also demonstrate a drop of brain-derived neurotrophic factor (BDNF) in their circulation, which suggests that replenishing BDNF or enhancing its downstream signaling pathway may be beneficial. Because of their protein nature, recombinant insulin or BDNF possess several limitations that hinder their clinical application in T2DM treatment. Thus, developing orally active "insulin pill" or "BDNF pill" is essential to provide a more convenient and effective therapy. This article reviews the current development of non-peptidyl chemicals that mimic insulin or BDNF and their potential as anti-diabetic agents.
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Affiliation(s)
- Chi Bun Chan
- School of Biological Sciences, The University of Hong Kong, Hong Kong
| | - Palak Ahuja
- School of Biological Sciences, The University of Hong Kong, Hong Kong
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University of School of Medicine, Atlanta, GA, United States
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Wang Z, Tang J, Li Y, Wang Y, Guo Y, Tu Q, Chen J, Wang C. AdipoRon promotes diabetic fracture repair through endochondral ossification-based bone repair by enhancing survival and differentiation of chondrocytes. Exp Cell Res 2019; 387:111757. [PMID: 31838062 DOI: 10.1016/j.yexcr.2019.111757] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 12/03/2019] [Accepted: 12/04/2019] [Indexed: 12/27/2022]
Abstract
Diabetic bone defects may exhibit impaired endochondral ossification (ECO) leading to delayed bone repair. AdipoRon, a receptor agonist of adiponectin polymers, can ameliorate diabetes and related complications, as well as overcome the disadvantages of the unstable structure of artificial adiponectin polymers. Here, the effects of AdipoRon on the survival and differentiation of chondrocytes in a diabetic environment were explored focusing on related mechanisms in gene and protein levels. In vivo, AdipoRon was applied to diet-induced-obesity (DIO) mice, a model of obesity and type 2 diabetes, with femoral fracture. Sequential histological evaluations and micro-CT were examined for further verification. We found that AdipoRon could ameliorate cell viability, apoptosis, and reactive oxygen species (ROS) production and promote mRNA expression of chondrogenic markers and cartilaginous matrix production of ATDC5 cells in high glucose medium via activating ERK1/2 pathway. Additionally, DIO mice with intragastric AdipoRon administration had more neocartilage and accelerated new bone formation. These data suggest that AdipoRon could stimulate bone regeneration via ECO in diabetes.
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Affiliation(s)
- Zhongyi Wang
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China
| | - Jinxin Tang
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China
| | - Ying Li
- Department of Stomatology, Jinan Central Hospital Affiliated to Shandong University, Jinan, 250013, China
| | - Yu Wang
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China
| | - Yanyang Guo
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China
| | - Qisheng Tu
- Tufts School of Dental Medicine, Sackler School of Graduate Biomedical Sciences, Tufts School of Medicine, Boston, 02111, USA
| | - Jake Chen
- Tufts School of Dental Medicine, Sackler School of Graduate Biomedical Sciences, Tufts School of Medicine, Boston, 02111, USA.
| | - Chen Wang
- Jiangsu Key Laboratory of Oral Diseases, Department of Prosthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, 210029, China.
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45
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[Diabetes mellitus and risk of hip fracture. A systematic review]. Rev Esp Geriatr Gerontol 2019; 55:34-41. [PMID: 31668564 DOI: 10.1016/j.regg.2019.08.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 07/22/2019] [Accepted: 08/25/2019] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND OBJECTIVES It has been reported that the risk of fracture is increased in patients with diabetes mellitus (DM). The aim of this study was to investigate the possible relationship between DM and hip fracture, as well as any associated risk factors, by means of a systemic review of the literature. METHODS PubMed and SCOPUS databases were used to search for relevant studies published from January 2001 to August 2018. Retrospective and prospective cohort studies were selected in which the estimated risk of hip fracture was demonstrated by comparing groups of diabetic patients with non-diabetics. A search was also made for risk factors independent from the association between DM and hip fracture. RESULTS A total of 27 articles that fulfilled the inclusion criteria were included. A clear association was observed in diabetic patients (women and men) compared to non-diabetics patients. Among the risk factors, the most important ones were the fact that diabetes was type 1, probably associated with greater risk to a longer duration of DM, and being a female. CONCLUSIONS There is an increased risk of hip fracture in patients diagnosed with DM. This association is more significant in diabetes type 1 and women.
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Hidayat K, Du X, Wu MJ, Shi BM. The use of metformin, insulin, sulphonylureas, and thiazolidinediones and the risk of fracture: Systematic review and meta-analysis of observational studies. Obes Rev 2019; 20:1494-1503. [PMID: 31250977 DOI: 10.1111/obr.12885] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/29/2019] [Accepted: 05/08/2019] [Indexed: 12/12/2022]
Abstract
Certain glucose-lowering medications have been implicated in the risk of fracture. While there is convincing evidence from randomized controlled trials (RCTs) that thiazolidinedione use is associated with a higher risk of fracture, the effects of metformin, insulin, and sulphonylureas on the risk of fracture remain equivocal because these medications are not generally investigated in RCTs. A meta-analysis of observational studies to provide further insights into the association between the use of metformin, insulin, sulphonylureas, or thiazolidinediones and the risk of fracture was performed. PubMed and Web of Science databases were searched to identify relevant observational studies. A random effects model was used to estimate the summary relative risks (RRs) with 95% confidence intervals (CIs). The use of insulin (RR 1.49, 95% CI 1.29, 1.73; n = 23 studies), sulphonylureas (RR 1.30, 95% CI 1.18, 1.43; n = 10), and thiazolidinediones (RR 1.24, 95% CI 1.13, 1.35; n = 14) was associated with an increased risk of fracture, whereas the use of metformin was associated with a reduced risk of fracture (RR 0.86, 95% CI 0.75, 0.99; n = 12). Regarding types of thiazolidinediones, both pioglitazone (RR 1.38, 95% CI 1.23, 1.54; n = 5) and rosiglitazone (RR 1.34, 95% CI 1.14, 1.58; n = 5) were positively associated with the risk of fracture. In summary, there is compelling evidence to discourage the use of thiazolidinediones in individuals with an increased risk of fracture, whereas metformin appears to have a good safety profile for the risk of fracture. The reduced risk of fracture with metformin could possibly be due to the reduced overall risk of fracture among metformin users, as this medication is typically prescribed in the early stages of type 2 diabetes mellitus. The use of insulin or sulphonylureas may increase fracture risk; this risk is most likely attributed to an increased risk of hypoglycaemia-induced falls. Further confirmation by additional RCTs is required to determine whether the observed association between the use of metformin, insulin, or sulphonylureas and the risk of fracture is due to treatment with these medications or confounding factors.
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Affiliation(s)
- Khemayanto Hidayat
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xuan Du
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Meng-Jiao Wu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Bi-Min Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, China
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Costantini S, Conte C. Bone health in diabetes and prediabetes. World J Diabetes 2019; 10:421-445. [PMID: 31523379 PMCID: PMC6715571 DOI: 10.4239/wjd.v10.i8.421] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 06/03/2019] [Accepted: 07/20/2019] [Indexed: 02/05/2023] Open
Abstract
Bone fragility has been recognized as a complication of diabetes, both type 1 diabetes (T1D) and type 2 diabetes (T2D), whereas the relationship between prediabetes and fracture risk is less clear. Fractures can deeply impact a diabetic patient's quality of life. However, the mechanisms underlying bone fragility in diabetes are complex and have not been fully elucidated. Patients with T1D generally exhibit low bone mineral density (BMD), although the relatively small reduction in BMD does not entirely explain the increase in fracture risk. On the contrary, patients with T2D or prediabetes have normal or even higher BMD as compared with healthy subjects. These observations suggest that factors other than bone mass may influence fracture risk. Some of these factors have been identified, including disease duration, poor glycemic control, presence of diabetes complications, and certain antidiabetic drugs. Nevertheless, currently available tools for the prediction of risk inadequately capture diabetic patients at increased risk of fracture. Aim of this review is to provide a comprehensive overview of bone health and the mechanisms responsible for increased susceptibility to fracture across the spectrum of glycemic status, spanning from insulin resistance to overt forms of diabetes. The management of bone fragility in diabetic patient is also discussed.
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Affiliation(s)
- Silvia Costantini
- Department of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan 20123, Italy
- Epatocentro Ticino, Lugano 6900, Switzerland
| | - Caterina Conte
- Department of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan 20123, Italy
- IRCCS Ospedale San Raffaele, Internal Medicine and Transplantation, Milan 20123, Italy
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Henderson S, Ibe I, Cahill S, Chung YH, Lee FY. Bone Quality and Fracture-Healing in Type-1 and Type-2 Diabetes Mellitus. J Bone Joint Surg Am 2019; 101:1399-1410. [PMID: 31393433 DOI: 10.2106/jbjs.18.01297] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Shasta Henderson
- Department of Orthopaedics, Pennsylvania State University, Hershey, Pennsylvania
| | - Izuchukwu Ibe
- Department of Orthopaedics and Rehabilitation (I.I.), Yale School of Medicine (S.C., Y.-H.C., and F.Y.L.), New Haven, Connecticut
| | - Sean Cahill
- Department of Orthopaedics and Rehabilitation (I.I.), Yale School of Medicine (S.C., Y.-H.C., and F.Y.L.), New Haven, Connecticut
| | - Yeon-Ho Chung
- Department of Orthopaedics and Rehabilitation (I.I.), Yale School of Medicine (S.C., Y.-H.C., and F.Y.L.), New Haven, Connecticut
| | - Francis Y Lee
- Department of Orthopaedics and Rehabilitation (I.I.), Yale School of Medicine (S.C., Y.-H.C., and F.Y.L.), New Haven, Connecticut
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Hygum K, Starup-Linde J, Langdahl BL. Diabetes and bone. Osteoporos Sarcopenia 2019; 5:29-37. [PMID: 31346556 PMCID: PMC6630041 DOI: 10.1016/j.afos.2019.05.001] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/11/2019] [Accepted: 05/03/2019] [Indexed: 12/16/2022] Open
Abstract
Bone disease is a serious complication to diabetes. Patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) suffer from an increased risk of fracture, most notably at the hip, compared with patients without diabetes. Confounders such as patient sex, age, body mass index, blood glucose status, fall risk, and diabetes medications may influence the fracture risk. Different underlying mechanisms contribute to bone disease in patients with diabetes. Bone quality is affected by low bone turnover in T1D and T2D, and furthermore, incorporation of advanced glycation end-products, changes in the incretin hormone response, and microvascular complications contribute to impaired bone quality and increased fracture risk. Diagnosis of bone disease in patients with diabetes is a challenge as current methods for fracture prediction such as bone mineral density T-score and fracture risk assessment tools underestimate fracture risk for patients with T1D and T2D. This review focuses on bone disease and fracture risk in patients with diabetes regarding epidemiology, underlying disease mechanisms, and diagnostic methods, and we also provide considerations regarding the management of diabetes patients with bone disease in terms of an intervention threshold and different treatments.
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Affiliation(s)
| | | | - Bente L. Langdahl
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
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50
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McGurnaghan S, Blackbourn LAK, Mocevic E, Haagen Panton U, McCrimmon RJ, Sattar N, Wild S, Colhoun HM. Cardiovascular disease prevalence and risk factor prevalence in Type 2 diabetes: a contemporary analysis. Diabet Med 2019; 36:718-725. [PMID: 30246473 PMCID: PMC6585697 DOI: 10.1111/dme.13825] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/20/2018] [Indexed: 01/01/2023]
Abstract
AIMS To describe the prevalence of major cardiovascular disease (CVD) and risk factor control in a contemporary population with Type 2 diabetes. METHODS We used data from the national registry in Scotland, Scottish Care Information-Diabetes, linked to hospital admissions. Using descriptive statistics and logistic regression we described associations of risk factors with CVD. CVD was defined based on diagnostic codes in primary or secondary care data for ischaemic heart disease, cerebrovascular disease peripheral arterial disease, heart failure, cardiac arrhythmia, hypertensive heart disease and revascularization procedures. RESULTS Among 248 400 people with Type 2 diabetes with a median age of 67.5 years (IQR 58.2, 76.1) and median diabetes duration of 7.8 years (3.8, 13.0), 32% had prior CVD (35% of men, 29% of women). Median HbA1c overall was 55 mmol/mol (7.2%), median SBP was 132 mmHg, median total cholesterol was 4.1 mmol/l and mean BMI was 32 kg/m2 . Overall two-thirds (65% of men, 68% of women) have two or more of the following CVD risk factor thresholds: HbA1c ≥ 53 mmol/mol (7%), SBP > 130 mmHg or DBP > 80 mmHg, total cholesterol ≥ 5 mmol/l or BMI ≥ 30 kg/m2 , or were currently smoking. Overall 84% were taking anti-hypertensives and 75% a statin. Use of metformin was common at 58%, but other diabetes drugs that reduce CVD were rarely used. CONCLUSIONS There continues to be a high prevalence of CVD among people with Type 2 diabetes and a high level of unmet need for risk factor control. This implies substantial scope for reducing the excess risk of CVD in diabetes through improved management of known risk factors.
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Affiliation(s)
- S. McGurnaghan
- MRC Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUK
| | - L. A. K. Blackbourn
- MRC Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUK
| | | | | | | | - N. Sattar
- Institute of Cardiovascular and Medical SciencesUniversity of GlasgowGlasgow
| | - S. Wild
- Usher Institute of Population Health Sciences and InformaticsUniversity of EdinburghEdinburghUK
| | - H. M. Colhoun
- MRC Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUK
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