Role of Metformin in Reversing the Negative Impact of Hyperglycemia on Bone Healing Around Implants Inserted in Type 2 Diabetic Rats

Serrão, Caroline Ribeiro; Bastos, Marta Ferreira; Cruz, Daniele Ferreira; Malta, Fernando de Souza; Vallim, Paolla Camacho; Duarte, Poliana Mendes

doi:10.11607/jomi.5754

Cited by 27 publications

(35 citation statements)

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“…In non‐diabetic female rodents (either C57BL/6 ovariectomized mice or female Wistar rats), metformin treatment had no beneficial effect on fracture healing . In diabetic Zucker rats, metformin had a negative effect on fracture repair, despite successfully improving blood glucose; similarly, in a rat model of T2D, metformin did not reverse the detrimental effects of hyperglycemia on bone healing around tibial titanium implants …”

Section: Drugs and Bonementioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Section: Drugs and Bonementioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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“…High-level glucose (>44 mmol/L) significantly decreased the gene expression levels of Runx2, IGF-1, and IGF-1R [38], which inhibited osteoblastic proliferation and development. Metformin increased the expression of OPG and decreased the RANKL/OPG ratio in the implant medullary area, yielding some molecular benefits in the osseointegration of implants under the hyperglycemic state, which suppressed the cell growth and mineralization [74]. Moreover, high-level glucose increased the intracellular cAMP level in a time-dependent manner, which reduces bone mass and negatively regulates osteoclastogenesis [75].…”

Section: Indirect Effect Of Metformin On Osteogenesismentioning

confidence: 99%

Role of Metformin on Osteoblast Differentiation in Type 2 Diabetes

Jiating

Buyun

Zhang

2019

BioMed Research International

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Metformin, an effective hypoglycemic, can modulate different points of malignant mass, polycystic ovary syndrome (PCOS), cardiovascular diseases, tuberculosis, and nerve regeneration. Recently, the effect of metformin on bone metabolism has been analyzed. Metformin relies on organic cation transporters (OCT1), a polyspecific cell membrane of the solute carrier 22A (SLC22A) gene family, to facilitate its intracellular uptake and action on complex I of the respiratory chain of mitochondria. These changes activate the cellular energy sensor AMP-activated protein kinase (AMPK). Thus, the increased cellular AMP/ATP ratio causes a dramatic and progressive activation of insulin and lysosomes, resulting in a decrease in intracellular glucose level, which promotes osteoblast proliferation and differentiation. AMPK also phosphorylates runt-related transcription factor 2 (Runx2) at S118, the lineage-specific transcriptional regulators, to promote osteogenesis. Metformin phosphorylates extracellular signal-regulated kinase (ERK), stimulates endothelial and inducible nitric oxide synthases (e/iNOS), inhibits the GSK3β/Wnt/β-catenin pathway, and promotes osteogenic differentiation of osteoblasts. The effect of metformin on hyperglycemia decreases intracellular reactive oxygen species (ROS) and advanced glycation end-products (AGEs) in collagen, and reduced serum levels of insulin-like growth factors (IGF-1) were beneficial for bone formation. Metformin has a certain effect on microangiopathy and anti-inflammation, which can induce osteoporosis, activate the activity of osteoclasts, and inhibit osteoblast activity, and has demonstrated extensive alteration in bone and mineral metabolism. The aim of this review was to elucidate the mechanisms of metformin on osteoblasts in insulin-deficient diabetes.

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“…Over the past decade, many strategies such as pharmacological agents and implant surface modifications attempted to increase osseointegration of implants in T2DM, but few of them are available as a routine treatment method in clinical settings. [3][4][5] Therefore, it is urgent to develop new treatment strategies to improve the osseointegration of implants in T2DM patients.…”

Section: Introductionmentioning

confidence: 99%

PTPN2 improves implant osseointegration in T2DM via inducing the dephosphorylation of ERK

Wang

Jia

Zhang

et al. 2019

Exp Biol Med (Maywood)

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Type 2 diabetes mellitus (T2DM) is considered to compromise implant osseointegration. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates glucose metabolism, systemic inflammation, and bone regeneration. This study aimed to investigate the role of PTPN2 in implant osseointegration in T2DM and explore the potential mechanisms. Streptozotocin-induced diabetic rats received implant surgery, with or without local overexpression of PTPN2 for three months, and implant osseointegration was examined by histological evaluation, micro-CT analysis, pull-out test, and scanning electron microscope. Rat bone marrow stem cells (RBMSCs) were isolated and exposed to high glucose, and osteogenic differentiation was evaluated by alizarin red staining, ALP assay, and Western blot analysis. Overexpression of PTPN2 could improve impaired implant osseointegration in T2DM rats and promote osteogenic differentiation of RBMSCs in high glucose. In addition, p-ERK level in RBMSCs was increased in high glucose and decreased after PTPN2 overexpression. These results suggest that PTPN2 promotes implant osseointegration in T2DM rats and enhances osteogenesis of RBMSCs in high glucose medium via inducing the dephosphorylation of ERK. PTPN2 may be a novel target for the therapy of impaired implant osseointegration in T2DM patients. Impact statement Using both in vivo and in vitro approaches, we made important findings that PTPN2 promoted implant osseointegration in T2DM rats and enhanced osteogenesis of RBMSCs in high glucose medium. The positive effects of PTPN2 on osteogenesis are related to the dephosphorylation of ERK and the inhibition of MAPK/ERK pathway. PTPN2 may be a novel target for the therapy of impaired implant osseointegration in T2DM patients.

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Role of Metformin in Reversing the Negative Impact of Hyperglycemia on Bone Healing Around Implants Inserted in Type 2 Diabetic Rats

Cited by 27 publications

References 0 publications

Diabetes pharmacotherapy and effects on the musculoskeletal system

Diabetes pharmacotherapy and effects on the musculoskeletal system

Role of Metformin on Osteoblast Differentiation in Type 2 Diabetes

PTPN2 improves implant osseointegration in T2DM via inducing the dephosphorylation of ERK

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