Advanced Glycation Endproducts and Bone Material Strength in Type 2 Diabetes

Furst, Jessica; Bandeira, Leonardo; Fan, Wen-Wei; Agarwal, Sanchita; Nishiyama, Kyle K.; McMahon, Donald J.; Dworakowski, Elzbieta; Jiang, Hongfeng; Silverberg, Shonni J.; Rubin, Mishaela R.

doi:10.1210/jc.2016-1437

Cited by 186 publications

(145 citation statements)

References 51 publications

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“…In response to physiological doses of insulin, cultured osteoblasts show increased proliferation, collagen synthesis, alkaline phosphatase production, and glucose uptake [120] and hyperinsulinaemia following insulin administration stimulates osteoblast activity and increases mineral apposition rates in rats [121]. However, despite high bone mass in adults with type 2 diabetes, bone quality is impaired and fracture risk is high suggesting that in the hyperinsulinaemic state, bone quality is impaired [122, 123]. To date, there are no studies in children to determine whether changes in skeletal ‘integrity’ secondary to hyperinsulinaemia occur as a result of chronic exposure to high blood glucose and insulin resistance.…”

Section: The Impact Of Childhood Obesity On the Endocrine Environmentmentioning

confidence: 99%

The Impact of Fat and Obesity on Bone Microarchitecture and Strength in Children

Farr

Dimitri

2016

Calcif Tissue Int

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A complex interplay of genetic, environmental, hormonal, and behavioral factors affect skeletal development, several of which are associated with childhood fractures. Given the rise in obesity worldwide, it is of particular concern that excess fat accumulation during childhood appears to be a risk factor for fractures. Plausible explanations for this higher fracture risk include a greater propensity for falls, greater force generation upon fall impact, unhealthy lifestyle habits, and excessive adipose tissue that may have direct or indirect detrimental effects on skeletal development. To date, there remains little resolution or agreement about the impact of obesity and adiposity on skeletal development as well as the mechanisms underpinning these changes. Limitations of imaging modalities, short duration of follow-up in longitudinal studies, and differences among cohorts examined may all contribute to conflicting results. Nonetheless, a linear relationship between increasing adiposity and skeletal development seems unlikely. Fat mass may confer advantages to the developing cortical and trabecular bone compartments, provided that gains in fat mass are not excessive. However, when fat mass accumulation reaches excessive levels, unfavorable metabolic changes may impede skeletal development. Mechanisms underpinning these changes may relate to changes in the hormonal milieu, with adipokines potentially playing a central role, but again findings have been confounding. Changes in the relationship between fat and bone also appear to be age and sex dependent. Clearly, more work is needed to better understand the controversial impact of fat and obesity on skeletal development and fracture risk during childhood.

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Section: The Impact Of Childhood Obesity On the Endocrine Environmentmentioning

confidence: 99%

The Impact of Fat and Obesity on Bone Microarchitecture and Strength in Children

Farr

Dimitri

2016

Calcif Tissue Int

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“…Instead, elevated fracture risk is attributed to secondary deficits in the microarchitecture and in the material properties of the bone tissue, along with pathophysiological and genetic factors intrinsic to diabetes itself . Variables inherent to both T1D and T2D, including chronic hyperglycemia and glycemic variation, tissue‐specific accumulation of advanced glycation end‐products (AGEs), dysregulation of insulin‐like growth factor 1 (IGF‐1) bioavailability, variable insulin exposure (endogenous or exogenous), enhanced oxidative stress, changes in bone mineral and vitamin D homeostasis, and regional diabetic microvascular disease, undoubtedly all impact the skeletal quality in diabetes . Added to these variables is an increased propensity to falling, whether attributable to acute hypoglycemia, peripheral neuropathy, decreased visual acuity, or postural instability .…”

Section: Introductionmentioning

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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“…Accumulation of PEN in skin and bone exponentially increase with age [45, 46], and these amounts may be closely related to each other. The material strength of the bones in patients with T2DM, as confirmed by microindentation, was inferior to the non-diabetic subjects and was significantly and inversely associated with the levels of skin autofluorescence [47], indicating that the bone accumulation of AGEs aggravates the material properties of bone. Cross-sectional and prospective clinical studies showed that increased serum and urinary PEN concentrations were related to an increased risk of fractures in patients with type 1 and type 2 diabetes mellitus [48–50, 51•] (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Advanced Glycation End Products, Diabetes, and Bone Strength

Yamamoto

Sugimoto

2016

Curr Osteoporos Rep

164

105

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Diabetic patients have a higher fracture risk than expected by their bone mineral density (BMD). Poor bone quality is the most suitable and explainable cause for the elevated fracture risk in this population. Advanced glycation end products (AGEs), which are diverse compounds generated via a non-enzymatic reaction between reducing sugars and amine residues, physically affect the properties of the bone material, one of a component of bone quality, through their accumulation in the bone collagen fibers. On the other hand, these compounds biologically act as agonists for these receptors for AGEs (RAGE) and suppress bone metabolism. The concentrations of AGEs and endogenous secretory RAGE, which acts as a “decoy receptor” that inhibits the AGEs-RAGE signaling axis, are associated with fracture risk in a BMD-independent manner. AGEs are closely associated with the pathogenesis of this unique clinical manifestation through physical and biological mechanisms in patients with diabetes mellitus.

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Advanced Glycation Endproducts and Bone Material Strength in Type 2 Diabetes

Abstract: Bone material properties are impaired in postmenopausal women with T2D as determined by reference point indentation. The results suggest a role for the accumulation of AGEs to account for inferior BMSi in T2D.

Cited by 186 publications

References 51 publications

The Impact of Fat and Obesity on Bone Microarchitecture and Strength in Children

The Impact of Fat and Obesity on Bone Microarchitecture and Strength in Children

Diabetes pharmacotherapy and effects on the musculoskeletal system

Advanced Glycation End Products, Diabetes, and Bone Strength

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