Unmasking the associations of lifestyle behaviors with type 2 diabetes, alzheimer’s disease and bone quality
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Authors
LLabre, Joan, Enid
Issue Date
2023-12
Type
Electronic thesis
Thesis
Thesis
Language
en_US
Keywords
Biomedical engineering
Alternative Title
Abstract
Bone is a dynamic tissue that, dependent on the state of its hierarchical levels, acts to provide support, and functions as a metabolic organ. The metabolism, structure, and function of bone can be affected by systemic diseases, such as Type 2 Diabetes (T2D) and Alzheimer’s Disease (AD). There are many contributing factors to T2D and AD occurrence, with research suggesting that lifestyle, environmental, and genetic factors all play an important role. Clinical studies have shown that lifestyle habits such as high-fat diets (HFDs) and circadian rhythm disruption (CRD) contribute to increase chronic inflammation and to the development and progression of T2D and AD. While these ubiquitous environmental factors can independently impact bone development, their interactions can have complex effects on bone quality and skeletal fragility. Indeed, skeletal fragility is a severe comorbidity of both T2D and AD. Diabetic patients, despite observed normal to elevated bone mineral density (BMD), have an increased risk for fragility fractures. In contrast, AD patients exhibit an increased risk for fracture with reduced BMD. Clinical studies link AD and osteoporosis, yet there is a lack of understanding on the effects of AD on bone beyond bone density. This study posits that, despite the contrary effects in bone quantity, both T2D and AD contribute to modifications of the primary constituents of bone (e.g., hydroxyapatite mineral, type I collagen, and non-collagenous proteins) and can decrease bone quality and increase bone fragility. For example, the increase levels of oxidative stress and inflammation, resulting from hyperglycemia or the neurodegeneration cascade, can promulgate the accumulation of advanced glycation end-products (AGEs). AGEs can stiffen the organic matrix, disrupt collagen organization, and alter fibrillar sliding leading to reduced energy dissipation in bone.
To address the above questions, this study utilizes a variety of preclinical animal (mouse) models to establish the effects of T2D and AD on bone matrix and skeletal fragility. The findings of this study highlight the two major pathways to skeletal fragility in AD through alteration of bone quality: accumulation of AGEs in the organic matrix; and loss of mineralization and crystallinity, and decreased crystal size. Furthermore, because HFD and CRD are often implicated in T2D and AD, an additional mouse model is employed here to determine the effects of the combination of CRD and a HFD on bone quality, independently of T2D and AD. Here, this study demonstrated that CRD together with a HFD during development leads to hyperglycemia and subsequent poor bone quality. A new strategy to manage AGEs from bone as a method for mitigating its effects on bone quality is also presented. This study demonstrated a partial rescue for HFD-induced skeletal fragility in a T2D mouse model using a combination of in vivo and in vitro approaches. It establishes the causality between accumulation of AGEs in bone fragility and provides a plausible avenue for clinical translation. Finally, a translational aspect of these preclinical findings is investigated using participant data from a nationally available clinical database to further explore the multivariable connection between sleep behaviors and incidence of diabetes, bone fracture risk, and cognitive dysfunction. This study examined the impact of sleep duration and sleep quality and an individual’s FRAX scores using the NHANES 2013-2014 dataset, wherein there was a trend of higher FRAX scores of the hip and of other sites for major osteoporotic fracturs amongst individual who reported sleep disturbances in an unadjusted model but also in a minimally and a fully adjusted model for all potential covariates.
Description
December 2023
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY