The influence of body composition and fluid volume distribution on renal and cognitive functions in middle-aged and older patients with type 2 diabetes mellitus

• Main Author: Low, Serena Kiat Mun
• Other Authors: Lim Chin Leong, Fabian
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2023
• Subjects: Science::Medicine
• Online Access: https://hdl.handle.net/10356/171362
• Institution: Nanyang Technological University

Background: Aging in diabetes mellitus (DM) is accompanied by changes in body composition, characterised by decreased muscle mass and increased fat mass (FM) as one ages. Moreover, patients with DM have extracellular water (ECW) expansion, as hyperglycemia results in hypertonicity leading to shift of fluid from the intracellular to the extracellular space. It is not clear if such pathophysiological changes may confer higher risk of diabetic complications. There remain significant knowledge gaps in appreciating the roles of body composition, especially in muscle mass and water balance and distribution, in the progression of type 2 diabetes mellitus (T2DM) and its complications in middle-aged and older patients. Aim: The aim of the thesis was to investigate the associations between body composition with renal and cognitive function in T2DM, and the association between water balance with renal and cognitive function in T2DM. The objectives were as follows: 1. To determine the association between sarcopenia with poorer renal function in T2DM. 2. To determine the association between sarcopenia and higher extracellular water to total body water (ECW/TBW) ratio with poorer cognitive function in T2DM. 3. To determine the association between higher ECW/ Total body water (TBW) ratio and poorer renal function in T2DM. 4. To determine the association between higher ECW/TBW ratio and poorer cognitive function in T2DM. Methodology The study involves prospective and cross-sectional designs. The prospective cohort comprises 2,100 individuals with T2DM who were recruited by the SMART2D (Singapore Study of Macroangiopathy and Micro-vascular Reactivity in Type 2 Diabetes) study in 2011-2013 and followed up till 2017. These individuals were subsequently recalled for follow-up in 2019 for prospective assessment of body composition, vascular function and diabetic complications. The prospective cohort study facilitates the investigation into the longitudinal relationship between body composition (in terms of low muscle mass and high ECW/TBW ratio) and CKD progression. The cross-sectional study comprises 1,235 individuals from the SMART2D cohort who had cognitive function assessed in 2014-2017. The cross-sectional study investigated the cross-sectional relationship between muscle mass and ECW/TBW ratio and cognitive function. Summary of the studies done: Study 1 investigated the association between baseline muscle mass and risk of chronic kidney disease (CKD) progression. It was observed that higher muscle mass at baseline was negatively associated with albuminuria and CKD progression, and loss of muscle mass over time was positively associated CKD progression. Furthermore, pigment epithelium-derived factor (PEDF) and leucine-rich α-2-glycoprotein (LRG-1) mediated the negative association between higher muscle mass and CKD progression. Increase in muscle mass may play a potential role in ameliorating the putative effect of PEDF and LRG-1 on CKD progression. Elucidating the pathophysiological mechanism of the relationship between muscle mass and CKD progression may improve our understanding of the role of muscle mass in preventing or delaying renal decline and highlight the important of maintaining or increasing muscle mass. Study 2 examined the association between extracellular volume excess (EVE) with reduced renal function. This study showed that higher ECW/TBW ratio was independently and positively associated with increased risk of CKD progression. Increase in severity of EVE over time also conferred a higher risk of CKD progression, compared to those with no change or reduction of ECW/TBW ratio to a lower ratio category. Higher ECW/TBW ratio also mediated the relationship between Metalloproteinase (MMP)-2 and CKD progression in T2DM. My finding highlighted the importance of checking fluid volume status early. As minor elevations of extracellular volume may be too subtle to be detected by physical examination, bio-impedance analysis (BIA) is a valid, non-invasive and inexpensive method to measure body fluid volume. Study 3 investigated the association between SO and cognitive function in T2DM. It was observed that about one in five patients with T2DM had SO, and SO was associated with reduced performance in certain cognitive domains, including immediate memory and language. There was also negative association between SO and delayed memory with statistical significance. These findings suggest that SO has negative impact on several cognitive domains, which implies a need to prevent or slow development of SO in order to delay or prevent cognitive impairment. Study 4 investigated the relationship between muscle mass in the lower limbs, in parallel with muscle mass in the upper limbs and overall muscle mass, with reduced cognitive function in people with T2DM. Despite being a component of sarcopenia, muscle mass in the upper limbs may lack the fine measurement accuracy that muscle mass in the lower limbs has because of higher prominence of weight-bearing stressor in muscle mass in the lower limbs. Given the mechanical stressor (e.g. weight bearing vs. non-weight bearing) on lower and upper limb muscles may differ anatomically, it is plausible that their myocytes biology may also differ, thereby contributing to the differential relationship with cognitive function. Muscle mass in the lower limbs measurement may potentially be a useful marker of possible co-occurring cognitive dysfunction in T2DM, thus facilitating earlier detection and active management. Study 5 explored the relationship between ECW/TBW ratio and cognitive function. Higher ECW/TBW ratio is indicative of slight edema. This in turn, was significantly associated with reduced cognitive function globally and in sub-domains of delayed memory and attention. The study also found significant negative association between edema, but not slight edema, with cognitive function in language. Increasing pulse pressure (PP) mediated the association between increasing ECW/TBW ratio and lower cognitive function. The findings highlight the importance of ECW/TBW ratio as a potential risk marker of cognitive impairment in future longitudinal studies and use of this marker to help identify patients at risk of cognitive dysfunction for early preventive intervention.