Fear of Falling and Balance Confidence in Older Adults with Diabetes Mellitus

Several determinants of fear of falling (FoF) and low balance confidence overlap with the consequences/complications of diabetes mellitus (DM). FoF is strongly associated with low balance confidence, and balance confidence mediates the relationship between FoF and balance and physical function. The purpose of this thesis was two-fold: (1) to examine the prevalence, severity and determinants of FoF in older adults (aged≥65) with DM, and (2) to evaluate the validity of the short version of the Activities-specific Balance Confidence scale (ABC-6) and its association with balance and postural control in older adults with DM. Three separate studies were conducted of older adults with DM (DM-group) and without DM (noDM-group). Study I revealed that although FoF prevalence adjusted for age and sex was not different between-groups, the DM-group had 8.8% fewer participants in the low and 8.4% more in the high Falls-Efficacy Scale International categories when compared to the noDM-group. Higher FoF severity in the DM-group was associated with poor physical performance, being female, fall history and clinical depressive symptoms. Study II provided evidence of convergent, discriminant and concurrent validity of the ABC-6 for use in older adults with DM with and without diabetic peripheral neuropathy (DPN). Notably, the ABC-6 was more sensitive in detecting subtle differences in balance confidence between the DM-group and noDM-group when compared to the original ABC scale (ABC-16), and can be administered in less time. Study III explored balance confidence (ABC-6) and its association with balance and postural control in older adults with DM. Subtle differences in axial segmental control (i.e., lower trunk roll velocity and higher head-trunk correlations) while walking and lower balance confidence were apparent in the DM-group, even in the absence of DPN, when compared to the noDM-group. Balance confidence partially explained the variance in head-trunk stiffening between-groups, and consequently low balance confidence in older adults with DM may contribute to the dependence on postural control strategies that are normally only utilized in high-risk situations. Findings from this thesis will help to guide the development of protocols for screening and intervention recommendations of patient education and targeted rehabilitation programs for older adults with DM.

Relationship between abnormal maternal inflammation and insulin resistance during pregnancy

Abnormal maternal inflammation during pregnancy is linked to complications such as preeclampsia and fetal growth restriction. There is growing evidence that insulin resistance is also associated with a heightened inflammatory state, and is linked to pregnancy complications such as gestational diabetes. This study tested the hypothesis that abnormal inflammation during pregnancy is causally linked to elevations in blood glucose and insulin resistance. To induce a state of abnormal systemic inflammation, bacterial lipopolysaccharide (LPS) was administered to pregnant rats on gestational days (GD) 13.5-16.5. Dams treated with LPS exhibited an abnormal immune response characterized by an elevation in white blood cells, which was linked to reduced fetal weight and increased glucose levels over pregnancy. Abnormal inflammation is characterized by increased levels of circulating pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF) and interleukin-6, which contribute to insulin resistance by inhibiting the insulin signalling pathway. TNF in particular induces a serine phosphorylation (pSer307) of insulin receptor substrate 1 (IRS-1). In our model, insulin resistance was assessed by measuring the extent of pSer307 of IRS-1 and total IRS-1 expression in skeletal muscle, as well as changes in metabolic parameters and pancreas tissue morphology associated with insulin resistance. LPS-treated dams exhibited a significant reduction in IRS-1 expression, elevation in fasting glucose levels, and reduction in insulin sensitivity indices. There were also biologically relevant increases in fasting plasma insulin levels and insulin resistance indices, but not pSer307 of IRS-1 and pancreatic islet size. To determine whether inflammation plays a role in reducing insulin signalling and the other changes associated with LPS administration, etanercept, a TNF antagonist, was administered on GDs 13.5 and 15.5 prior to LPS injections. With the exception of IRS-1 expression, in rats treated with etanercept all of the measured parameters remained at the levels observed in saline controls, indicating a link between abnormal inflammation and insulin resistance. The results of this study support the practice of monitoring the inflammatory conditions of the mother prior to and during pregnancy, and support further investigation into the potential use of anti-inflammatory agents during pregnancy in women at risk of insulin resistance and gestational diabetes.

Differences in Abdominal and Liver Fat Accumulation Between Obesity-Matched Adults With and Without Type 2 Diabetes

Despite attempts to identify the mechanisms by which obesity leads to the development of Type 2 Diabetes (T2D), it remains unclear why some but not all adults with obesity develop T2D. Given the established associations between visceral adipose tissue (VAT) and liver fat with insulin resistance, we hypothesized that compared to age and obesity matched adults who were non-diabetic (NT2D), adults with T2D would have greater amounts of VAT and liver fat. The International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship with Cardiometabolic Risk/Intra-Abdominal Adiposity (INSPIRE ME IAA) aims to study the associations between VAT and liver fat and risk of developing T2D and cardiovascular disease. Four thousand, five hundred and four participants were initially recruited; from this, 2383 White and Asian adults were selected for this ancillary analysis. The NT2D and T2D groups were matched for age, body mass index (BMI) and waist circumference (WC). The T2D and NT2D groups were also compared to participants with either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT; IFG/IGT)). Abdominal adipose tissue was measured by computed tomography; liver fat was estimated using computed tomography-derived mean attenuation. Secondary analysis determined whether differences existed between NT2D and T2D groups in VAT and liver fat accumulation within selected BMI categories for Whites and Asians. We report across sex and race, T2D and IFG/IGT groups had elevated VAT and liver fat compared to the NT2D group (p<0.05). VAT was not different between IFG/IGT and T2D groups (p>0.05), however liver fat was greater in the T2D group compared to the IFG/IGT group in both Whites and Asians (p<0.05). Within each BMI category, the T2D group had elevated VAT and liver fat compared to the age and anthropometrically matched NT2D group in both Whites and Asians (p<0.05). With few exceptions, abdominal subcutaneous adipose tissue was not different in the T2D or IFG/IGT groups compared to the NT2D group independent of sex and race. Compared to age and obesity-matched adults who are NT2D, we observe that White and Asian adults with T2D, and those with IFG/IGT, present with greater levels of both VAT and liver fat.