We performed a systematic review of prospective population-based studies addressing the association between DM and various geriatric conditions among community-dwelling adults. The risk for cognitive impairment, dementia, mobility decline, or disability increased with diabetes compared to those without. The pooled risk for all dementia, Alzheimer's disease, and vascular dementia were 1.4 to 2.4 times higher in older diabetic adults compared to non-diabetics. Identified studies reporting the association between DM and the incidence of falls or urinary incontinence were limited to older women, and all indicate a positive association. Available evidence did not suggest that DM was an independent predictor of incident depression.
There is biological evidence supporting the causality that DM may lead to geriatric conditions. Several molecular mechanisms have been proposed to explain the mediation between DM and hyperglycemia-induced tissue damage, including the advanced glycation end products (AGEs) 
. Chronic hyperglycemia may induce oxidative stress or through aforementioned mechanisms, thereby causing subsequent systematic endothelial dysfunction and diabetic vascular complications 
. DM-associated metabolic derangements, AGEs, systemic inflammation, along with traditional diabetic vascular complications, may play critical roles in the development of geriatric conditions.
Diabetes may exert its negative impact on cognitive function through several pathways. Hyperglycemia promotes the formation of AGEs, which were found in senile plaques and intracellular neurofibrillary tangles 
. Increase or decrease in plasma glucose concentrations can affect cognitive function 
. Insulin resistance and subsequent hyperinsulinemia also contribute. Insulin inhibits the degradation of beta-amyloid (the main product of the AD process) through competitive inhibition of insulin-degrading enzyme in the brain, thus increasing amyloid protein deposition in plaques 
. Hyperinsulinemia may also activate inflammatory network in the periphery and the brain, thereby increases the risk of AD 
. DM-related vasculopathy in the brain may lead to lacunes, leukoariosis, large artery ischemic stroke, and cortical atrophy. These structural changes are known to be risk factors for cognitive dysfunction and dementia.
Diabetes may affect physical performance in older adults through several mechanisms. In animal studies, non-enzymatic glycation alters the structures and functions of myosin and actins, which further interfere with muscle contraction 
. In addition, hyperglycemia- induced chronic inflammation status exerts negative impact on skeletal muscle function 
. These were in line with clinical observations that older diabetic adults have poorer muscle quality compared with their non-diabetic counterparts, and lose their muscle strength and quality more rapidly, especially those with longer disease duration and poorer glycemic control 
. Furthermore, cerebral vasculopathy, peripheral artery disease, peripheral polyneuropathy, autonomic neuropathy, and retinopathy are also responsible for the mobility limitations and falls among older adults with diabetes.
The effect of DM on voiding function is more complex, which may involve pathophysiological changes in the detrusor muscle, urothelium, central and autonomic nervous systems, and blood supply to the bladder 
. Hyperglycemia may cause an increased volume of urine, polyuria, or detrusor instability. Additionally, diabetes may contribute to the development of urinary incontinence through associated cognitive dysfunction, functional limitation, or medical comorbidities, even though the lower urinary tract is intact. Hence the impact of DM on urinary incontinence is likely multi-factorial.
Strengths and Limitations
To our knowledge, the present review is the first one that summarizes prospective data relating DM to geriatric conditions. Cukierman and colleagues conducted a systematic review of prospective studies to examine the relationship between DM and changes in cognitive function 
. They found that people with diabetes have a greater rate of cognitive decline and an increased risk of future dementia (RR, 1.6 [CI, 1.4 to 1.8]), which was concordant with our results. However, studies conducted in a historical cohort or with questionable baseline diabetes ascertainment were included in their analysis.
In this review, we included only prospectively-designed studies exploring the causal relationship of DM to various aging phenotypes. Therefore, the temporal relationship was appropriate (i.e. DM preceded the incidence of geriatric conditions). In addition, studies with questionable DM ascertainment were excluded in order to minimize misclassification of patients. Because there are also possible non-causal explanations for the association between DM and geriatric conditions, we excluded studies without appropriate adjustment for potential confounders, especially cardiovascular comorbidities. Hence the results provide more precise estimates of the impact of DM on older adults.
Our searches did not include conference papers and thesis, which may bring a selection bias. Geriatric syndromes are complex multi-factorial problems. Cognitive status, mobility, sensory function, and psychosocial status of older adults are all crucial to the development of geriatric conditions. Nevertheless, not all included studies have thoroughly considered these factors. In addition, studies included in our review did not consistently report disease-related factors, such as duration of DM, status of glycemic control, and treatment. These factors may confound the outcomes of interest. Finally, literatures regarding DM to several outcomes (e.g., falls and UI) were limited to older women, hence the generalizability was limited.
The evidence supported that older diabetic adults have an increased risk for selected multi-system aging phenotypes, which were associated with substantial morbidity and adverse outcomes among older population 
. In addition, some of the problems (e.g., cognitive dysfunction, mobility impairment) may significantly interfere with disease management 
. While physicians try to do their best to manage DM in older adults, this additional evidence may encourage increased awareness, management and patient education in their daily practice.
Future research should attempt to explore the underlying mechanisms linking DM to geriatric conditions, and address complex interaction between risk factors. DM as a shared risk factors across different geriatric conditions raises the possibility of shared pathophysiological mechanisms across aging phenotypes, such as AGEs formation, oxidative stress, systemic inflammation, and vasculopathy. On the other hand, test of causal relationship can only rely on interventional studies showing that intensive glycemic control can prevent or delay the incidence of geriatric conditions. However, given that older adults are more vulnerable to adverse effect of strict glucose control, modification of other cardiovascular factors may be an alternative. Prior investigation has confirmed the benefit of tight blood pressure control on cardiovascular disease risk reduction among patients with type 2 diabetes 
. Angiotensin-converting-enzyme (ACE) inhibitors and statins are also promising in vasculoprotective effect among diabetic patients 
. More randomized control studies are needed to determine whether these therapies alone or in combination could reduce or delay the development of multi-system aging phenotypes.
Despite methodological limitations of the observational studies reviewed, the consistency of reported relationship between DM and selected geriatric conditions among community-dwelling older adults across studies support the proclaim that DM is a major risk factor for multi-system aging phenotypes. Primary care physician should be aware and appropriately manage these problems. Future research is required to elucidate the underlying pathological pathway linking DM to geriatric conditions. Interventional studies with glucose-lowering therapy are needed to test the hypotheses that intensive glycemic control can reduce adverse geriatric outcomes.