End-Organ Sequelae That Lead to Disability
Impaired vascular function can interact with diabetic peripheral neuropathy (DPN) to cause foot ulcerations and amputations. Hyperglycemia and advanced glycation end products (AGEs) increase oxidative stress, which activates kinases such as protein kinase C and increases production of proinflammatory mediators, collagen, and fibronectin. These pathways also deplete endothelial and neural nitric oxide, leading to endothelial dysfunction and damage to the vasa nervorum, thereby contributing to nerve fiber injury and DPN. However, there are few data on the interaction of DPN with the vasculature in older adults with diabetes.
Although cognitive decline has not been viewed as a traditional diabetes complication, type 2 diabetes increases the risk for both vascular dementia and Alzheimer disease.[3,28] Diabetes and Alzheimer disease pathology can exert synergistic effects with age on the brain vasculature, blood flow, and delivery of substrates necessary for cognition. The brain can be affected by hyperglycemia, which increases production of AGEs and their receptors, and by hypoglycemia, which creates excitotoxic insults and, in extreme cases, neuron cell death.
Defects in memory and executive function appear in midlife and become progressively worse and disabling with older age, creating a cycle of increasing cognitive impairment and poor self-management. Both type 2 diabetes and Alzheimer disease are associated with reduced cholesterol synthesis in the brain. Among middle-aged adults with prediabetes and diabetes, areas of glucose hypometabolism, gray matter atrophy, and reduced blood flow are apparent in the brain in a pattern similar to that seen with Alzheimer disease.[29,30] Obesity, hypertension, and dyslipidemia influence age-related risk for dementias,[28,30] particularly in midlife. Around the age of 70 years, however, mild elevations in blood pressure, cholesterol, and weight appear to be associated inversely with dementia, and work in animal models suggests that these abnormalities might even be protective.
Alzheimer disease pathology, and particularly β-amyloid, also may contribute to brain insulin resistance. β-Amyloid induces insulin resistance by downregulating insulin receptors from dendritic membranes, administration of β-amyloid in nonhuman primates induces insulin resistance in the hippocampus, and dietary induction of mild insulin resistance in older human adults decreases memory and increases β-amyloid levels and markers of oxidative injury. In contrast, administration of insulin blocks the synapse loss induced by β-amyloid, and in an initial study, intranasal administration of insulin improved memory and peripheral insulin sensitivity. A large clinical trial of intranasal insulin is now under way to test effects on cognition.
Diabetic kidney disease (defined as the presence of albuminuria, an impaired glomerular filtration rate (GFR), or both) occurs in approximately 35% of patients with diabetes. The prevalence of diabetic kidney disease increases with age, exceeding 50% among diabetic patients aged 65 years or older. Diabetic kidney disease is associated with longer duration of diabetes and with diabetes-related complications, such as impaired lower-extremity function, incident disability, and incident dementia. Diabetic kidney disease contributes to the excess cardiovascular mortality risk among patients with type 2 diabetes. Mechanisms through which diabetic kidney disease contributes to CVD are a subject of intensive current research.
Diabetes. 2014;63(8):2578-2589. © 2014 American Diabetes Association, Inc.