Inside the Diabetic Brain: Role of Different Players Involved in Cognitive Decline

Abstract

Diabetes mellitus is the most common metabolic disease, and its prevalence is increasing. A growing body of evidence, both in animal models and epidemiological studies, has demonstrated that metabolic diseases like obesity, insulin resistance, and diabetes are associated with alterations in the central nervous system (CNS), being linked with development of cognitive and memory impairments and presenting a higher risk for dementia and Alzheimer's disease. The rising prevalence of diabetes together with its increasing earlier onset suggests that diabetes-related cognitive dysfunction will increase in the near future, causing substantial socioeconomic impact. Decreased insulin secretion or action, dysregulation of glucose homeostasis, impairment in the hypothalamic-pituitary-adrenal axis, obesity, hyperleptinemia, and inflammation may act independently or synergistically to disrupt neuronal homeostasis and cause diabetes-associated cognitive decline. However, the crosstalk between those factors and the mechanisms underlying the diabetes-related CNS complications is still elusive. During the past few years, different strategies (neuroprotective and antioxidant drugs) have emerged as promising therapies for this complication, which still remains to be preventable or treatable. This Review summarizes fundamental past and ongoing research on diabetes-associated cognitive decline, highlighting potential contributors, mechanistic mediators, and new pharmacological approaches to prevent and/or delay this complication.

Diabetes and Cognitive Impairment

“…In diabetes, there is an increase in the expression of pro-inflammatory cytokines in the brain under diabetic conditions and this plays an important role in neuronal damage [80••]. NF-kB has been postulated to be involved in cognitive function.…”

Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease

“…In that regard, neuro-inflammation may produce secondary bystander injury rather than operate as the primary driver of neurodegeneration. In humans with peripheral insulin resistance diseases, including diabetes mellitus and metabolic syndrome, cognitive impairment and AD are partly driven by brain insulin resistance, together with neuro-inflammation and vasculopathy [37–39]. …”

The Expanding Role of Ketogenic Diets in Adult Neurological Disorders

“…This reduction is associated with downregulation of the glucose transporter GLUT1 in the brain of individuals with AD [40,100]. Increasing evidence has demonstrated an association between high-glycemic diet and greater cerebral amyloid burden in humans [101] and that increased insulin resistance contributes to the development of sporadic AD [102,103], suggesting diet as a potential modifiable behavior to prevent cerebral amyloid accumulation and reduce AD risk.…”