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The metabolic syndrome (MetS) and Alzheimer's disease share several pathological features, including insulin resistance, abnormal protein processing, mitochondrial dysfunction and elevated inflammation and oxidative stress. The MetS constitutes elevated fasting glucose, obesity, dyslipidaemia and hypertension and increases the risk of developing Alzheimer's disease, but the precise mechanism remains elusive. Insulin resistance, which develops from a diet rich in sugars and saturated fatty acids, such as palmitate, is shared by the MetS and Alzheimer's disease. Extracellular vesicles (EVs) are also a point of convergence, with altered dynamics in both the MetS and Alzheimer's disease. However, the role of palmitate- and glucose-induced insulin resistance in the brain and its potential link through EVs to Alzheimer's disease is unknown. We demonstrate that palmitate and high glucose induce insulin resistance and amyloid precursor protein phosphorylation in primary rat embryonic cortical neurons and human cortical stem cells. Palmitate also triggers insulin resistance in oligodendrocytes, the supportive glia of the brain. Palmitate and glucose enhance amyloid precursor protein secretion from cortical neurons via EVs, which induce tau phosphorylation when added to naïve neurons. Additionally, EVs from palmitate-treated oligodendrocytes enhance insulin resistance in recipient neurons. Overall, our findings suggest a novel theory underlying the increased risk of Alzheimer's disease in MetS mediated by EVs, which spread Alzheimer's pathology and insulin resistance., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

The world faces a pandemic-level prevalence of type 2 diabetes. In parallel with this massive burden of metabolic disease is the growing prevalence of dementia as the population ages. The two health issues are intertwined. The Lancet Commission on dementia prevention, intervention, and care was convened to tackle the growing global concern of dementia by identifying risk factors. It concluded, along with other studies, that diabetes as well as obesity and the metabolic syndrome more broadly, which are frequently comorbid, raise the risk of developing dementia. Type 2 diabetes is a modifiable risk factor; however, it is uncertain whether anti-diabetic drugs mitigate risk of developing dementia. Reasons are manifold but constitute a critical knowledge gap in the field. This review outlines studies of type 2 diabetes on risk of dementia, illustrating key concepts. Moreover, it identifies knowledge gaps, reviews strategies to help fill these gaps, and concludes with a series of recommendations to mitigate risk and advance understanding of type 2 diabetes and dementia., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Diabetic peripheral neuropathy (DPN) occurs in up to half of individuals with type 1 or type 2 diabetes. DPN results from the distal-to-proximal loss of peripheral nerve function, leading to physical disability and sometimes pain, with the consequent lowering of quality of life. Early diagnosis improves clinical outcomes, but many patients still develop neuropathy. Hyperglycaemia is a risk factor and glycaemic control prevents DPN development in type 1 diabetes. However, glycaemic control has modest or no benefit in individuals with type 2 diabetes, probably because they usually have comorbidities. Among them, the metabolic syndrome is a major risk factor for DPN. The pathophysiology of DPN is complex, but mechanisms converge on a unifying theme of bioenergetic failure in the peripheral nerves due to their unique anatomy. Current clinical management focuses on controlling diabetes, the metabolic syndrome, and pain, but remains suboptimal for most patients. Thus, research is ongoing to improve early diagnosis and prognosis, to identify molecular mechanisms that could lead to therapeutic targets, and to investigate lifestyle interventions to improve clinical outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Dementia is a complex set of disorders affecting normal cognitive function. Recently, several clinical studies have shown that diabetes, obesity, and components of the metabolic syndrome (MetS) are associated with cognitive impairment, including dementias such as Alzheimer's disease. Maintaining normal cognitive function is an intricate process involving coordination of neuron function with multiple brain glia. Well-orchestrated bioenergetics is a central requirement of neurons, which need large amounts of energy but lack significant energy storage capacity. Thus, one of the most important glial functions is to provide metabolic support and ensure an adequate energy supply for neurons. Obesity and metabolic disease dysregulate glial function, leading to a failure to respond to neuron energy demands, which results in neuronal damage. In this review, we outline evidence for links between diabetes, obesity, and MetS components to cognitive impairment. Next, we focus on the metabolic crosstalk between the three major glial cell types, oligodendrocytes, astrocytes, and microglia, with neurons under physiological conditions. Finally, we outline how diabetes, obesity, and MetS components can disrupt glial function, and how this disruption might impair glia-neuron metabolic crosstalk and ultimately promote cognitive impairment., (Copyright © 2022. Published by Elsevier Inc.)

The metabolic syndrome (MetS) and Alzheimer's disease share several pathological features, including insulin resistance, abnormal protein processing, mitochondrial dysfunction and elevated inflammation and oxidative stress. The MetS constitutes elevated fasting glucose, obesity, dyslipidaemia and hypertension and increases the risk of developing Alzheimer's disease, but the precise mechanism remains elusive. Insulin resistance, which develops froma diet rich in sugars and saturated fatty acids, such as palmitate, is shared by the MetS and Alzheimer's disease. Extracellular vesicles (EVs) are also a point of convergence, with altered dynamics in both the MetS and Alzheimer's disease. However, the role of palmitate- and glucose-induced insulin resistance in the brain and its potential link through EVs to Alzheimer's disease is unknown. We demonstrate that palmitate and high glucose induce insulin resistance and amyloid precursor protein phosphorylation in primary rat embryonic cortical neurons and human cortical stem cells. Palmitate also triggers insulin resistance in oligodendrocytes, the supportive glia of the brain. Palmitate and glucose enhance amyloid precursor protein secretion from cortical neurons via EVs, which induce tau phosphorylation when added to naïve neurons. Additionally, EVs from palmitatetreated oligodendrocytes enhance insulin resistance in recipient neurons.Overall, our findings suggest a novel theory underlying the increased risk of Alzheimer's disease inMetS mediated by EVs, which spreadAlzheimer's pathology and insulin resistance. [ABSTRACT FROM AUTHOR]