Cardiorenal Metabolic Syndrome and Diabetic Cognopathy

Abstract

The prevalence of the cardiorenal metabolic syndrome (CRS) is increasing in parallel with obesity, type 2 diabetes mellitus, Alzheimer's disease, and other forms of dementia. Along with metabolic, inflammatory, and immunological abnormalities, there is maladaptive structural remodeling of the heart, kidney, and brain. The term ‘diabetic cognopathy' (DC) may be used when discussing functional and structural changes in the brain of the diabetic patient. DC likely represents an advanced form of these changes in the brain that evolve with increasing duration of the CRS and subsequent clinical diabetes. We posit that DC develops due to a convergence of aging, genetic and lifestyle abnormalities (overnutrition and lack of exercise), which result in multiple injurious metabolic and immunologic toxicities such as dysfunctional immune responses, oxidative stress, inflammation, insulin resistance, and dysglycemia (systemically and in the brain). These converging abnormalities may lead to endothelial blood-brain barrier tight junction/adherens junction (TJ/AJ) complex remodeling and microglia activation, which may result in neurodegeneration, impaired cognition, and dementia. Herein, we describe the brain ultrastructural changes evolving from a normal state to maladaptive remodeling in rodent models of CRS including microglia activation/polarization and attenuation and/or loss of the TJ/AJ complexes, pericytes and astrocytes of the neurovascular unit. Further, we discuss the potential relationship between these structural changes and the development of DC, potential therapeutic strategies, and future directions.

High‐fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss

“…Loss of pericytes has been shown to promote capillary rarefaction in pancreatic islets and skeletal muscle, thus leading to or exacerbating glucose intolerance [12,13]. As Figure 8A and B show, HFD also resulted in a dramatic loss of pericytes in WT mice.…”

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

“…is a result of the relative or complete impairment of insulin actions, signaling, and associated with a progressive decline in pancreatic beta cell function [4,5,6,7,8,9,11,12,13,14,15,16].…”

“…Additionally, there are mural vascular cells coursing throughout the brain consisting of endothelial cell(s) (EC), pericyte(s) (Pcs) and vascular smooth muscles cells. Each of these cells have multiple unique identifying ultrastructural forms and functions [4][5][6][7][8][9]. This review focuses on type 2 diabetes mellitus (T2DM) and the increased risk of late-onset Alzheimer's disease (LOAD) and the capillary neurovascular unit(s) (NVU) and neuroglia.…”

Blood–Brain Barrier Disruption and Neurovascular Unit Dysfunction in Diabetic Mice: Protection with the Mitochondrial Carbonic Anhydrase Inhibitor Topiramate

“…Diabetes eventually results in changes in the microvasculature of the brain and retina, leading to retinopathy and dysfunction and disruption of the blood-brain barrier (BBB) (Banks et al, 1997;Bouchard et al, 2002;Starr et al, 2003;Huber et al, 2006). Diabetes is also associated with cognitive dysfunction and an increased risk of Alzheimer's disease (Ott et al, 1999;Gispen and Biessels, 2000;Manschot et al, 2006;Stranahan et al, 2008) that is associated with the microvascular (Manschot et al, 2006;Cheung et al, 2014) and neurovascular unit (NVU) changes (Hayden et al, 2013). Although there is a great deal of diversity in microvascular and macrovascular diabetic complications, they are all thought to arise through common hyperglycemia-induced pathways (Brownlee, 2005).…”