Cardiorenal metabolic syndrome and diabetic cognopathy.
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.
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Mo., USA ; Diabetes and Cardiovascular Research Lab, University of Missouri, Mo., USA.
M R
MR
Hayden
Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Wash., USA.
W A
WA
Banks
Division of Endocrinology, Department of Internal Medicine, Saint Louis University, St. Louis, Mo., USA.
G N
GN
Shah
Diabetes and Cardiovascular Research Lab, University of Missouri, Mo., USA.
Z
Z
Gu
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Mo., USA ; Diabetes and Cardiovascular Research Lab, University of Missouri, Mo., USA ; Department of Medical Pharmacology and Physiology, University of Missouri, Mo., USA ; Harry S. Truman Memorial Veterans Hospital, Columbia, Mo., USA.
J R
JR
Sowers
Alzheimer's disease; Blood-brain barrier; Diabetic cognopathy; Neurovascular unit; Remodeling; Type 2 diabetes mellitus; Ultrastructure