Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview

Abstract

A host of diabetes-related insults to the central nervous system (CNS) have been clearly documented in type-1 and -2 diabetic patients as well as experimental animal models. These host of neurological disorders encompass hemodynamic impairments (e.g., stroke), vascular dementia, cognitive deficits (mild to moderate), as well as a number of neurochemical, electrophysiological and behavioral alterations. The underlying causes of diabetes-induced CNS complications are multifactorial and are relatively little understood although it is now evident that blood-brain barrier (BBB) damage plays a significant role in diabetes-dependent CNS disorders. Changes in plasma glucose levels (hyper- or hypoglycemia) have been associated with altered BBB transport functions (e.g., glucose, insulin, choline, amino acids, etc.), integrity (tight junction disruption), and oxidative stress in the CNS microcapillaries. Last two implicating a potential causal role for upregulation and activation of the receptor for advanced glycation end products (RAGE). This type I membrane-protein also transports amyloid-beta (Aβ) from the blood into the brain across the BBB thus, establishing a link between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD, also referred to as “type 3 diabetes”). Hyperglycemia has been associated with progression of cerebral ischemia and the consequent enhancement of secondary brain injury. Difficulty in detecting vascular impairments in the large, heterogeneous brain microvascular bed and dissecting out the impact of hyper- and hypoglycemia in vivo has led to controversial results especially with regard to the effects of diabetes on BBB. In this article, we review the major findings and current knowledge with regard to the impact of diabetes on BBB integrity and function as well as specific brain microvascular effects of hyper- and hypoglycemia.

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

“…This change in permeability is potentially of great importance as it could lead to decreased brain insulin levels and decreased insulin-facilitated neural and glial activity 40 . On the other hand, T2DM can lead to damage of the BBB, which results in increased permeability to a variety of substances 164–166 .…”

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

“…Dysfunction of the BBB has been demonstrated in the pathogenesis and progression of AD (Kalaria, 2010), even before dementia onset (Skoog et al, 1998) and also in the aging human hippocampus, which worsens with mci, a condition preceding AD (Montagne et al, 2015). Changes in plasma glucose levels have been associated with altered BBB transport functions, with paracellular integrity (tight junction disruption) and with oxidative stress in the CNS microcapillaries (Prasad, Sajja, Naik, & Cucullo, 2014). At what stage BBB breakdown occurs in the brain, and whether it triggers the development of AD, remains, however, controversial.…”

Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition

“…Neurocognitive and neurologic complications including vascular dementia, stroke, anxiety/depression and cognitive impairment are well documented in diabetes mellitus (DM)(Prasad et al, 2014). Furthermore, DM can aggravate epilepsy (Schober et al, 2012) (McCorry et al, 2006) and stroke (Peng et al, 2013), leading to increased mortality.…”

“…Impairment of the BBB/neurovascular unit (NVU) is now considered to be one of the critical factors leading to development of diabetic encephalopathy (Norhammar et al, 2002; Allen and Bayraktutan, 2009). The role of BBB dysfunction in the pathogenesis of diverse neurologic conditions is unquestionable; however, it has not been well-studied in DM (Prasad et al, 2014) as compared to diabetic retinopathy or renal complications.…”