Downregulation of Blood-Brain Barrier Glucose Transporter in Experimental Diabetes

Pardridge, William M.; Triguero, Domingo; Farrell, Christine R.

doi:10.2337/diab.39.9.1040

Cited by 136 publications

(42 citation statements)

References 31 publications

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“…Existing evidence indicates a decreased GLUT-1 activity and glucose clearance in chronic hyperglycemia, with a parallel decrease in expression of GLUT-1 at BBB [46], as confirmed by subsequent studies [47,48]. On the other hand, chronic hypoglycemia increased BBB glucose transport resulting from a concomitant increase in GLUT-1 transcription and expression on lumenal side of brain capillaries [49].…”

Section: Discussionmentioning

confidence: 66%

Impact of altered glycaemia on blood-brain barrier endothelium: an in vitro study using the hCMEC/D3 cell line

Sajja

Prasad

Cucullo

2014

Fluids Barriers CNS

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BackgroundCerebrovascular complications involving endothelial dysfunction at the blood-brain barrier (BBB) are central to the pathogenesis of diabetes-related CNS disorders. However, clinical and experimental studies have reported contrasting evidence in relation to the effects of hyperglycemia on BBB permeability and function. Similarly the effect of hypoglycemia on BBB integrity is not well understood. Therefore, we assessed the differential impact of hypo and hyperglycemic conditions on BBB integrity and endothelial function in vitro using hCMEC/D3, a well characterized human brain microvascular endothelial cell line.MethodsParallel monolayers of hCMEC/D3 were exposed to normal, hypo- or hyperglycemic media, containing 5.5, 2.2 or 35 mM D-glucose, respectively. Following 3-24h exposure, the expression and distribution of BBB tight junction (ZO-1 and claudin-5) adherence junction (VE-cadherin) proteins, and glucose transporters as well as inflammatory (VCAM-1) and oxidative stress (Nrf-2) markers were analyzed by immunofluorescence and western blotting. Endothelial release of growth factors and pro-inflammatory cytokines were determined by ELISA. Further, the impact of altered glycemia on BBB permeability was assessed in hCMEC/D3 – astrocyte co-cultures on Transwell supports using fluorescent dextrans (4–70 kDa).ResultsCompared to controls, exposure to hypoglycemia (3 and 24h) down-regulated the expression of claudin-5 and disrupted the ZO-1 localization at cell-cell contacts, while hyperglycemia marginally reduced claudin-5 expression without affecting ZO-1 distribution. Permeability to dextrans (4-10 kDa) and VEGF release at 24h were significantly increased by hypo- and hyperglycemia, although 70 kDa dextran permeability was increased only under hypoglycemic conditions. The expression of SGLT-1 was up-regulated at 24h hypoglycemic exposure while only a modest increase of GLUT-1 expression was observed. In addition, the expression of Nrf-2 and release of interleukin-6 and PDGF-BB, were down-regulated by hypoglycemia (but not hyperglycemia), while both conditions induced a marginal and transient increase in VCAM-1 expression from 3 to 24h, including a significant increase in VE-cadherin expression at 3 h following hyperglycemia.ConclusionsIn summary, our findings demonstrate a potential impairment of BBB integrity and function by hypo or hyperglycemia, through altered expression/distribution of TJ proteins and nutrient transporters. In addition, hypoglycemic exposure severely affects the expression of oxidative and inflammatory stress markers of BBB endothelium.

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Section: Discussionmentioning

confidence: 66%

Impact of altered glycaemia on blood-brain barrier endothelium: an in vitro study using the hCMEC/D3 cell line

Sajja

Prasad

Cucullo

2014

Fluids Barriers CNS

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“…The first report showing a decrease in blood-brain glucose transfer in rats with chronic hyperglycemia was published in 1981 using an intravenous bolus infusion method [103]. Later, findings of this study were subsequently confirmed by several investigators using different experimental approaches [97,104–106]. Differences in the techniques utilized and inherent problems in calculating glucose transfer rates using these techniques were detailed in peer review by Pelligrino et al .…”

Section: Diabetes: Glucose Metabolism and Glucose Transporters In mentioning

confidence: 70%

The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

Shah

Silva

Abbruscato

2012

IJMS

225

175

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The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain.

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“…This suggests that the biological answer to chronic excess of glucose in the systemic circulation should be down regulation of its transporters. In this line, many experimental studies report a down-regulation of BBB glucose transporters in hyperglycemic animals [63,78,79], indicating the measures taken by brain from preventing excessive glucose intake. However, this is not a universal scientific consensus since other studies (in both animals and humans) did not reveal significant changes in the BBB glucose transporters expression in DM [41,80-83].…”

Section: Effect Of Hyperglycemia On Bbb Glucose Transport In Dmmentioning

confidence: 99%

Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview

Prasad

Sajja

Naik

et al. 2014

J Pharmacovigilance

147

106

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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.

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Downregulation of Blood-Brain Barrier Glucose Transporter in Experimental Diabetes

Cited by 136 publications

References 31 publications

Impact of altered glycaemia on blood-brain barrier endothelium: an in vitro study using the hCMEC/D3 cell line

Impact of altered glycaemia on blood-brain barrier endothelium: an in vitro study using the hCMEC/D3 cell line

The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview

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