Effect of Diabetes Mellitus on the Permeability of the Blood–Brain Barrier to Insulin

Banks, William A.; Jaspan, Jonathan B.; Kastin, Abba J.

doi:10.1016/s0196-9781(97)00238-6

Cited by 132 publications

(83 citation statements)

References 23 publications

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“…Microvascular pathologies are apparent in the retina, renal glomerulus, and peripheral nerve and result in blindness, end-stage renal disease, and a variety of debilitating neuropathies. 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).…”

Section: Introductionmentioning

confidence: 99%

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

Salameh

Shah

Price

et al. 2016

J Pharmacol Exp Ther

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All forms of diabetes mellitus are characterized by chronic hyperglycemia, resulting in the development of a number of microvascular and macrovascular pathologies. Diabetes is also associated with changes in brain microvasculature, leading to dysfunction and ultimately disruption of the blood-brain barrier (BBB). These changes are correlated with a decline in cognitive function. In diabetes, BBB damage is associated with increased oxidative stress and reactive oxygen species. This occurs because of the increased oxidative metabolism of glucose caused by hyperglycemia. Decreasing the production of bicarbonate with the use of a mitochondrial carbonic anhydrase inhibitor (mCAi) limits oxidative metabolism and the production of reactive oxygen species. In this study, we have demonstrated that 1) streptozotocin-induced diabetes resulted in BBB disruption, 2) ultrastructural studies showed a breakdown of the BBB and changes to the neurovascular unit (NVU), including a loss of brain pericytes and retraction of astrocytes, the two cell types that maintain the BBB, and 3) treatment with topiramate, a mCAi, attenuated the effects of diabetes on BBB disruption and ultrastructural changes in the neurovascular unit.

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Section: Introductionmentioning

confidence: 99%

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

Salameh

Shah

Price

et al. 2016

J Pharmacol Exp Ther

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“…Insulin and IGF-1 levels are decreased in the brains of patients with Alzheimer's disease due to impaired transport across the blood-brain barrier (11), and the cerebral cellular sensitivities to these factors are attenuated (12)(13)(14). Apart from several mutations that have been identified and linked to the pathophysiology in a small percentage of Alzheimer's disease cases (15,16), other factors invoked in the pathogenesis of sporadic Alzheimer's disease include vascular dysfunction, accummulation of free radicals, immune dysfunction, and hypercholesterolemia (17)(18).…”

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confidence: 99%

Alzheimer-Like Changes in Rat Models of Spontaneous Diabetes

2007

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OBJECTIVE-To examine whether changes characteristic of Alzheimer's disease occur in two rat models with spontaneous onset of type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS-The frontal cortices of 8-month-diabetic rats were examined with respect to neuronal densities, neurite degeneration, expression, and/or immunolocalization of amyloid precursor protein (APP), ␤-secretase, ␤-amyloid, COOH-terminal fragment (CTF), insulin receptor, IGF-1 receptor, glycogen synthase kinase 3-␤ (GSK-3␤), protein kinase B (Akt), phosphorylated (phospho-), synaptophysin, and phosphorylated neurofilaments (SMI-31).RESULTS-Neuronal loss occurred in both models, significantly more so in type 2 diabetic BBZDR/Wor rats compared with type 1 diabetic BB/Wor rats and was associated with a ninefold increase of dystrophic neurites. APP, ␤-secretase, ␤-amyloid, and CTF were significantly increased in type 2 diabetic rats, as was phospho-. The insulin receptor expression was decreased in type 1 diabetes, whereas IGF-1 receptor was decreased in both models, as were Akt and GSK-3␤ expression. CONCLUSIONS-The data show that ␤-amyloid and phosphoaccumulation occur in experimental diabetes and that this is associated with neurite degeneration and neuronal loss. The changes were more severe in the type 2 diabetic model and appear to be associated with insulin resistance and possibly hypercholesterolemia. The two models will provide useful tools to unravel further mechanistic associations between diabetes and Alzheimer's disease.

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“…It is well established that stroke compromises the integrity of the BBB, and this exacerbates tissue injury and dysfunction (44). Many studies have examined the effects of diabetes on BBB function (45) and its response to stroke. The results have been in striking agreement, showing that diabetes exacerbates the disruption of the BBB (15,38).…”

Section: Dysfunction Of the Blood-brain Barriermentioning

confidence: 99%

Illuminating the Effects of Stroke on the Diabetic Brain: Insights From Imaging Neural and Vascular Networks in Experimental Animal Models

2016

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Type 1 diabetes is known to cause circulatory problems in the eyes, heart, and limbs, and the brain is no exception. Because of the insidious effects of diabetes on brain circulation, patients with diabetes are two to four times more likely to have an ischemic stroke and are less likely to regain functions that are lost. To provide a more mechanistic understanding of this clinically significant problem, imaging studies have focused on how stroke affects neural and vascular networks in experimental models of type 1 diabetes. The emerging picture is that diabetes leads to maladaptive changes in the cerebrovascular system that ultimately limit neuronal rewiring and recovery of functions after stroke. At the cellular and systems level, diabetes is associated with abnormal cerebral blood flow in surviving brain regions and greater disruption of the blood-brain barrier. The abnormal vascular responses to stroke can be partly attributed to aberrant vascular endothelial growth factor (VEGF) signaling because genetic or pharmacological inhibition of VEGF signaling can mitigate vascular dysfunction and improve stroke recovery in diabetic animals. These experimental studies offer new insights and strategies for optimizing stroke recovery in diabetic populations.

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Effect of Diabetes Mellitus on the Permeability of the Blood–Brain Barrier to Insulin

Cited by 132 publications

References 23 publications

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

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

Alzheimer-Like Changes in Rat Models of Spontaneous Diabetes

Illuminating the Effects of Stroke on the Diabetic Brain: Insights From Imaging Neural and Vascular Networks in Experimental Animal Models

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