Insulin Transport into the Brain and Cerebrospinal Fluid

Begg, Denovan P.

doi:10.1016/bs.vh.2014.12.007

Cited by 24 publications

(18 citation statements)

References 144 publications

(146 reference statements)

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“…When plasma insulin increases, CSF insulin levels also rise [96]. While some brain insulin may be synthesized in the CNS [97], most is thought to come from the bloodstream [98]. Obesity increases CSF insulin levels in rodents [47], sheep [48], and humans [49].…”

Section: Cell Populations Involved In Hypothalamic Insulin Functiomentioning

confidence: 99%

“…Therefore, hypothalamic insulin resistance is partly explained by disrupted insulin transport into the brain. A portion of insulin in the brain is transported from the bloodstream into the brain by IR-expressing brain endothelial cells [14,38,96,98]. Insulin transport by brain endothelial cells reportedly decreases by HFD feeding [12], while insulin transport via receptor-mediated endothelial transcytosis remains controversial [96].…”

Section: Cell Populations Involved In Hypothalamic Insulin Functiomentioning

confidence: 99%

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Molecular Mechanisms of Hypothalamic Insulin Resistance

Ono

2019

IJMS

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Insulin exists in the central nervous system, where it executes two important functions in the hypothalamus: the suppression of food intake and the improvement of glucose metabolism. Recent studies have shown that both are exerted robustly in rodents and humans. If intact, these functions exert beneficial effects on obesity and diabetes, respectively. Disruption of both occurs due to a condition known as hypothalamic insulin resistance, which is caused by obesity and the overconsumption of saturated fat. An enormous volume of literature addresses the molecular mechanisms of hypothalamic insulin resistance. IKKβ and JNK are major players in the inflammation pathway, which is activated by saturated fatty acids that induce hypothalamic insulin resistance. Two major tyrosine phosphatases, PTP-1B and TCPTP, are upregulated in chronic overeating. They dephosphorylate the insulin receptor and insulin receptor substrate proteins, resulting in hypothalamic insulin resistance. Prolonged hyperinsulinemia with excessive nutrition activates the mTOR/S6 kinase pathway, thereby enhancing IRS-1 serine phosphorylation to induce hypothalamic insulin resistance. Other mechanisms associated with this condition include hypothalamic gliosis and disturbed insulin transport into the central nervous system. Unveiling the precise molecular mechanisms involved in hypothalamic insulin resistance is important for developing new ways of treating obesity and type 2 diabetes.

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Section: Cell Populations Involved In Hypothalamic Insulin Functiomentioning

confidence: 99%

Section: Cell Populations Involved In Hypothalamic Insulin Functiomentioning

confidence: 99%

Molecular Mechanisms of Hypothalamic Insulin Resistance

Ono

2019

IJMS

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“…Changes in csf are tempered in comparison with peripheral variations of glucose or insulin, but do exist, showing some delay and variations of lower magnitude. The adjustment of csf insulin is disturbed in some pathologies (Begg, 2015 ). In contrast, changes in csf glucose level have been observed in chickens in various conditions: a decrease in response to peripheral hypoglycemia (induced by intravenous tolbutamide or insulin injection) with a delay of about 20 to 40 minutes (Anderson and Hazelwood, 1969 ; Simon and Leclercq, 1985 ) or in response to overnight fasting of 16 h (Simon and Leclercq, 1985 ).…”

Section: Discussionmentioning

confidence: 99%

Insulin immuno-neutralization decreases food intake in chickens without altering hypothalamic transcripts involved in food intake and metabolism

Proszkowiec‐Weglarz

Dupont²,

Rideau³

et al. 2017

Poultry Science

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In mammals, insulin regulates blood glucose levels and plays a key regulatory role in appetite via the hypothalamus. In contrast, chickens are characterized by atypical glucose homeostasis, with relatively high blood glucose levels, reduced glucose sensitivity of pancreatic beta cells, and large resistance to exogenous insulin. The aim of the present study was to investigate in chickens the effects of 5 h fasting and 5 h insulin immuno-neutralization on hypothalamic mRNA levels of 23 genes associated with food intake, energy balance, and glucose metabolism. We observed that insulin immune-neutralization by administration of anti-porcine insulin guinea pig serum (AI) significantly decreased food intake and increased plasma glucose levels in chickens, while 5 h fasting produced a limited and non-significant reduction in plasma glucose. In addition, 5 h fasting increased levels of NPY, TAS1R1, DIO2, LEPR, GLUT1, GLUT3, GLUT8, and GCK mRNA. In contrast, AI had no impact on the levels of any selected mRNA. Therefore, our results demonstrate that in chickens, food intake inhibition or satiety mechanisms induced by insulin immuno-neutralization do not rely on hypothalamic abundance of the 23 transcripts analyzed. The hypothalamic transcripts that were increased in the fasted group are likely components of a mechanism of adaptation to fasting in chickens.

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“…The insulin receptor (IR) facilitates the transport of insulin, produced nearly exclusively by the pancreas, across the BBB so it can contribute in an array of vital signaling pathways [89]. Engineered monoclonal antibodies with a binding affinity towards the IR can be used to ferry therapeutic materials across the BBB via IR-mediated transcytosis.…”

Section: Structural Components Of the Bbbmentioning

confidence: 99%

Approaches to CNS Drug Delivery with a Focus on Transporter-Mediated Transcytosis

Razzak

Florence

Gunn-Moore

2019

IJMS

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Drug delivery to the central nervous system (CNS) conferred by brain barriers is a major obstacle in the development of effective neurotherapeutics. In this review, a classification of current approaches of clinical or investigational importance for the delivery of therapeutics to the CNS is presented. This classification includes the use of formulations administered systemically that can elicit transcytosis-mediated transport by interacting with transporters expressed by transvascular endothelial cells. Neurotherapeutics can also be delivered to the CNS by means of surgical intervention using specialized catheters or implantable reservoirs. Strategies for delivering drugs to the CNS have evolved tremendously during the last two decades, yet, some factors can affect the quality of data generated in preclinical investigation, which can hamper the extension of the applications of these strategies into clinically useful tools. Here, we disclose some of these factors and propose some solutions that may prove valuable at bridging the gap between preclinical findings and clinical trials.

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Insulin Transport into the Brain and Cerebrospinal Fluid

Cited by 24 publications

References 144 publications

Molecular Mechanisms of Hypothalamic Insulin Resistance

Molecular Mechanisms of Hypothalamic Insulin Resistance

Insulin immuno-neutralization decreases food intake in chickens without altering hypothalamic transcripts involved in food intake and metabolism

Approaches to CNS Drug Delivery with a Focus on Transporter-Mediated Transcytosis

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