Characterization and Regulation of Insulin Receptors in Rat Brain

Zahniser, Nancy R.; Goens, M.B.; Hanaway, Patrick; Vinych, J V

doi:10.1111/j.1471-4159.1984.tb02795.x

Cited by 100 publications

(57 citation statements)

References 39 publications

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“…Insulin can be transported from plasma into brain through the blood brain barrier, achieving concentrations of about 3 pmol/l in the CNS [30,31]. The existence of insulin receptors [32,33] and GLUT-4, an insulin-sensitive glucose transporter [34,35,36], in the CNS supports the idea that insulin can exert direct actions in the CNS. Pre-incubation with insulin promotes survival of cultured neurons during glucose deprivation by facilitating glial glycogen synthesis [37].…”

Section: Discussionmentioning

confidence: 67%

Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats

et al. 2003

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Aims/Hypothesis. Cognitive deficits occur commonly in diabetic patients. It is unclear whether these impairments result from hypoglycaemia during intensive insulin therapy, or from the diabetes itself. The aim of this study was to examine if impaired energy utilization resulting from insulin deficiency contributes to impaired long-term potentiation (reflecting impaired synaptic plasticity). As long-term potentiation is considered a candidate cellular mechanism underlying learning and memory, understanding how diabetes alters long-term potentiation may provide insight into mechanisms producing cognitive deficits in diabetes. Methods. Electrophysiologic recordings were used to study long-term potentiation in the CA1 region of hippocampal slices from healthy rats and rats with streptozotocin-induced diabetes.Results. Long-term potentiation was difficult to induce in slices from diabetic rats in standard recording buffer (contains 10 mmol/l glucose). In slices from diabetic rats, increasing extracellular glucose failed to recover long-term potentiation induction, but 10 mmol/l pyruvate added to standard buffer enabled long-term potentiation induction. Moreover, incubation of slices from diabetic rats with insulin enabled long-term potentiation induction in standard buffer. Acute administration of streptozotocin alone did not impair long-term potentiation in slices from healthy animals, and changing extracellular glucose concentrations over the range of 5 mmol/l to 30 mmol/l did not alter long-term potentiation in slices from control rats. Conclusions/interpretation. These observations suggest that impaired energy utilization from insulin deficiency, rather than the accompanying hyperglycaemia, impair long-term potentiation in diabetes. Impaired hippocampal synaptic plasticity could contribute to learning and cognitive impairment in diabetic patients. [Diabetologia (2003) Poor academic performance in diabetic children and memory impairment in adults with diabetes are viewed as increasing public health concerns. These problems are typically thought to result from hypoglycaemic attacks [1,2], which occur more frequently during intensive insulin therapy [3]. Although insulininduced hypoglycaemia could contribute to learning problems [4], one recent prospective study did not find a relationship between severe hypoglycaemic events and cognitive impairment [5], raising the possibility that the diabetic condition alone might adversely affect learning and memory. Experimental evidence supporting an independent effect of diabetes upon

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Section: Discussionmentioning

confidence: 67%

Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats

et al. 2003

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“…Functional properties ofthe a-subunit of the insulin receptor, such as the binding kinetic parameters, pH optima, time, and temperature dependence, and specificity of insulin binding, are indistinguishable from the peripheral receptors (1,2,5,7). In contrast, other properties of adult rodent brain receptor, such as its apparent inability to down-regulate after exposure to high insulin concentration (7,8), differ from those of peripheral insulin receptors. The structure ofthe receptor's a-subunit in rat brain differs from that of other tissues: the electrophoretic mobility of the a-subunit covalently labeled with '25I-insulin is consistently more rapid (Mr-115,000 vs.…”

Section: Introductionmentioning

confidence: 80%

“…ID50 range Regulation ofcerebral glial insulin receptors. Studies in the past showed failure of insulin to down-regulate its receptors in rat neuron-enriched cultured brain tissue (7,8). When cells of the cultured human glioblastoma line were preincubated with various concentrations ofinsulin at 370C, and 251I-insulin binding was carried out after extensive washing of the cells, the glial insulin receptors were down-regulated by the ambient insulin concentrations (Fig.…”

Section: Insulin-stimulated Glucose Uptakementioning

confidence: 99%

Insulin receptor of human cerebral gliomas. Structure and function.

et al. 1986

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The insulin receptor from human brain tumors of glial origin was examined for the first time using intact cells (from an established cultured human glioblastoma cell line) and partially purified solubilized membranes (from cultured cells and freshly isolated human brain tumors). The structure of the glial insulin receptor subunits was assessed by affinity cross-linking of 125I-insulin with the a-subunit of the receptor, neuraminidase treatment of the cross-linked receptor, behavior of the receptor on lectin columns, and electrophoretic mobility of the phosphorylated ,8-subunit. The functions of the insulin receptor were examined by measuring specific "SI-insulin binding (receptor concentration, affinity, specificity, pH-, time-, and temperature dependence), insulin-induced down-regulation of the receptor, insulin-stimulated autophosphorylation of the 13-subunit, and phosphorylation of exogenous substrates as well as insulin-stimulated glucose uptake in glioblastoma cells. All of these properties were typical for the insulin receptor from target tissues for insulin action. The insulin receptor of the normal human brain showed the altered electrophoretic mobility and lack of neuraminidase sensitivity of its a-subunit previously reported for the rat brain receptor. There was no difference, however, in the functions of the receptor subunits (binding, phosphorylation) from the normal brain tissue and the eight human gliomal tumors. Since the glial elements compose a majority of the brain cells, the "normal" structure and function of their insulin receptor might provide a key to understanding the role of insulin in the carbohydrate metabolism of the human central nervous system.

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“…This parallel decrease of insulin and its degrading enzyme IDE in AD raises the possibility that insulin might normally upregulate IDE in the brain via a negative feedback control mechanism to limit the insulin response. Also, unlike peripheral insulin receptors, insulin receptors in the brain are not downregulated by high concentrations of insulin (Boyd and Raizada, 1983;Zahniser et al, 1984), leaving IDE as a plausible effector molecule with upregulation that could turn off insulin signaling in the presence of high insulin levels. Consistent with this hypothesis, a recent report by Ho et al (2004) showed that insulin-resistance caused by a high-fat diet is associated with reduced IDE levels and increased amyloidosis in an AD animal model.…”

Section: Introductionmentioning

confidence: 99%

Insulin-Degrading Enzyme as a Downstream Target of Insulin Receptor Signaling Cascade: Implications for Alzheimer's Disease Intervention

Zhao¹,

Teter²,

Morita³

et al. 2004

J. Neurosci.

296

188

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Insulin-degrading enzyme (IDE) is one of the proteins that has been demonstrated to play a key role in degrading ␤-amyloid (A␤) monomer in vitro and in vivo, raising the possibility of upregulating IDE as an approach to reduce A␤. Little is known, however, about the cellular and molecular regulation of IDE protein. Because one of the main functions of IDE is to degrade insulin, we hypothesized that there is a negative feedback mechanism whereby stimulation of insulin receptor-mediated signaling upregulates IDE to prevent chronic activation of the pathway. We show that treatment of primary hippocampal neurons with insulin increased IDE protein levels by ϳ25%. Insulin treatment also led to phosphatidylinositol-3 (PI3) kinase activation evidenced by Akt phosphorylation, which was blocked by PI3 kinase inhibitors, wortmannin and LY 294002. Inhibition of PI3 kinase abolished the IDE upregulation by insulin, indicating a causeeffect relationship between insulin signaling and IDE upregulation. Further support for this link was provided by the findings that deficient insulin signaling (decreased PI3 kinase subunit P85) was correlated with reduced IDE in Alzheimer's disease (AD) brains and in Tg2576 Swedish amyloid precursor protein transgenic mice fed a safflower oil-enriched ("Bad") diet used to accelerate pathogenesis. Consistent with IDE function in the degradation of A␤ monomer, the IDE decrease in the Bad diet-fed Tg2576 mice was associated with increased A␤ monomer levels. These in vitro and in vivo analyses validate the use of enhanced CNS insulin signaling as a potential strategy for AD intervention to correct the IDE defects occurring in AD.

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Characterization and Regulation of Insulin Receptors in Rat Brain

Cited by 100 publications

References 39 publications

Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats

Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats

Insulin receptor of human cerebral gliomas. Structure and function.

Insulin-Degrading Enzyme as a Downstream Target of Insulin Receptor Signaling Cascade: Implications for Alzheimer's Disease Intervention

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