Stimulation of synaptosomal uptake of neurotransmitter amino acids by insulin: Possible role of insulin as a neuromodulator

Rhoads, Dennis E.; DiRocco, Richard J.; Osburn, L. D.; Peterson, N. A.; Raghupathy, E.

doi:10.1016/0006-291x(84)90903-3

Cited by 44 publications

(23 citation statements)

References 21 publications

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“…Other mechanisms that could be involved in the inhibition of glutamate uptake by ROS may be the direct oxidation of the transporter sulfhydryl groups (43,44) or the impairment of Na ϩ ,K ϩ ATPase activity (45). The modulatory effect of insulin on amino acid accumulation in brain remains controversial (14,46). In some studies, 3 mol/l insulin stimulated glutamate and GABA accumulation in rat brain synaptosomes (14), whereas in others, the same concentration was shown to inhibit GABA uptake in embryonic chick retina and newborn mouse cerebral cortex astroglial cells (11,47).…”

Section: Diabetes Vol 53 August 2004mentioning

confidence: 99%

“…The modulatory effect of insulin on amino acid accumulation in brain remains controversial (14,46). In some studies, 3 mol/l insulin stimulated glutamate and GABA accumulation in rat brain synaptosomes (14), whereas in others, the same concentration was shown to inhibit GABA uptake in embryonic chick retina and newborn mouse cerebral cortex astroglial cells (11,47). According to Rhoads et al (14), insulin dose-dependently stimulates synaptosomal amino acid uptake, and 1 mol/l was the lowest insulin concentration that increased glutamate uptake by cortical synaptosomes, by an effect maintained during 1-20 min of in vitro incubation.…”

Section: Diabetes Vol 53 August 2004mentioning

confidence: 99%

“…Some authors (11,14) hypothesized that insulin-induced changes in GABA transport can be exerted indirectly through the stimulation of Na ϩ ,K ϩ ATPase activity, thus increasing the transmembrane Na ϩ gradient and the ⌬⌿ m . However, Guyot et al (48) postulated that these changes could be related to stimulation of glycolysis and pyruvate dehydrogenase, increasing lactate and ATP levels, which stimulate ion pumps and, ultimately, the synaptosomal amino acid transport.…”

Section: Diabetes Vol 53 August 2004mentioning

confidence: 99%

“…Moreover, insulin immunoreactivity occurs in the endoplasmic reticulum and Golgi apparatus in vivo (9,10). In the central nervous system, insulin seems to play an important role, particularly in the complications caused by diabetes, involving the regulation of brain metabolism (11,12), neuronal growth and differentiation (9,13), or neuromodulation (13,14). Insulin may also protect against brain damage induced by stress conditions, such as oxidative stress or ischemia (12,15).…”

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Oxidative Stress Affects Synaptosomal γ-Aminobutyric Acid and Glutamate Transport in Diabetic Rats

et al. 2004

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Evidence suggests that oxidative stress is involved in the pathophysiology of diabetic complications and that insulin has a neuroprotective role in oxidative stress conditions. In this study, we evaluated the in vitro effect of insulin in the susceptibility to oxidative stress and in the transport of the amino acid neurotransmitters ␥-aminobutyric acid (GABA) and glutamate in a synaptosomal fraction isolated from male type 2 diabetic Goto-Kakizaki (GK) rat brain cortex. The ascorbate/ Fe 2؉ -induced increase in thiobarbituric acid reactive substances (TBARSs) was similar in Wistar and GK rats and was not reverted by insulin (1 mol/l), suggesting that other mechanisms, rather than a direct effect in membrane lipid peroxidation, may mediate insulin neuroprotection. Diabetes did not affect GABA and glutamate transport, despite the significant decrease in membrane potential and ATP/ADP ratio, and insulin increased the uptake of both GABA and glutamate in GK rats. Upon oxidation, there was a decrease in the uptake of both neurotransmitters and an increase in extrasynaptosomal glutamate levels and in ATP/ADP ratio in GK rats. Insulin treatment reverted the ascorbate/Fe 2؉ -induced decrease in GABA accumulation, with a decrease in extrasynaptosomal GABA. These results suggest that insulin modulates synaptosomal GABA and/or glutamate transport, thus having a neuroprotective role under oxidizing and/or diabetic conditions.

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Section: Diabetes Vol 53 August 2004mentioning

confidence: 99%

Section: Diabetes Vol 53 August 2004mentioning

confidence: 99%

Section: Diabetes Vol 53 August 2004mentioning

confidence: 99%

mentioning

confidence: 99%

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Oxidative Stress Affects Synaptosomal γ-Aminobutyric Acid and Glutamate Transport in Diabetic Rats

et al. 2004

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“…Presently the results of studies that have investigated the effects of insulin on brain glucose uptake are inconclusive (1)(2)(3)(4)(5)(6)(7)(8). Although the central nervous system is not considered an insulin sensitive tissue, recent studies have demonstrated high concentrations of insulin in the brain (9), and the presence of insulin receptors in microvessels (10,11) as well as within the brain substance (12)(13)(14)(15). Difficulties of interpretation of the present data may be related to the use of in vitro techniques and in vivo investigations that do not have a steady state of blood glucose or insulin levels.…”

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confidence: 67%

The Effect of Euglycemic Hyperinsulinemia on Cerebral Cortical Glucose Metabolism in Newborn Beagles

et al. 1988

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ABSTRACT. There is a paucity of information on the significance of insulin on neonatal cerebral glucose metabolism. The effect of insulin on neonatal cerebral glucose uptake and cerebral cortical metabolic intermediates was investigated with the euglycemic hyperinsulinemic clamp in unanesthetized beagles during the first day of life. Insulin was infused at various rates to sustain an elevated steady state plasma insulin concentration in individual pups. Furthermore, blood glucose and 2-deoxyglucose levels were also maintained ("clamped") in a steady state by infusion of glucose and 2-deo~y-['~C]-glucose. Mean ( f SD) plasma insulin levels were 20 f 12 and 2971 f 3386 (33-14330) pU/ml in control and hyperinsulinemic pups. Blood glucose concentration was 4.43 f 2.64 mM during basal periods and 4.54 f 2.87 mM during the clamp period in study pups. Basal fasting glucose utilization in study pups was 43.9 f 24 pmol/kg/min and increased to 60.9 f 35.2 pmol/ kg/min (p < 0.001) during hyperinsulinemia. Immediately after the euglycemic hyperinsulinemic clamp or fasting in control pups, the cerebral cortex was frozen to the temperature of liquid nitrogen. No differences were noted for any cerebral cortical intermediate between the two pup groups. In addition, there was no relationship between the cerebral intermediates concentration when analyzed as a function of plasma insulin levels. The uptake of cerebral Z-deoxyglucose was analyzed as a function of plasma insulin concentration (120-6900 pU/ml). Brain tissue demonstrated a positive linear relationship for 2-deoxyglucose uptake as a function of plasma insulin concentration. Although static determination of brain metabolites were not influenced by hyperinsulinemia, there was a positive effect of insulin on cerebral glucose uptake. Either directly or indirectly, insulin may increase brain glucose utilization in the newborn dog. (Pediatr Res 23: 474-479, 1988) Glucose is considered the major substrate for brain energy metabolism. While it is know that insulin affects glucose uptake and metabolism in peripheral tissues, it is a matter of speculation whether insulin affects the uptake and utilization of glucose by the brain. Presently the results of studies that have investigated the effects of insulin on brain glucose uptake are inconclusive (1-8). Although the central nervous system is not considered an insulin sensitive tissue, recent studies have demonstrated high concentrations of insulin in the brain (9), and the presence of insulin receptors in microvessels (10, 11) as well as within the brain substance (12-15). Difficulties of interpretation of the present data may be related to the use of in vitro techniques and in vivo investigations that do not have a steady state of blood glucose or insulin levels.Investigations on the effects of insulin on the developing nervous system suggest that insulin may have an action on cerebral macromolecule synthesis (16,17). In the developing brain, insulin stimulates protein, and RNA and DNA synthesis in vitro (1 6, 17).Although i...

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The role of nitric oxide in the protective effect of insulin against pentylenetetrazole-induced seizures in mice

Ulugöl

Arikan

Dost

et al. 2000

Neurosci. Res. Comm.

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Both insulin, depending on the glycemic state, and nitric oxide (NO), depending on the experimental conditions, have been suggested to have either proconvulsant or anticonvulsant effects. It is also known that NO plays an important role in some of the peripheral effects of insulin. The aim of the present study was to investigate the effects of NO and insulin against convulsions produced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) in mice and whether NO plays a role in the effect of insulin. Nitric oxide synthase (NOS) inhibitor, NG‐nitro‐L‐arginine‐methyl ester (L‐NAME, 1‐100 mg/kg, i.p.) shortened the onset of PTZ‐induced convulsioins and increased the incidence and mortality rate, at the higher doses. Insulin (1 U/kg, i.p.), when given with dextrose (3 g/kg, i.p.) to counteract the hypoglycemic effect of the hormone, prolonged the onset of convulsions and decreased the incidence and mortality rate. L‐NAME pretreatment (3 mg/kg, i.p.), at the dose which it produced no effect on PTZ‐induced convulsions, attenuated the protective effect of 1 U/kg insulin + 3 g/kg dextrose combination significantly. Concomitant administration of the NO synthesis precursor, L‐arginine (500 mg/kg), completely reversed this facilitatory effect of L‐NAME. Our results indicate that NO has a protective effect against PTZ‐induced convulsions in mice; insulin has a similar effect when given with dextrose; and, NO production may play an important role in the anticonvulsant effect of insulin.

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Stimulation of synaptosomal uptake of neurotransmitter amino acids by insulin: Possible role of insulin as a neuromodulator

Cited by 44 publications

References 21 publications

Oxidative Stress Affects Synaptosomal γ-Aminobutyric Acid and Glutamate Transport in Diabetic Rats

Oxidative Stress Affects Synaptosomal γ-Aminobutyric Acid and Glutamate Transport in Diabetic Rats

The Effect of Euglycemic Hyperinsulinemia on Cerebral Cortical Glucose Metabolism in Newborn Beagles

The role of nitric oxide in the protective effect of insulin against pentylenetetrazole-induced seizures in mice

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