Central NMDA enhances hepatic glucose output and non-insulin-mediated glucose uptake by a nonadrenergic mechanism

Molina, Patricia E.; Tepper, Patrick G.; Yousef, Khalil A.; Abumrad, Naji N.; Lang, Charles H.

doi:10.1016/0006-8993(94)90256-9

Cited by 24 publications

(10 citation statements)

References 20 publications

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“…On the other hand, direct stimulation of hypothalamic centers can modify peripheral glucose utilization. This has been shown by the direct intracerebroventricular administration of N-methyl-D-aspartate, which produced a rapid and sustained increase in whole-body glucose turnover (38) and individual skeletal muscle glucose utilization (39). In this latter study, glucose utilization was prevented when the skeletal muscles were denervated.…”

Section: Discussionmentioning

confidence: 54%

Portal glucose infusion in the mouse induces hypoglycemia: evidence that the hepatoportal glucose sensor stimulates glucose utilization.

2000

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To analyze the role of the murine hepatoportal glucose sensor in the control of whole-body glucose metabolism, we infused glucose at a rate corresponding to the endogenous glucose production rate through the portal vein of conscious mice (Po-mice) that were fasted for 6 h. Mice infused with glucose at the same rate through the femoral vein (Fe-mice) and mice infused with a saline solution (Sal-mice) were used as controls. In Po-mice, hypoglycemia progressively developed until glucose levels dropped to a nadir of 2.3 ± 0.1 mmol/l, whereas in Fe-mice, glycemia rapidly and transiently developed, and glucose levels increased to 7.7 ± 0.6 mmol/l before progressively returning to fasting glycemic levels. Plasma insulin levels were similar in both Po-and Fe-mice during and at the end of the infusion periods (21.2 ± 2.2 vs. 25.7 ± 0.9 µU/ml, respectively, at 180 min of infusion). The whole-body glucose turnover rate was significantly higher in Po-mice than in Fe-mice (45.9 ± 3.8 vs. 37.7 ± 2.0 mg · kg -1 · min -1 , respectively) and in Sal-mice (24.4 ± 1.8 mg · kg -1 · min -1 ). Somatostatin co-infusion with glucose in Po-mice prevented hypoglycemia without modifying the plasma insulin profile. Finally, tissue glucose clearance, which was determined after injecting 14 C-2-deoxyglucose, increased to a higher level in Po-mice versus Fe-mice in the heart, brown adipose tissue, and the soleus muscle. Our data show that stimulation of the hepatoportal glucose sensor induced hypoglycemia and increased glucose utilization by a combination of insulin-dependent and insulin-independent or -sensitizing mechanisms. Furthermore, activation of the glucose sensor and/or transmission of its signal to target tissues can be blocked by somatostatin. Diabetes 49:1635-1642, 2000

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Section: Discussionmentioning

confidence: 54%

Portal glucose infusion in the mouse induces hypoglycemia: evidence that the hepatoportal glucose sensor stimulates glucose utilization.

2000

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“…Possible interactions of EAAs and central catechol amines were discussed in several reports [21,36,37], Cen trally administered EAA agonists were found to influence also the peripheral catecholaminergic system, in particu lar to increase sympathetic activity [9,10]. Our data pro vide the first piece of evidence on the involvement of glu tamatergic pathways in the control of epinephrine and norepinephrine secretion into the blood under stress con ditions.…”

Section: Discussionmentioning

confidence: 63%

Endogenous Excitatory Amino Acids Are Involved in Stress-Induced Adrenocorticotropin and Catecholamine Release

Jezová

Tokarev

Rusnak³

1995

Neuroendocrinology

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The effect of N-methyl-D-aspartic acid (NMDA) receptor blockade on adrenocorticotropin (ACTH) and catecholamine activation during stress was investigated in conscious rats with indwelling catheters for both blood sampling and drug treatment. Secretion of ACTH in response to immobilization stress (20 min) was inhibited by pretreatment (20 min before stress exposure) with the centrally acting noncompetitive antagonist of NMDA receptors MK-801 (dizocilpine, the racemic form, 1 mg/kg i.p.) but not by 3-[( ± )-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP; 10 mg/kg i.p.), a competitive NMDA receptor antagonist. Administration of MK-801 (1 mg/kg i.p.) inhibited norepinephrine and totally prevented epinephrine response during acute immobilization stress. Pretreatment with a low dose of MK-801 (0.1 mg/kg i.p.) failed to modify basal or stress-induced ACTH and catecholamine release. The stress-induced rise in plasma epinephrine was found to be attenuated by the peripherally injected competitive antagonist CPP (10 mg/kg i.p.) suggesting that modulation not only of central but also of peripheral NMDA receptors may come into play. Our results indicate the involvement of endogenous excitatory amino acids in the control of ACTH and particularly of epinephrine secretion during stress.

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“…For example, there is evidence suggesting that the combined administration of a acetylcholinesterase inhibitors and anti-oxidants (Formula F or Ginkgo biloba-EGb 761) can more effectively improve cognitive performance than either compound alone [261, 262]. Since NMDA can promote insulin resistance [263], and NMDA neurotoxicity can be attenuated or prevented by insulin stimulation [264]. Therefore, therapeutic measures to inhibit glutamate excitotoxicity may help restore brain metabolic functions, particularly in the context of insulin or insulin sensitizer treatments.…”

Section: Mechanisms Of Brain Insulin/igf Resistance In Neurodegeneratmentioning

confidence: 99%

Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease

Monte

2012

CAR

377

219

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Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.

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Central NMDA enhances hepatic glucose output and non-insulin-mediated glucose uptake by a nonadrenergic mechanism

Cited by 24 publications

References 20 publications

Portal glucose infusion in the mouse induces hypoglycemia: evidence that the hepatoportal glucose sensor stimulates glucose utilization.

Portal glucose infusion in the mouse induces hypoglycemia: evidence that the hepatoportal glucose sensor stimulates glucose utilization.

Endogenous Excitatory Amino Acids Are Involved in Stress-Induced Adrenocorticotropin and Catecholamine Release

Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease

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