Elevated plasma glucagon in amyotrophic lateral sclerosis

Hubbard, Richard W.; Will, Albrecht; Peterson, Gary; Sanchez, Albert; Gillan, Wynn; Tan, Song

doi:10.1212/wnl.42.8.1532

Cited by 26 publications

(17 citation statements)

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“…This suggests that an increase in disease severity in ALS patients is correlated with increased circulating glucagon levels. Indeed, given that impaired glucose homeostasis in ALS could occur as a consequence of higher levels of circulating glucagon [46], our data is congruent with observations that insulin resistance is related to disease severity and outcome in ALS [47].…”

Section: Discussionsupporting

confidence: 91%

Altered expression of metabolic proteins and adipokines in patients with amyotrophic lateral sclerosis

Ngo

Steyn

Huang

et al. 2015

Journal of the Neurological Sciences

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Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the loss of upper cortical and lower motor neurons. ALS causes death within 2-5years of diagnosis. Diet and body mass index influence the clinical course of disease, however there is limited information about the expression of metabolic proteins and fat-derived cytokines (adipokines) in ALS. In healthy controls and subjects with ALS, we have measured levels of proteins and adipokines that influence metabolism. We find altered levels of active ghrelin, gastric inhibitory peptide (GIP), pancreatic polypeptide (PP), lipocalin-2, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6) and 8 (IL-8), and tumor necrosis factor alpha (TNFα) in the plasma of ALS patients relative to controls. We also observe a positive correlation between the expression of plasma nerve growth factor (NGF) relative to disease duration, and an inverse correlation between plasma glucagon and the ALS functional rating scale-revised (ALSFRS-R). Further studies are required to determine whether altered expression of metabolic proteins and adipokines contribute to motor neuron vulnerability and how these factors act to modify the course of disease.

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Section: Discussionsupporting

confidence: 91%

Altered expression of metabolic proteins and adipokines in patients with amyotrophic lateral sclerosis

Ngo

Steyn

Huang

et al. 2015

Journal of the Neurological Sciences

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“…As glucose intolerance and insulin resistance have been linked to ALS [24], [25], and in light of the neurotrophic and protective actions of GLP-1R activation in diverse cellular and animal models of neurodegeneration, we hypothesize that GLP-1 and analogues may provide neuroprotective actions in ALS. To test this hypothesis, we investigated the therapeutic potential of Ex-4 in both cell culture and rodent models of ALS.…”

Section: Introductionmentioning

confidence: 99%

Exendin-4 Ameliorates Motor Neuron Degeneration in Cellular and Animal Models of Amyotrophic Lateral Sclerosis

et al. 2012

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS.

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“…In ALS, glucose intolerance and abnormal levels of glucagon, insulin and plasma amino acids have been observed [103]. Thus, while some authors support the notion that many ALS patients have some of the features of type II diabetes mellitus [104], others have shown that ALS patients are indeed hypermetabolic [105].…”

Section: Resultsmentioning

confidence: 99%

Neuroendocrinology of Neurodegenerative Diseases

Aguilar

Frydman²,

Dupuis³

et al. 2003

Neuroendocrinology

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The nervous system plays a key role in the regulation of neuroendocrine axes and, in turn, the released neurohormones modulate the activity of different brain regions. Neurodegenerative diseases, which are known to affect specific neuronal populations, may provoke neuroendocrine dysfunctions that alter the intimate relationship between both systems. In addition, these modifications may influence the progression of the neurodegenerative process. In the present review, we summarise some of the endocrine changes characterising three major neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Special attention is focused on the contribution of disease transgenic models to elucidate such alterations.

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Elevated plasma glucagon in amyotrophic lateral sclerosis

Cited by 26 publications

References 0 publications

Altered expression of metabolic proteins and adipokines in patients with amyotrophic lateral sclerosis

Altered expression of metabolic proteins and adipokines in patients with amyotrophic lateral sclerosis

Exendin-4 Ameliorates Motor Neuron Degeneration in Cellular and Animal Models of Amyotrophic Lateral Sclerosis

Neuroendocrinology of Neurodegenerative Diseases

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