Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes

Muhič, Marko; Vardjan, Nina; Chowdhury, Helena H.; Zorec, Robert; Kreft, Marko

doi:10.1074/jbc.m114.629063

Cited by 49 publications

(43 citation statements)

References 83 publications

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“…Previous 13 C‐MRS studies in rats under light α‐chloralose anesthesia, have estimated similar (Choi, Tkác, Ugurbil, & Gruetter, ) or slightly faster (0.7 µmol/g/h, van Heeswijk, Morgenthaler, Xin, & Gruetter, ) glycogen turnover rates. The discrepancy on the measured turnover rates in our study and these previous publications could be caused by either the deepness of anesthesia that modulates brain activity and metabolism (Sonnay, Gruetter, & Duarte, ), or the brain levels of insulin that might stimulate glycogen synthesis (Fernandez et al, ; Muhič et al, ). Accordingly, administration of insulin to anaesthetized rats was previously reported to increase brain glycogen levels (Morgenthaler et al, ).…”

Section: Discussioncontrasting

confidence: 95%

“…levels of insulin that might stimulate glycogen synthesis (Fernandez et al, 2017;Muhič et al, 2015). Accordingly, administration of insulin to anaesthetized rats was previously reported to increase brain glycogen levels (Morgenthaler et al, 2006).…”

Section: Brain Glycogen Metabolismmentioning

confidence: 99%

“…Indeed, AD has been proposed as an insulin resistance‐associated neurodegenerative disorder, with brain alterations that resemble those observed in individuals with T2D regarding brain insulin signaling (Steculorum, Solas, & Brüning, ). Insulin resistance might be directly associated to impaired cortical glucose consumption and cognitive impairment (Baker et al, ), and insulin signaling was proposed to modulate glycogen stores in astrocytes (Muhič, Vardjan, Chowdhury, Zorec, & Kreft, ). However, little is known on brain glycogen metabolism in T2D.…”

Section: Introductionmentioning

confidence: 99%

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Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto‐Kakizaki rats

Soares

Nissen

García-Serrano

et al. 2019

J of Neuroscience Research

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Diabetes impacts the central nervous system predisposing to cognitive decline. While glucose is the main source of energy fueling the adult brain, brain glycogen is necessary for adequate neuronal function, synaptic plasticity and memory. In this study, we tested the hypothesis that brain glycogen metabolism is impaired in type 2 diabetes (T2D). 13C magnetic resonance spectroscopy (MRS) during [1‐13C]glucose i.v. infusion was employed to detect 13C incorporation into whole‐brain glycogen in male Goto‐Kakizaki (GK) rats, a lean model of T2D, and control Wistar rats. Labeling from [1‐13C]glucose into brain glycogen occurred at a rate of 0.25 ± 0.12 and 0.48 ± 0.22 µmol/g/h in GK and Wistar rats, respectively (p = 0.028), despite similar brain glycogen concentrations. In addition, the appearance of [1‐13C]glucose in the brain was used to evaluate glucose transport and consumption. T2D caused a 31% reduction (p = 0.031) of the apparent maximum transport rate (Tmax) and a tendency for reduced cerebral metabolic rate of glucose (CMRglc; −29%, p = 0.062), indicating impaired glucose utilization in T2D. After MRS in vivo, gas chromatography‐mass spectrometry was employed to measure regional 13C fractional enrichment of glucose and glycogen in the cortex, hippocampus, striatum, and hypothalamus. The diabetes‐induced reduction in glycogen labeling was most prominent in the hippocampus and hypothalamus, which are crucial for memory and energy homeostasis, respectively. These findings were further supported by changes in the phosphorylation rate of glycogen synthase, as analyzed by Western blotting. Altogether, the present results indicate that T2D is associated with impaired brain glycogen metabolism.

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Section: Discussioncontrasting

confidence: 95%

Section: Brain Glycogen Metabolismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto‐Kakizaki rats

Soares

Nissen

García-Serrano

et al. 2019

J of Neuroscience Research

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“…Another important aspect confirmed by our findings is that IR and IGF‐IR display ligand‐independent activities that may, or may not, be related to the actions of their ligands (Boucher et al, ). In this regard, different authors have shown that IGF‐I and insulin also affect glucose handling by astrocytes at different levels, including enhanced glucose uptake (Kum et al, ; Masters et al, ) and/or enhanced glycogen production (Dringen and Hamprecht, ; Hamai et al, ; Muhic et al, ). These observations suggest that insulin peptides and their receptors form an intricate glucose regulatory network in astrocytes that may even act in apparently opposing manners.…”

Section: Discussionmentioning

confidence: 99%

The insulin‐like growth factor I receptor regulates glucose transport by astrocytes

Hernández-Garzón

Fernández

Pérez-Álvarez

et al. 2016

Glia

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Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using 18 FGlucose PET we found that shRNA interference of IGF-IR in mouse somatosensory cortex significantly increased glucose uptake upon sensory stimulation. In vivo microscopy using astrocyte specific staining showed that after IGF-IR shRNA injection in somatosensory cortex, astrocytes displayed greater increases in glucose uptake as compared to astrocytes in the scramble-injected side. Further, mice with the IGF-IR knock down in astrocytes showed increased glucose uptake in somatosensory cortex upon sensory stimulation. Analysis of underlying mechanisms indicated that IGF-IR interacts with glucose transporter 1 (GLUT1), the main facilitative glucose transporter in astrocytes, through a mechanism involving interactions with the scaffolding protein GIPC and the multicargo transporter LRP1 to retain GLUT1 inside the cell. These findings identify IGF-IR as a key modulator of brain glucose metabolism through its inhibitory action on astrocytic GLUT1 activity.

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“…Several factors can regulate glycogen production and utilization in astrocytes, with insulin, insulin-like growth factor (IGF)-1 (305, 306), and leptin (203, 307) increasing their production of glycogen. More recently, ghrelin has been reported to possibly promote glycogenolysis in hypothalamic neurons (122).…”

Section: Functions Of Non-neuronal Cellsmentioning

confidence: 99%

Non-Neuronal Cells in the Hypothalamic Adaptation to Metabolic Signals

et al. 2017

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Although the brain is composed of numerous cell types, neurons have received the vast majority of attention in the attempt to understand how this organ functions. Neurons are indeed fundamental but, in order for them to function correctly, they rely on the surrounding “non-neuronal” cells. These different cell types, which include glia, epithelial cells, pericytes, and endothelia, supply essential substances to neurons, in addition to protecting them from dangerous substances and situations. Moreover, it is now clear that non-neuronal cells can also actively participate in determining neuronal signaling outcomes. Due to the increasing problem of obesity in industrialized countries, investigation of the central control of energy balance has greatly increased in attempts to identify new therapeutic targets. This has led to interesting advances in our understanding of how appetite and systemic metabolism are modulated by non-neuronal cells. For example, not only are nutrients and hormones transported into the brain by non-neuronal cells, but these cells can also metabolize these metabolic factors, thus modifying the signals reaching the neurons. The hypothalamus is the main integrating center of incoming metabolic and hormonal signals and interprets this information in order to control appetite and systemic metabolism. Hence, the factors transported and released from surrounding non-neuronal cells will undoubtedly influence metabolic homeostasis. This review focuses on what is known to date regarding the involvement of different cell types in the transport and metabolism of nutrients and hormones in the hypothalamus. The possible involvement of non-neuronal cells, in particular glial cells, in physiopathological outcomes of poor dietary habits and excess weight gain are also discussed.

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Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes

Cited by 49 publications

References 83 publications

Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto‐Kakizaki rats

Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto‐Kakizaki rats

The insulin‐like growth factor I receptor regulates glucose transport by astrocytes

Non-Neuronal Cells in the Hypothalamic Adaptation to Metabolic Signals

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