Placental transport and metabolism
Hung N. Winn, Frank A. Chervenak, Roberto Romero in Clinical Maternal-Fetal Medicine Online, 2021
Glucose transport is facilitated by a family of isoforms with the prefix GLUT. In human placenta, six GLUT isoforms have been identified at the mRNA level (35,36). The major placental GLUTs are GLUT1 and GLUT3 (37–39), whose abundance and activity differ in response to a variety of environmental factors, including diabetes, maternal nutritional status, hypoxia, and reduced uterine blood flow (28). These GLUTs have different kinetic activity and are differentially expressed within the placental membranes. GLUT3 occurs in the MVM at the maternal–fetal interface and is presumed to be responsible for the rate of glucose delivery to the fetus. GLUT1 tends to be located in the plasma BM and may modulate placental glucose consumption as well as being the rate-limiting step in transplacental glucose transport (39,40).
Mitochondrial Dysfunction Affecting the Peripheral Nervous System in Diabetic Neuropathy and Avenues for Therapy
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Nutrient excess is thought to be driving the depolarization effect, and could occur as a direct response to glucose levels. Extracellular glucose is driven across the plasma membrane of neuron by GLUT3 in an insulin independent manner resulting in high levels inside the cell under hyperglycemic conditions (68,69). High levels of glucose, and also fatty acids, can cause an excess of NADH and FADH2 electron donors, as generated from β-oxidation and the glycolytic citric acid cycle. High levels of NADH and FADH2 disturb the inner mitochondrial membrane potential, and high glucose concentrations down-regulates the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator-1α (PGC- 1α) signaling axis (47,63,70,71). The AMPK/PGC-1α signaling axis is a fundamental energy sensing metabolic pathway controlling mitochondrial function and biogenesis (70–75), where AMPK is required for optimal mitochondrial function under the stress of high ATP demands. This signaling axis is also known to be critical for axonal plasticity and growth-cone motility (39,76–78), and it has a key role in the expression of oxidative phosphorylation proteins. Along these lines, studies in skeletal muscle, liver and cardiac tissues have shown that the activity of AMPK and PGC-1α signaling axis declines under diabetic conditions (66,79–82).
New Understanding of the Nature and Causes of Major Depression
Scott Mendelson in Herbal Treatment of Major Depression, 2019
Neurons do not require insulin to take up glucose. Indeed, the two main glucose transporters in the brain, GLUT1 and GLUT3, have classically been seen as not being responsive to insulin. In turn, it has been assumed that insulin has no important role in brain activity. However, insulin is actively transported into the brain, and insulin receptors are found in a variety of important areas of the brain, particularly the frontal cortex.63 There are also areas of the brain, such as the hippocampus, where insulin-sensitive GLUT4 reside.64 Recent studies have shown that insulin can increase the uptake and metabolism of glucose in the brain.65 Thus, one might expect that insulin resistance would dampen glucose metabolism in the brain and contribute to mood disorder. However, effects of insulin on the cell signaling pathways within the neurons and glial cells of the brain may be more important than effects on glucose metabolism. Indeed, insulin treatment increases the expression of BDNF and its transducer, tropomyosin receptor kinase B (TrkB) receptors in the hippocampi of young rats.66 Another study showed that in the brains of rats made insulin-resistant by high fat diets, insulin no longer fully activated the Akt and mTOR, nor inhibited GSK-3β pathways in the cerebral cortex, which led to decreases in dendritic spine density.67
SLC2A3 rs12842 polymorphism and risk for Alzheimer’s disease
Published in Neurological Research, 2020
Stylianos Arseniou, Vasileios Siokas, Athina-Maria Aloizou, Polyxeni Stamati, Alexios-Fotios A. Mentis, Zisis Tsouris, Metaxia Dastamani, Eleni Peristeri, Varvara Valotassiou, Dimitrios P. Bogdanos, Georgios M. Hadjigeorgiou, Efthimios Dardiotis
The brain relies heavily on glucose, as its main energy source. Specific membrane transporters are required in order for hydrophilic substances, such as glucose, to cross the blood-brain barrier (BBB) [20]. Glucose transport is mediated by three families of solute carriers: (a) the Major Facilitator Superfamily (MFS) glucose SLC2 family of facilitated transporters, GLUTs, (b) the SLC5 family of active sodium-driven glucose transporters (SGLTs), and (c) the SLC50 family of uniporters (SWEETs) [21]. The most highly encountered glucose transporters (GLUTs) in the brain are GLUT1 and GLUT3. GLUT1 is the product of the SLC2A1 gene, and it is predominantly expressed in the human erythrocyte membrane, the endothelial cells of the BBB, and astrocytes [22]. GLUT3, on the other hand, is encoded by the SLC2A3 gene, which is specifically expressed in neurons [23], and it is consequently named the neuronal glucose transporter [24]. In the brain, GLUT1 mediates the transport of glucose from circulating blood in the microvasculature to the interstitial fluid [25]. Following the above process, GLUT3 transports glucose from the extracellular space into the neuron [26].
Effects of constraint-induced movement therapy on brain glucose metabolism in a rat model of cerebral ischemia: a micro PET/CT study
Published in International Journal of Neuroscience, 2018
Ying-Ying Li, Bei Zhang, Ke-Wei Yu, Ce Li, Hong-Yu Xie, Wei-Qi Bao, Yan-Yan Kong, Fang-Yang Jiao, Yi-Hui Guan, Yu-Long Bai
The brain is a highly metabolically active organ that relies almost exclusively on glucose as its energy source. 18FDG PET studies are employed to identify activity-dependent metabolic increases in human subjects [32]. However, the mechanism of improved motor function induced by CIMT in ischemic rats remains unclear. Previous reports demonstrated that forced exercise induced a significant increase in cerebral glycolysis, including expression of glucose transporters (GLUT-1, GLUT-3), compared to voluntary exercise, and neurons preferentially uptake glucose compared to astrocytes in fundamentally different states of brain activity [33]. Similarly, another report observed that the level of glucose utilization correlated with the degree of neuronal activity [19]. Therefore, 18FDG PET studies can reflect the neural activity in ischemic rats. GLUT3 is observed at the plasma membrane of neurons and is responsible for the uptake of glucose into neurons [34]. Several studies suggested that CIMT induces neurogenesis in the lesional hemisphere in the rat brain following cerebral ischemia [12,35]. However, few studies focused on morphological and molecular changes in the contralateral hemisphere. We hypothesized that CIMT promotes increased glucose metabolism in the contralateral hemisphere by inducing neurogenesis in the contralateral brain region or increasing GLUT-3 expression. We combined CT scans with 18FDG PET data for anatomical identification within the animal skull to test our hypothesis [36].
Blood-brain barrier receptors and transporters: an insight on their function and how to exploit them through nanotechnology
Published in Expert Opinion on Drug Delivery, 2019
Rui Pedro Moura, Cláudia Martins, Soraia Pinto, Flávia Sousa, Bruno Sarmento
Glucose transporters (GLUTs) are a group of glycoproteins composed of 12 transmembrane α-helixes, assembled in tags of 3 sharing similar structure. GLUTs possess other two and three extracellular and intracellular helixes, respectively. Similarly to the previously mentioned receptors, after undergoing protein synthesis, these transporters are carried to the endoplasmic reticulum for post-translational modifications, consisting of adequate protein folding, glycosylation, and phosphorylation [74]. The main role of GLUTs is the transport of glucose or other hexose and/or pentose sugars from the blood to the interior of the cell. Thus, GLUTs are expressed in several tissues throughout the body. Since there are many members of the GLUT family, each one of them may have higher or lower expression levels, depending on the biologic site where it is located. In what concerns the brain, it has been described that GLUT1, is mainly expressed in endothelial cells with a considerably high glycosylation percentage, presenting a molecular weight of 55 kDa. Also, GLUT1 is thoroughly expressed in astrocytes and other cellular components of the neurovascular unit, although with a considerably lower rate of glycosylation, holding a molecular weight of 45 kDa. GLUT3 is the main transporter expressed by neurons. The microglia present a wide expression of GLUT5; however, it holds a lower affinity for glucose and a higher affinity towards fructose [75].