Medical Hypotheses 139 (2020) 109614

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Does hyperglycemia downregulate glucose transporters in the brain? T

a b b b
Luana Lemos Leão , Gro Tangen , Maria Lage Barca , Knut Engedal ,
Sérgio Henrique S. Santosa,c, Frederico Sander M. Machadoa, Alfredo Maurício B. de Paulaa,
⁎
Renato Sobral Monteiro-Juniora,d,e,
a
Post-graduate Program of Health Sciences, State University of Montes Claros, Montes Claros, Minas Gerais, Brazil
b
Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
c
Institute of Agricultural Sciences, Universidade Federal de Minas Gerais, Brazil
d
Post-Graduate Program of Medicine (Neurology/Neuroscience), Federal Fluminense University, Niterói, Rio de Janeiro, Brazil
e
Neuroscience of Exercise Institute, Aroldo Tourinho Hospital, Montes Claros, MG, Brazil

A B S T R A C T

Diabetes is a metabolic condition associated with hyperglycemia manifested by the elevation of blood glucose levels occurring when the pancreas decreases or stops
the production of insulin, in case of insulin resistance or both. The current literature supports that insulin resistance may be responsible for the memory decline
associated with diabetes. Glucose transporters (GLUTs) are a family of proteins involved in glucose transport across biological membranes. GLUT-1 and GLUT-3 are
involved in glucose delivery to the brain. Evidence suggests that both transporters are downregulated in chronic peripheral hyperglycemia. Here we show the
mechanisms of glucose transport and its influence on cognitive function, including a hypothesis of how peripheral hyperglycemia related genes network interactions
may lead to glucose transporters downregulation and its possible consequences.

Introduction energy and are based on the glucose concentration gradient across cell
membrane [10]. In humans, 14 different GLUTs have been identified.
According to WHO Global Report on Diabetes, the number of adults Under basal metabolic conditions, most of these transporters, especially
living with this disease is 422 million, and in 2016, an estimated 1.6 the GLUT-4 strongly relies on insulin dependent mechanisms and pre-
million deaths were directly caused by diabetes [1,2]. In 2019, the sents a major role on glucose uptake of adipocytes, cardiac and skeletal
global diabetes prevalence was 463 million people, rising to 578 million muscle cells and plays an important function in whole-body glucose
by 2030 and to 700 million by 2045 [3]. Diabetes is a chronic metabolic homeostasis [11,12].
condition associated with hyperglycemia manifested by the elevation of In the last decade, studies have shown that diabetes is associated
blood glucose levels when pancreas decreases the production or stops with an increased risk of cognitive decline [13,14], affecting learning,
producing insulin (type 1 diabetes) or in cases of the cells’ insulin re- working and episodic memory, cognitive flexibility and speed proces-
sistance (type 2 diabetes) or both [4,5]. Insulin resistance or deficiency sing [15–18]. Cognitive impairment related to diabetes is traditionally
is associated with impairments in glucose metabolism disrupt brain associated with atherosclerosis, since diabetes has an influence in per-
energy balance increasing oxidative stress, reactive oxygen species ipheral vascular disease and dyslipidemia that may lead to small vessel
production that leads to DNA damage, and mitochondrial dysfunction, disease in the brain, which in turn may cause vascular dementia. Al-
all of which drive pro-apoptosis, pro-inflammatory, and the amyloid though, dyslipidemia has been also related to amyloid beta protein
beta protein cascades [6]. production [19–20]. However, more recent studies suggest that the
Two different family types of glucose transporter are found in the binding mechanisms between diabetes and dementia are related to
neurovascular unit at the blood–brain barrier. The sodium-dependent hyperinsulinemia and consequent insulin resistance, and this will cause
unidirectional transporters (SLC5), which 12 isoforms (SGLTs 1–12) dementia due to Alzheimer’s disease (AD), not vascular dementia
have been identified. However, the most prevalent transporters are the [21–24]. In fact, in type 2 diabetes, insulin is not capable to reduce the
sodium-independent bidirectional GLUT [7–9]. Glucose transporters levels of blood glucose after a meal. In most cases the reason for this is
(GLUT) are a family of integral membrane proteins that provide bi- that the insulin messenger signal no longer triggers the cellular cascade
directional transport of D-glucose and its analogues without consuming of events that leads to an increased uptake of glucose by cells [25].

⁎
Corresponding author at: Grupo de Estudos e Pesquisas em Neurociência, Exercício, Saúde e Esporte - GENESEs - Universidade Estadual de Montes Claros, Av.
Doutor Rui Braga s/n, Vila Mauricéia, Montes Claros, Minas Gerais, Brazil.
E-mail address: [email protected] (R.S. Monteiro-Junior).

https://doi.org/10.1016/j.mehy.2020.109614
Received 23 December 2019; Received in revised form 30 January 2020; Accepted 5 February 2020
0306-9877/ © 2020 Elsevier Ltd. All rights reserved.
L.L. Leão, et al. Medical Hypotheses 139 (2020) 109614

The human brain is almost entirely dependent upon glucose as an homeostasis is strongly implicated by a variety of genetically en-
energy source, taking in around 100–150 g of glucose per day [26]. Due gineered mouse models. Dysfunctional GLUT-4 in skeletal muscle is the
to the restrictive permeability of the blood–brain barrier (BBB) and the main cause of peripheral insulin resistance [47,48].
relative lack of local brain carbohydrate storage, the CNS heavily relies
upon BBB expression of transporters for the delivery of key nutrients The basis of glucose transport in the brain
and solutes to the brain [27]. The delivery of blood glucose to the brain
requires crossing of glucose mediated by glucose transporter proteins. Glucose availability in the CNS is critical for neuronal function, and
Within the central nervous system, GLUT-1, mostly expressed in red glucose levels in the brain regulate local neuronal activity and whole-
blood cells and endothelial cells in heavily glycosylated form (55 kDa) body energy metabolism [49]. Among the membrane transport pro-
and in astrocytes in low glycosylated form (45 kDa), involves glucose teins, GLUT-1 is known to be a key transporter of glucose transport into
movement across the BBB’s endothelial cells [28]. Furthermore, the the brain across the BBB acting to maintain central nervous system
GLUT-3 aids glucose to pass through the neural cell membrane [29,30]. glucose homeostasis. Expression of different isoforms of the GLUT has
Studies have shown that chronic hypoglycemia upregulates the GLUT-1 also been identified at BBB endothelial cells although with relative
and GLUT-3 gene expression and increases their protein abundance. lower levels of GLUT-3 and GLUT-4 [50]. Considering the distribution
However, whether the expression of GLUT-1 and GLUT-3 is reduced in and properties of GLUT transporters, GLUT-1 and GLUT-3 will be
diabetes is unclear and is controversial. Any deficiency in GLUT treated together as they are both particularly involved in delivery of
transporter proteins leads to a major impact on brain energy metabo- glucose to the brain. As glucose is the obligatory substrate for cerebral
lism [31,32]. metabolism under normal conditions, glucose transport is fundamental
Studies have shown that vascular endothelial cells exposed to high in this organ [51,35].
glucose levels downregulate the rate of glucose transport by reducing Glucose transport into the brain is a complex process involving the
GLUT-1 mRNA and protein expression, as well as GLUT-1 plasma endothelial cells of small blood vessels, glial cells, particularly astro-
membrane localization [33,34]. In response to these recent findings, a cytes and neurons. GLUT-1 is highly expressed in the endothelial cells
couple of interesting questions arose: 1] could hyperglycemia be a of the microvasculature of the brain and is responsible for glucose
cause of downregulation of GLUT transporters in the brain? 2] if the transfer across the BBB. The transport of glucose to neurons is mediated
downregulation of GLUTs occurs in the brain, could it be one of the by astrocytes [52], which also express GLUT-1. GLUT-1 is localized to
mechanisms related to AD? Therefore, the aim of this study is to hy- both luminal and abluminal membranes of the BBB endothelial cells
pothesize a cause-effect relationship of hyperglycemia and AD based on with the ratio of 1:4 respectively, and approximately 40% of the total
GLUT transporters downregulation. Available bioinformatic data were cellular GLUT-1 resides in intracellular membrane [53–56].
used as guidance to establish the hypothesis. In order to develop a Once glucose enters the brain extracellular space, it is rapidly taken
working model, this article was organized in the following sections: i) up by the different brain cells. The neuron glucose uptake to support
The basis of glucose transport in the peripheral tissues, ii) The basis of energy metabolism is mediated by GLUT-3. GLUT-3 has higher “affi-
glucose transport in the brain, iii) Gene network analyses, iv) Genes nity” and higher glucose transporter capacity compared to GLUT-1
network model and hypothetical influence of peripheral hyperglycemia [44,57]. Interestingly, during a high cognitive demand, astrocytes’
on downregulation of GLUT transporters in the astrocytes and neurons glycolysis results in lactate production which will be delivered to ac-
and its relationship with dementia, and v) Final considerations. tivated neurons and used as energetic substrate [58]. Therefore, a
continuous supply of glucose is required for brain function.
The basis of glucose transport in the peripheral tissues
Gene network analyses
Glucose cellular uptake is an essential physiological process. The
maintenance of a relatively constant blood glucose concentration is To explore proteins-related genes associated to hyperglycemia and
necessary in order to sustain cerebral metabolism and the delivery of AD, the GeneCards database (https://www.genecards.org) was used.
glucose to peripheral tissues for energetic storage and utilization. Based on An et al. [59] who have investigated the relationship between
Indeed, glucose transport across cell membranes plays an important hyperglycemia and Alzheimer’s disease (AD), the following terms were
role in physiological regulation and control of metabolic processes [35]. inserted at GeneCards to search for genes related cellular receptors,
Cell membranes are impermeable to glucose, so the transport of hormones, proteins, and amino acids associated glucose metabolism
glucose across biological membranes must be mediated by specialized and AD. Such cellular and molecular structures searched were: GLUT-1,
protein transporters. In the 1970s, glucose uptake into liposome was GLUT-3, insulin, alanine, hexokinase, amyloid beta protein, apolipo-
reconstituted with proteins partially purified from red blood cells protein E, tau protein, and phosphofructokinase. Several genes were
[36–37]. This specific type of glucose transporter was later named as retrieved from GeneCards, as follow: SLC2A1 (GLUT-1) and SLC2A3
GLUT-1. Subsequently, glucose transporters were recognized from dif- (GLUT-3), INS (insulin), GPT (alanine), HK1/HK2/HK3 (hexokinase 1,
ferent tissues, GLUT-2, GLUT-3 and GLUT-4 [38–40]. Research devel- 2, and 3), GCK (glucokinase), APP (amyloid precursor protein), APOE
opment during the following years lead to the discovery of tissue dis- (apolipoprotein E), MAPT (microtubule-associated protein tau), PFKL/
tribution of subtypes of GLUTs, biochemical characterization of PFKP/PFKM (phosphofructokinases), and GRN (granulins). Genes
transport functions, and the formulation of the correlation between aforementioned were inserted in String database (https://string-db.
mutation or dysregulation of GLUTs and specific diseases [41–43]. org), which permits to explore genes and their interactions as a net-
Among the GLUT family, GLUT-4 is an insulin-stimulated trans- work. Our exploration of interactions was performed considering Homo
porter and it is primarily localized intracellularly in peripheral tissues sapiens as the studied species.
when not stimulated and can be acutely redistributed to the plasma Many specific and non-specific (unclear) significant interactions
membrane in response to insulin and other stimuli. GLUT-4 is primarily (PPI Enrichment p-value < 0.01) [60] were found among genes in the
expressed in adipose tissues, skeletal and cardiac muscle, and it facil- network displayed at String (Fig. 1). In String, each protein–protein
itates the diffusion of circulating glucose across its gradient into muscle interaction is annotated with one or more 'scores'. The scores indicate
and fat cells [44]. Upon binding of insulin, the insulin receptor kinase is how likely String judges an interaction to be true, given the available
activated, and it promotes the activation of downstream targets and evidence. Interactions were explored when a combined score above 0.4,
progression of signaling cascade leading to the translocation of GLUT-4 determined as medium confidence, was found. As the main question of
from intracellular pool to cell surface where it facilitates glucose entry this study was related to downregulation of GLUTs, only direct inter-
inside the cell [45,46]. The central role of GLUT-4 in glucose actions with genes associated with these transporters (SLC2A1 and

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L.L. Leão, et al. Medical Hypotheses 139 (2020) 109614

Fig. 1. Genes network found at String. Direct binding among genes GRN, HK3, HK2, and SLC2A1 is shown. Color lines show molecular interactions, while grey lines
show no molecular interactions but associations co-mentioned in PubMed abstracts. Arrows: activation. Circles: unspecified interaction.

not known [67]. However, according to our genes network model,

bindings among granulin, HK3 and HK2 exist. In addition, a post-
translational interaction between HK2 and SLC2A1 is present in the
network. Hence, dysfunctional granulin, which is an important cell
growth factor associate to wound repair and inflammation, could affect
HK3 and HK2 interactions and the synthesis of GLUT-1. Dysfunctional
HK3 and HK2 and attenuated synthesis of GLUT-1 could result in glu-
cose excess in the extracellular space in the brain, causing a down-
Fig. 2. Specific network among genes related GLUT-1 found at String. Blue lines
mean direct binding among genes. Pink line: posttranslational modification. regulation of GLUT-1 and GLUT-3 transporters. In summary, these
Circle: unspecified interaction. mechanisms would affect astrocytes and neurons metabolism.
Evidence suggests that chronic hyperglycemia reduces intracellular
glucose transport in diabetes [35]. As a protective mechanism, the
SLC2A3) in the network were analyzed. Then, the following genes re-
decreased glucose influx can diminish the cytotoxic effect of the high
mained in the model: GRN, HK3, HK2, and SLC2A1 (Fig. 2).
sugar content. It has been suggested that the reduction of glucose
transport is related to a downregulation of 55 kDa isoform GLUT-1
Genes network model and hypothetical influence of peripheral (presented in microvessels) and GLUT-3 in patients with AD, which are
hyperglycemia on downregulation of GLUT transporters in the the principal factors affecting glucose transport and metabolism in the
astrocytes and neurons, and its relationship with dementia brain [41,68]. In a study with diabetic rat model, chronic hypergly-
cemia downregulated GLUT-1 and GLUT-3 gene expression levels in the
Diabetes is associated with hyperglycemia and it is caused by partial brain [61]. The downregulation of GLUT-1 and GLUT-3 expression
or total insulin insufficiency. Clinically, the rapid decline in blood might be the adaptive reaction of the body to prevent excessive glucose
glucose in patients with diabetes, even when the blood glucose is above entering the cell that may lead to cell damage [61].
normal, can lead to “hypoglycemia phenomenon”, including neu- It is well known that glucose transport from the peripheral circu-
roglycopenia symptoms. The exact mechanism remains unclear, but it is lation across the BBB and capillary endothelial cells into the interstitial
possibly related to the downregulation of GLUT-1 and GLUT-3 expres- fluid and brain tissue are largely insulin-independent processes. Many
sion in diabetes [61]. epidemiological studies indicate that peripheral insulin resistance and
GLUT-1, which is expressed and localized at the endothelial cells of diabetes are risk factors for AD [69–74], however, it is not known
the BBB, is the first step in the transport of glucose from the blood into whether brain glucose dysregulation is a key feature of AD and is re-
the tissue layers. Then, the glucose transport from extracellular space lated to severity of AD pathology or symptom expression [75].
into neuronal cells is taken by GLUT-3, localized at the neuronal cell In patients with AD, several components of the insulin signaling
membrane. After it is within the cell, glucose is phosphorylated to pathway are abnormal, including genes encoding insulin, IGF-1, and
glucose-6-phosphate by HK, a key enzyme for glucose utilization in the IGF-2 peptides and their receptors [76,77]. Evidence suggests that ab-
cell [62,63]. The downstream cascade of glucose breakdown is mainly normal insulin signaling contributes to clinical trials targeting ab-
mediated by HK, hence it is reasonable to hypothesize that any change normalities in patients with mild cognitive impairment and AD, but
in this enzyme could affect glucose metabolism. implications of these abnormalities are yet to be elucidated [78,79].
Granulin (GRN) is a protein related to inflammation and wound Some studies have shown reduced brain glucose uptake in regions
repair originated from progranulin (PGRN). Mutations in PGRN genes vulnerable to AD pathology [80–82]. It is unclear whether an overall
are associated with neurodegenerative diseases, such as frontotemporal failure in the regulation of brain glucose metabolism is a key aetio-
dementia [64]. PGRN was demonstrated to interact with the HK3. pathogenic factor in AD and whether abnormalities of brain glucose
Autopsy studies had shown associations of PGRN and beta-amyloid homeostasis in AD are related to peripheral glucose concentration.
plaques [65,66]. PGRN plaques were most dense in medial temporal Since dysfunctional granulin could affect HK3 and HK2 interactions,
and frontal regions and predominated over aggregated amyloid beta it could also result in glucose excess in extracellular space in the brain.
protein. At this moment, physiological significance of this interaction is These mechanisms would lead to GLUT-1 downregulation affecting

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