Glucose transporters in ADHD

The brain accounts for only 2% of body weight and less than 0.01% of body cells, but consumes around 20%¹ to 25%² of the body’s total energy both at rest and in action. As the brain has no energy reserves of its own, the neurons are dependent on a constant supply of energy.

• 1. Glucose transporter
  • 1.1. GLUT1
    • 1.1.1. Occurrence of GLUT1
    • 1.1.2. What influences GLUT1
  • 1.2. GLUT3
    • 1.2.1. Occurrence of GLUT3
    • 1.2.2. What influences GLUT3
      • 1.2.2.1. Food rich in fat and n-6 fatty acids during pregnancy: GLUT3 reduces
      • 1.2.2.2. Dexamethasone in pregnancy: GLuT3 reduced
      • 1.2.2.3. Food high in fat and sugar before or during pregnancy: GLUT3 increased
      • 1.2.2.4. Hypoxic ischemia: only transient change in GLUT3?
      • 1.2.2.5. High-fat food before or during pregnancy: GLUT3 unchanged
    • 1.2.3. GLUT3 in ADHD and other disorders
• 2. Monocarboxylate transporter (MCT)
• 3. Na+/glucose co-transporter (SGLT)

1. Glucose transporter¶

Under normal conditions, glucose is the primary energy source for neuronal oxidative metabolism in mammals.

Glucose is transported by glucose transporters (GLUT) through bilayer lipid membranes by means of a concentration gradient. The necessary concentration gradient between intracellular space and extracellular space is maintained by catalyzing glucose to glucose-6-phosphate (G6P) by hexokinase after entry into the cytosol. G6P is the starting product for glycolysis, the pentose phosphate pathway and glycogen synthesis.³
GLUT are encoded by the SLC2A genes.

• Class I (glucose transporter)⁴
  • GLUT1
    • see below
  • GLUT2
    • Insulin-independent
    • regulates food intake
    • regulates glucose influx into the glucose-sensitive cells of the median eminence, which control CNS glucose homeostasis
    • also in the brain, in small quantities
  • GLUT3
    • see below
  • GLUT4
    • Insulin-dependent
    • Cerebrum (specific regions)
    • peripherally in tissues that respond to insulin (e.g. muscle or fat cells)
  • GLUT14
• Class II (fructose transporter)⁴
  • GLUT5
  • GLUT7
  • GLUT9 (urate transporter)
    • GLUT9a
    • GLUT9b
  • GLUT11
• Class III⁴
  • GLUT6 (former designation GLUT9)
    • Brain, in small quantity
    • white fatty tissue
    • Spleen
  • GLUT8
    • Brain, in small quantity
    • intracellular
    • Placenta (rodents)
    • early embryo
      • Absence reduces litter size rather than causing complete death of all embryos.
  • GLUT10
    • Liver
    • Pancreas
    • Brain
    • SLC2A10 gene is located in a chromosomal region associated with type 2 diabetes
    • Placenta (rodents)
  • GLUT12
  • GLUT13
    • Brain, in small quantity
  • H+/myo-inositol co-transporter (HMIT)

The isoforms GLUT1 and GLUT3 play a special role.⁴

1.1. GLUT1¶

GLUT1 is insulin-independent.

1.1.1. Occurrence of GLUT1¶

GLUT1 (gene: SLC2A1) is mainly expressed in:

• Brain
  • Endothelial cells of the blood-brain barrier
    • on the luminal and abluminal membrane
    • transports glucose from the blood in the capillaries into the interstitium of the brain
  • Astrocytes
  • Oligodendrocytes of the gray and white matter
  • Transport in glial cells
• Placenta
  • Care of the embryo
  • GLUT1 appears to mediate intra-placental glucose transport, while GLUT3 mediates trans-placental glucose transport from the mother to the fetus and thus influences the weight gain of the offspring⁴
• early embryo
  • in apical membranes of the trophectoderm
  • in the cells of the inner cell mass
  • Absence impairs normal embryonic development and leads to death
  • Deficiency leads to cellular apoptosis
• later embryo (up to 9 weeks)
• Fetus (from 9 weeks)
  • Neural tube
  • Intestine
  • Heart
  • Optic nerves

1.1.2. What influences GLUT1¶

Mice fed a high-fat diet before conception and during pregnancy:

• GLUT1 in placenta increases⁵ by a factor of 5⁶
• CD36 increased in placenta⁵
• reduced birth weight of the offspring with 27 % carbohydrate energy content of the diet, which normalized with normal food⁵
• significant increase in fetal growth (+43 %) with 52 % carbohydrate energy content of the diet⁶
• fetal weight increased by 18% with food high in fat and sugar⁷
• maternal obesity (measured by the weight of the fat deposits)
  • increased with high-fat food⁶
  • increased by a factor of 2-2 with foods high in fat and sugar⁷
• increased circulating maternal leptin⁶
• Serum adiponectin reduced⁶
• transplacental transport of neutral amino acids increased (10-fold)⁶
• SNAT2 (sodium-coupled neutral amino acid transporter) in placenta increases⁷ by 9-fold ⁶
• GLUT3 in placenta unchanged with only high-fat food⁶⁵
• GLUT3 in placenta increased with food high in fat and sugar⁷
• SNAT4 in placenta unchanged⁶

Dexamethasone administration during pregnancy:⁴

• reduces GLUT1 in the placenta
• reduces GLUT1 in the placenta
• can lead to intrauterine growth retardation (IUGR)

1.2. GLUT3¶

Insulin-independent.

1.2.1. Occurrence of GLUT3¶

GLUT3 (gene: SLC2A3) is mainly expressed in:

• Brain

  • plentiful
  • in pre- and postsynaptic neuronal dendrites
  • in other small neuronal processes
  • in axons
  • not in glial cells
  • Cerebral cortex
  • Cerebellum
  • mediates glucose transport in neurons with high energy requirements
  • Transport requires no energy supply
  • highest glucose affinity of all GLUT isoforms (Km: 1.4 mM)
    • normal physiological plasma glucose concentration is between 3.0 and 7.8 mM
    • Glucose concentration in the cerebrospinal fluid is 0.5-2.5 mM
    • high glucose affinity of GLUT3 therefore indispensable
  • crucial for neurotransmission (more than GLUT1)

• Placenta

  • little
  • Care of the embryo
  • while GLUT3 is responsible for trans-placental glucose transport from the mother to the fetus and thus influences the weight gain of the offspring, GLUT1 appears to mediate intra-placental glucose transport⁴

• early embryo

  • little
  • basal aspect of the trophectoderm
  • Absence impairs normal embryonic development and leads to death
  • Deficiency leads to cellular apoptosis

• later embryo (up to 9 weeks)

• Fetus (from 9 weeks)

  • Trophectoderm
  • embryonic intestine

• Testicles

  • little

• Sperm

  • little

• white blood cells

• Blood platelets

• PFC

• Thalamus

• Putamen

• Caudate

• Hippocampus

• Subfornicus

• in gray matter (high metabolic activity): frequent

• in white substance: low

1.2.2. What influences GLUT3¶

Any condition that can lead to GLUT3 deficiency can trigger the neurodevelopmental disorders described above.⁴
GLUT3 gene variants with reduced/increased activity can have an influence here.

1.2.2.1. Food rich in fat and n-6 fatty acids during pregnancy: GLUT3 reduces¶

A combination of a high-fat diet enriched with n-3 fatty acids during the suckling period and a high-fat diet enriched with n-6 fatty acids during pregnancy had a positive effect on the offspring:⁸

• Microcephaly
• GLUT3 reduced
• GLUT1 unchanged

A diet rich in n-6 fatty acids and high in fat from the 21st day of pregnancy had the following effects on the offspring:⁹

• Migration and maturation of periventricular stem cells in the fetal brain reduced

1.2.2.2. Dexamethasone in pregnancy: GLuT3 reduced¶

Dexamethasone administration during pregnancy:⁴

• reduces GLUT1 in the placenta
• reduces GLUT3 in the placenta
• can lead to intrauterine growth retardation (IUGR)

1.2.2.3. Food high in fat and sugar before or during pregnancy: GLUT3 increased¶

• GLUT3 in placenta increased with food high in fat and sugar⁷

1.2.2.4. Hypoxic ischemia: only transient change in GLUT3?¶

Hypoxic ischemia (associated with extensive nutrient deprivation and oxygen starvation) early in development or later in adolescence or adulthood increases GLUT3 expression in the brain during the early energy-consuming recovery period. This could be an adaptive response.
This is rapidly reduced again in the cortex and thalamus due to apoptotic and necrotic brain damage in the early reaction phase (24 hours). The later reaction phase (72 hours) leads to extensive regional necrosis.⁴

1.2.2.5. High-fat food before or during pregnancy: GLUT3 unchanged¶

High-fat food before conception and during pregnancy did not alter GLUT3 in the placenta.⁶⁵

1.2.3. GLUT3 in ADHD and other disorders¶

GLUT3 is a candidate gene in ADHD. More on this under Gene candidates without a plausible pathway in relation to ADHD
GLUT3-KO mice are an animal model that shows ASD symptoms. For more information see ADHD animal models with unknown dopamine alterations

GLUT3 deficiency can trigger neurodevelopmental disorders such as

• ADHD¹⁰
• ASS⁴
• Dyslexia¹¹
• Epilepsy¹²⁴
• Huntington’s disease (later in life)⁴
• Alzheimer’s disease (later in life)¹³

2. Monocarboxylate transporter (MCT)¶

In the case of glucose deficiency in the brain (neuroglycopenia), energy requirements are met instead by burning the less efficient ketone bodies, lactate and fatty acids.
Ketones and lactate can cross the blood-brain barrier. In the brain, they are not transported via GLUT, but via monocarboxylate transporters (MCT):⁴

• MCT1
  • in blood-brain barrier
  • in astrocytes
• MCT2
  • in neurons

3. Na+/glucose co-transporter (SGLT)¶

Family of membrane-bound glucose transporters that are energy-dependent and function as active transporters. SGLTs transport glucose against a glucose concentration gradient, but are dependent on the co-transport of sodium⁴
Coding gene: SLC5 with 12 members

• SGLT1
  • Intestinal mucosa
    • mediates the transport of glucose and galactose
  • Brain
    • Glucose uptake and glucose efflux in certain neurons lining the choroid plexus and the periventricular region
• SGLT2
  • expressed in the early part of the proximal renal tubule
  • mediates glucose reabsorption
  • SGLT2 inhibitors are used for the treatment of type 2 diabetes mellitus
  • Cerebellum (low)
• SGLT3
  • glucose sensor rather than glucose transporter
  • in cholinergic neurons
  • in the skeletal muscles
• SGLT4
  • Small intestine
  • Skeletal muscles
  • not in the brain
  • transports glucose and mannose
• SGLT5
  • Kidney
  • not in the brain
  • transports glucose and galactose
• SGLT6 (also Na+/inositol cotransporter (SMIT) 2)
  • Hypothalamus
  • Substantia nigra
  • Transport of glucose and inositol in the control of food intake and reward processing by recognizing nutrients