Trait: Sugar consumption (GLUT2)
Dr Haran Sivapalan
May 23, 2021
What is glucose?
Glucose is a simple sugar that forms a major fuel source for cells in the body. Through a process of respiration, cells can use glucose to generate ATP (adenosine triphosphate), the currency of chemical energy in the body.
ATP is then used to power all sorts of essential cell functions, including transport of molecules, DNA replication, metabolic reactions, and muscle contraction.
Glucose can be found as a simple sugar (monosaccharide) in foods such as sweets, syrups, and sports drinks. We also generate glucose by breaking down larger sugars (e.g. sucrose – a disaccharide, formed of glucose and fructose) and carbohydrates (polysaccharides e.g. amylose), which are long chains of simple sugars joined together.
- Glucose is a simple sugar that forms a major fuel source for cell respiration.
- Glucose can be found as a simple sugar in certain foods, or be generated by breaking down longer sugars and carbohydrates.
Why does the brain need glucose?
The human brain, which contains around 86 billion neurons, is unsurprisingly a very metabolically active organ and has the largest energy requirement of all organs in the body.
It’s thought that the brain accounts for roughly 20% of total energy consumption, with glucose being the main fuel source.
Individual neurons in the brain require glucose to produce ATP, which is then used to power ion pumps that create voltage differences – all of which allows nerve impulses to be transmitted. The brain also uses glucose to make neurotransmitters and receptors.
In total, it’s estimated that the average brain consumes about 120g of glucose per day. Unlike muscle tissue, which stores glycogen, the brain does not have its own fuel stores. Furthermore, the brain cannot use fatty acids (the building blocks of fat) as an energy source.
All of this means that the brain requires a steady supply of glucose. Due to these energy demands, the brain has several mechanisms that tightly control glucose supply and that alter appetite, hunger, food intake, and glucose metabolism in response to changing glucose levels. This is known as the glucostatic theory of appetite.
For example, when blood glucose levels fall, this stimulates brain circuits that give rise to feelings of hunger, which drives food intake. Conversely, intake of carbohydrate and subsequent increases in blood glucose levels are shown to reduce feelings of hunger, stimulate satiety (i.e. feelings of fullness), and inhibit food intake.
For this glucostatic feedback mechanism to work, however, the brain first needs to sense levels of glucose in the bloodstream and local tissue.
- Our brains have the largest energy needs of all organs in the body.
- The brain needs a steady supply of glucose to meet its energy needs.
- The brain has mechanisms to stimulate hunger when blood glucose levels are low and suppress appetite when glucose levels are high.
How does the brain sense glucose?
The brain has specialized neurons, known as glucose-sensing neurons, that are either activated (“glucose-excited neurons”) or inhibited (“glucose-inhibited neurons”) by glucose.
Glucose-sensing neurons are found in particularly high density in a part of the brain called the hypothalamus. This region of the brain also has circuits that control energy balance, food intake, and appetite. (You can read more about these hypothalamic circuits in the Leptin Resistance trait article).
By interacting with brain circuits in the hypothalamus, glucose-sensing neurons can regulate food intake and appetite in response to changes in blood glucose levels.
Source: Jordan, S. D., Könner, A. C., & Brüning, J. C. (2010). Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis. Cellular and molecular life sciences, 67(19), 3255-3273.
But, how do glucose-sensing neurons sense levels of glucose in the bloodstream in the first place?
One of the several mechanisms by which neurons in the brain sense glucose, is using a specialized glucose transporter protein called GLUT2.
Glucose circulating in the bloodstream also enters capillaries in the brain. Using glucose transporter proteins, such as GLUT1, which facilitate its diffusion across cell membranes, glucose can move across endothelial cells that line blood vessels and capillaries into supporting cells in the brain known as astrocytes.
Once in astrocytes, the GLUT2 transporter protein allows glucose to move into glucose-sensing neurons. In response to the entry of glucose, the glucose-sensing neurons alter their activity (either becoming excited or inhibited), which then has wider effects on brain circuits in the hypothalamus that control hunger and appetite.
Source: Koepsell, H. (2020). Glucose transporters in brain in health and disease. Pflügers Archiv-European Journal of Physiology, 1-45.
More specifically, when blood glucose levels are low, entry of glucose to neurons in the brain also falls. The ‘sensing’ of low glucose levels then stimulates hunger, resulting in the intake of food.
Conversely, when blood glucose levels are high, more glucose enters glucose-sensing neurons in the brain, which suppresses hunger and stimulates satiety (feelings of fullness).
- The brain has glucose-sensing neurons that detect changes in circulating blood glucose levels.
- Glucose-sensing neurons express GLUT2 proteins that allow glucose to move from the bloodstream into neurons and change neuronal activity.
- When blood glucose levels fall, glucose entry into neurons in the brain falls. This activates brain circuits that stimulate hunger.
- When blood glucose levels rise, glucose entry into neurons in the brain increases. This activates brain circuits that suppress hunger and stimulate satiety.
How do GLUT2 gene variants affect glucose-sensing?
The GLUT2 transporter protein is coded for by your GLUT2 gene (also known as the SLC2A2 gene).
Studies in both animals and humans suggest the GLUT2 gene plays a crucial role in glucose-sensing and, by extension, in the control of food intake in response to changes in blood glucose levels.
For example, normal mice reduce their food intake in response to infusions of glucose into the brain. By contrast, mice that are engineered to lack to the GLUT2 gene (and therefore do not express the GLUT2 protein) fail to alter their food intake in response to glucose infusion. This suggests that the GLUT2 gene enables the brain to sense rises in glucose and suppress hunger accordingly.
In humans, studies have focussed on a variant of the GLUT2 gene created by the rs5400 SNP (Single Nucleotide Polymorphism). This SNP causes a ‘C’ to ‘T’ single letter change in the DNA sequence of the GLUT2 gene, giving rise to two different gene variants or alleles ‘C’ and ‘T’.
The ‘T’ allele codes for a different amino acid (isoleucine instead of threonine) in the GLUT2 protein. It’s thought that this amino acid change may result in a structural change, resulting in lower amounts of glucose transported through the GLUT2 transporter protein.
This, in turn, may blunt glucose-sensing in people who carry the ‘T’ allele, although studies are yet to directly demonstrate this. Nevertheless, as explained in the next section, ‘T’ allele carriers have been shown to have higher sugar intakes, which may be due to impaired glucose-sensing.
- The GLUT2 transporter protein is encoded by the GLUT2 (SLC2A2) gene.
- The rs5400 SNP creates two different GLUT2 gene variants: 'C' and 'T'.
- 'T' allele carriers may have impaired glucose-sensing due to reduced capacity of the GLUT2 protein to transport glucose.
- Impaired glucose-sensing may lead to increased sugar consumption in 'T' allele carriers.
How do GLUT2 gene variants affect sugar intake?
Studies have shown that people who carry the ‘T’ allele (rs5400) of the GLUT2 gene consume significantly more sugar per day compared non-carriers (i.e. those with the CC genotype).
In one study, researchers assessed the dietary habits of subjects enrolled in two different trials, the Canadian Trial of Carbohydrates in Diabetes and the Toronto Nutrigenomics and Health Study.
When looking at daily food intake over the past month, those with the CC genotype consumed on average 115 g of sugar per day. By contrast, ‘T’ allele carriers consumed 131 g of sugar per day: an average difference of 16 g more sugar per day.
There was no difference between genotypes with respect to total calories, protein, fat, or alcohol intake. This suggests that GLUT2 genotype specifically affects sugar intake, rather than overall food intake.
Further analysis of sugar type revealed that ‘T’ allele carriers consumed more glucose (26.0 vs 23.7 g/day), fructose (28.0 vs 25.4 g/day), and sucrose (55 vs 47 g/day) compared to non-carriers.
This is shown in the table below. (Note that the 'C' and 'T' allele are referred to as a 'Thr' (threonine) and 'Ile' (isoleucine) alleles respectively.
Source: Eny, K. M., Wolever, T. M., Fontaine-Bisson, B., & El-Sohemy, A. (2008). Genetic variant in the glucose transporter type 2 is associated with higher intakes of sugars in two distinct populations. Physiological genomics, 33(3), 355-360.
So, T allele carriers habitually consumed more sugar, but was this centred around any particular foods?
This question is important as sugars are present in generally healthier foods such as fruits and vegetables (esp. vegetables such as carrots, sweet potatoes, beets), as well as in conventionally unhealthy foods (e.g. pastries, sweets, cookies).
Rather than eating more servings of fruit, ‘T’ allele carriers were shown to consume more sweets (1.45 vs 1.08 servings per day) and sweetened beverages (0.49 vs 0.34 servings per day) compared to non-carriers.
Why did ‘T’ allele carriers consume more sugars? Further research is required to answer to this question conclusively, but it is possible that people carrying the ‘T’ allele of GLUT2 gene have impaired glucose-sensing.
According to the glucostatic theory of food intake, reduced ability to detect rises in circulating blood glucose levels and transport glucose into glucose-sensing neurons in the brain would mean that hunger is well suppressed. This would lead to higher intakes of sugar.
- Studies show that 'T' allele carriers habitually consume more sugar (including glucose, fructose, and sucrose) compared to those with the CC genotype.
- 'T' allele carriers are shown to consume more sweets and sweetened beverages compared to those with the CC genotype.
- The 'T' allele may cause impaired glucose-sensing in the brain, meaning that 'T' allele carriers are less sensitive to rises in blood glucose levels. This may drive higher sugar intake.
Your Sugar consumption (GLUT2) trait
Your Sugar consumption (GLUT2) trait analyses the rs5400 SNP of the GLUT2 gene. You will be classified into one of two categories:
- Risk of higher sugar consumption - you carry the 'T' allele linked to higher sugar consumption, which may be driven by poorer glucose-sensing in the brain.
- No risk of higher sugar consumption - you do not carry the 'T' allele linked to higher sugar consumption. Your genotype is CC.
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