DNA Diet
Glucose Transporter Type 2 (GLUT2) Coded by SLCA2
SLC2A2 Thr110Ile C>T rs5400
Allele Frequency
T allele global frequencies are noted as 21.5% by the 1000 Genomes Project Database or 22.03% the genome Aggregation Database (gnomAD) (NIH).
SLC2A2
Function
SLC2A2 Gene Detail
The SLC2A2 gene codes for glucose transporter type 2 (GLUT2), a facilitative transporter of glucose in the liver, pancreatic β-cells, the kidneys, brain and intestinal cells.
In addition to its function as transmembrane transporter of sugars, the low affinity GLUT2 also seems to act as glucose sensor. Its glucose sensing function may not only initiate a signalling pathway assisting in insulin secretion from pancreatic β-cells but it may also regulate food intake by enhancing the preference for a high-sugar diet.
SLC2A2
Variant
SLC2A2 Thr110Ile C>T
GLUT2 forms part of the GLUT family of glucose transporters and is known to be responsible for initiating glucose-induced insulin secretion by facilitating the entry of glucose into the pancreatic β-cell. GLUT2 is however present in most tissues involved in glucose homeostasis, not just the pancreas.
The GLUT2 transporter expression from SLC2A2 is thought to be regulated by various factors, some that include sugars and hormones i.e. glycemia and insulinemia. The translocation of GLUT2 in apical membranes of certain GLUT2-expressing cells seem to be regulated by insulin. This means that with higher insulin levels GLUT2 can move towards the intracellular environment (called internalisation) or in the absence of insulin continue towards the apical membrane bordering the lumen where absorption (such as in enterocytes) or reabsorption (such as in kidney tubular cells) of sugars are essential. In addition to the transport of glucose, GLUT2 also transports fructose and galactose especially when concentrations of these monosaccharides are high in the intestinal lumen after the ingestion of a meal containing carbohydrates.
It is reported that GLUT2 influences glucose homeostasis by fuelling intracellular metabolism to trigger adequate insulin release from pancreatic β-cells, renal reabsorption and intestinal absorption when it responds to extracellular glucose concentrations by activating a signalling cascade, regardless the of amount of intracellular energy stores. The functionality of GLUT2 is dependent on its amino acid sequence where alterations in some crucial amino acids may leave the transporter severely impaired.
The Thr110Ile SNP is described as a missense mutation occurring in an exon of the SLA2A2 gene. This SNP entails a cytidine (C) to thymine (T) substitution that results in an amino acid change at codon 110 from threonine (Thr) to isoleucine (Ile). The SNP was first identified in 1994 when a genetic linkage analysis on acute insulin secretion was done in Pima Native Americans. Since then studies have found conflicting results regarding this SNP’s involvement in type 2 diabetes risk and the transitioning of glucose intolerance to type 2 diabetes.
The Thr110Ile SNP has been associated with a high daily intake of sugars. This suggests a link to type 2 diabetes risk as GLUT2 possesses a glucose sensing mechanism that potentially controls food intake and sugar preference. The expression of GLUT2 has been localised to areas of the brain involved in food intake regulation for both rodents and humans. This has led to the belief that the central glucose sensor system in the brain may potentially rely on GLUT2 for essential input.
A study within two different populations similarly found that Ile-allele (T) carriers had a significantly higher intake of sugar as compared to Thr/Thr (CC) homozygotes. The findings were consistent across older and younger adults, among those with or without type 2 diabetes mellitus (T2DM) as well as across normal weight to obese subjects. It might be noteworthy to mention that participants preferred sweets, baked goods and chocolate as well as sugar-sweetened beverages rather than naturally sweet foods like fruit. The fact that healthy weight and obese Ile-allele carriers as well as those with and without T2DM all reported a significantly increased sugar intake suggests that the underlying mechanism is not due to a lack of glucose utilisation associated with insulin resistance, but rather due to glucose sensing. A significantly higher sugar intake in Ile-allele carriers seems to be directly related to GLUT2, independent of circulating insulin, glucose and leptin levels.
It is thought that the Ile-allele might be associated with diminished GLUT2 transport activity in the brain or portal vein, resulting in less glucose being sensed to stimulate the appropriate responses involved in food intake regulation. In Michau et al. (2013) however, the study found no impairment in the transporting ability of GLUT2 in the presence of the rs5400 SNP but does report that the preference to sugar may be altered.
The study of GLUT2-null mice has given some clarity as to the effects of an impaired GLUT2 on food intake regulation and thus its potential role as glucose sensor. In comparison to wild-type mice, GLUT2-null mice were found to consume more food at baseline and failed to alter the amount of food consumed after receiving a glucose infusion like their wild-type counterparts who decreased their food intake appropriately. This behaviour corresponded to the abnormal regulation of hypothalamic neuropeptides, neuropeptide Y (NPY) and proopiomelanocortin (POMC) gene expression, involved in food intake regulation. After the glucose infusion wild-type mice had reduced expression of NPY, an orexigenic neuropeptide, and increased expression of POMC, an anorexigenic neuropeptide. The expression of the neuropeptides was unaltered in GLUT2-null mice, suggesting that GLUT2 acts as glucose sensor that regulates neuropeptides involved in food intake regulation.
SLC2A2
Interventions
Carbohydrate And Sugar Intake
Since Ile-allele (T) carriers are more prone to a high sugar consumption, it is advised that refined sugars in the form of sugary foods and sugar-sweetened beverages be limited in the diet. It might be necessary to monitor the total carbohydrate intake in the diet to optimise blood sugar management.
SLC2A2
Articles
Mutations in SLC2A2 Gene Reveal hGLUT2 Function in
Pancreatic Cell Development
Michau et al, 2013.
