| Gene Symbol | SLC5A1 |
| Common Names | SGLT1, Sodium-glucose cotransporter 1 |
| Protein | [SGLT1 Protein](/proteins/sglt1-protein) |
| Location | 22q13.1 |
| NCBI Gene ID | 6523 |
| UniProt | [P13866](https://www.uniprot.org/uniprot/P13866) |
| Aliases | SGLT1, NAGT, D22S675 |
Sodium/glucose cotransporter 1 (SGLT1), encoded by the SLC5A1 gene, is a high-affinity, low-capacity transporter that mediates active glucose uptake across cell membranes using the sodium gradient.[1] While primarily known for its role in intestinal glucose absorption and renal glucose reabsorption, SGLT1 is expressed in the brain and may play roles in cerebral glucose metabolism relevant to neurodegenerative diseases.[2]
SLC5A1 encodes a 664-amino acid protein with 14 transmembrane domains. The transporter uses the sodium electrochemical gradient maintained by Na+/K+-ATPase to actively transport glucose against its concentration gradient.[3]
In the nervous system, SGLT1 expression includes:
Unlike GLUT transporters, SGLT1 can transport glucose into cells even when extracellular glucose is low, making it potentially important during metabolic stress.[5]
SLC5A1 serves multiple physiological functions:
Glucose Absorption: Primary mechanism for dietary glucose uptake in the small intestine.[6]
Renal Reabsorption: Reabsorbs filtered glucose in the kidney proximal tubule (S3 segment).[7]
Brain Glucose Transport: Contributes to glucose uptake across the blood-brain barrier and in specific neuronal populations.[8]
Sodium Transport: Couples glucose transport with sodium movement, contributing to cellular sodium homeostasis.
Osmoregulation: May participate in water transport through downstream effects on osmolarity.[9]
Intestinal Secretion: In cholera and other diarrheal diseases, SGLT1 can facilitate sodium and water absorption when co-administered with glucose.[10]
SGLT1 may play important roles in Alzheimer's disease:
Cerebral Glucose Hypometabolism: AD is characterized by reduced brain glucose utilization, and SGLT1 upregulation may represent a compensatory mechanism.[11]
Blood-Brain Barrier: SGLT1 at the BBB may help maintain glucose supply when glucose levels are low.[12]
Neuronal Vulnerability: Hippocampal neurons expressing SGLT1 may have enhanced survival during metabolic stress.[13]
SGLT Inhibitors: Pharmacological SGLT1 inhibition may worsen or improve AD depending on context and dosing.[14]
In Parkinson's disease, SGLT1 involvement is less studied but potentially relevant:
SGLT1's ability to transport glucose even at low concentrations makes it potentially protective during:
Mice lacking SGLT1 show increased vulnerability to hypoglycemia-induced brain damage, suggesting a protective role.[17]
Given that type 2 diabetes is a risk factor for dementia, SGLT1's role in glucose homeostasis is relevant:
Several SGLT1-targeting drugs are approved or in development:
| Drug | Type | Indication | Brain Penetration |
|---|---|---|---|
| Sotagliflozin | SGLT1/2 inhibitor | Type 1 diabetes adjunct | Limited |
| Mizagliflozin | SGLT1-selective | Type 2 diabetes | Unknown |
| LX4211 | SGLT1/2 inhibitor | Type 2 diabetes | Limited |
Neurological considerations:
| Variant | Effect | Disease Association |
|---|---|---|
| Loss-of-function mutations | Glucose-galactose malabsorption | Severe osmotic diarrhea |
| rs2294628 | Altered expression | Diabetes risk modifier |
| Polymorphisms | Variable activity | Inflammatory bowel disease |
Glucose-Galactose Malabsorption: Rare autosomal recessive disorder caused by SLC5A1 mutations, presenting with life-threatening diarrhea in neonates.[21]
SGLT1 interacts with several pathways relevant to metabolism and neurodegeneration:
Wright EM, et al. Sodium/glucose cotransporters. Journal of Physiology. 2003. ↩︎
Elfeber K, et al. SLC5A1 expression in the brain. Biochemical and Biophysical Research Communications. 2004. ↩︎
Turk E, et al. Structure and function of SGLT1. Journal of Biological Chemistry. 2003. ↩︎
O'Malley D, et al. SGLT1 in brain endothelial cells. Neurochemistry International. 2006. ↩︎
Wright EM, et al. Active vs passive glucose transport. American Journal of Physiology-Renal Physiology. 2006. ↩︎
Drozdowski LA, Thomson AB. Intestinal sugar transport. Canadian Journal of Physiology and Pharmacology. 2006. ↩︎
Hummel CS, et al. Glucose transport in the kidney. American Journal of Physiology-Renal Physiology. 2010. ↩︎
Shah K, et al. Brain glucose transport. Journal of Neurochemistry. 2012. ↩︎
Loo DD, et al. SGLT1 and water transport. Journal of General Physiology. 2002. ↩︎
Ramakrishna BS, et al. [ORS and SGLT1 in cholera](https://doi.org/10.1016/S0140-6736(09). The Lancet. 2009. ↩︎
An Y, et al. Cerebral glucose metabolism in Alzheimer's disease. Acta Neuropathologica. 2018. ↩︎
Nizari S, et al. Glucose transporters at the blood-brain barrier. Neurochemistry International. 2019. ↩︎
Yu J, et al. SGLT1 expression in hippocampal neurons. Neuroscience. 2010. ↩︎
Wiciński M, et al. SGLT inhibitors and neuroprotection. International Journal of Molecular Sciences. 2020. ↩︎
Sripalakit P, et al. SGLT2 inhibitors and Parkinson's disease. Nutrients. 2020. ↩︎
Horikawa N, et al. SGLT1 and hypoglycemia protection. Diabetes. 2011. ↩︎
Gagnon DG, et al. SGLT1 knockout mice. American Journal of Physiology-Cell Physiology. 2006. ↩︎
Daniele G, et al. SGLT1 inhibitors and glucose homeostasis. Diabetologia. 2017. ↩︎
Zambrowicz B, et al. LX4211 and glucose absorption. Clinical Pharmacology & Therapeutics. 2012. ↩︎
Powell DR, et al. SGLT1 inhibition and metabolism. Diabetes. 2013. ↩︎
Turk E, et al. Glucose-galactose malabsorption mutations. Nature Genetics. 1993. ↩︎