Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences
Open accessAbstract
Traditional treatments for type 1 and type 2 diabetes are often associated with side effects, including weight gain and hypoglycaemia that may offset the benefits of blood glucose lowering. The kidneys filter and reabsorb large amounts of glucose, and urine is almost free of glucose in normoglycaemia. The sodium-dependent glucose transporter (SGLT)-2 in the early proximal tubule reabsorbs the majority of filtered glucose. Remaining glucose is reabsorbed by SGLT1 in the late proximal tubule. Diabetes enhances renal glucose reabsorption by increasing the tubular glucose load and the expression of SGLT2 (as shown in mice), which maintains hyperglycaemia. Inhibitors of SGLT2 enhance urinary glucose excretion and thereby lower blood glucose levels in type 1 and type 2 diabetes. The load-dependent increase in SGLT1-mediated glucose reabsorption explains why SGLT2 inhibitors in normoglycaemic conditions enhance urinary glucose excretion to only ~50% of the filtered glucose. The role of SGLT1 in both renal and intestinal glucose reabsorption provides a rationale for the development of dual SGLT1/2 inhibitors. SGLT2 inhibitors lower blood glucose levels independent of insulin and induce pleiotropic actions that may be relevant in the context of lowering cardiovascular risk. Ongoing long-term clinical studies will determine whether SGLT2 inhibitors have a safety profile and exert cardiovascular benefits that are superior to traditional agents.
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Inhibitors of sodium-glucose cotransporter 2 reduce rates of hyperglycemia in patients with type 2 diabetes by decreasing renal glucose reabsorption, thereby increasing urinary glucose excretion.
“Inhibitors of sodium-glucose cotransporter 2 reduce rates of hyperglycemia in patients with type 2 diabetes by decreasing renal glucose reabsorption, thereby increasing urinary glucose excretion. 10”
From Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (2015) · cites this paper as [10]
SGLT2 inhibitors lower blood glucose by preventing glucose and sodium reabsorption in the proximal tubule.
“Sodium/glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by preventing glucose and sodium reabsorption in the proximal tubule (8–10).”
From SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation (2021) · cites this paper as [9]
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Potential role of sodium glucose cotransporter 2 inhibitors in the treatment of hypertension
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- Authors
- Gallo, L. A., Wright, E. M., & Vallon, V.
- Affiliations
- Translational Research Institute (AU)
- University of California, Los Angeles (US)
- University of California San Diego (US)
- Venue
- Diabetes and Vascular Disease Research
- Publisher
- SAGE Publications
- Published
- 2015-01-23
- Volume
- 12
- Issue
- 2
- Pages
- 78-89
- ISSN
- 1479-1641 (ISSN-L)
- 1752-8984
- PMC
- PMC5886707
- OpenAlex
- W2142065502
- Cited by
- 395
- References
- 92
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 45 · 2023: 33 · 2022: 45 · 2021: 60 · 2020: 47 · 2019: 30 · 2018: 36 · 2017: 20 · 2016: 19 · 2015: 16 · 2014: 2
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes and Vascular Disease Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL094728)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK19567, R01 DK-56248, R01DK019567, P30DK079337, R01DK056248)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- SGLT2 inhibitors, type 1 diabetes, type 2 diabetes, renal glucose reabsorption, proximal tubule, SGLT1, urinary glucose excretion, hyperglycemia, cardiovascular risk, drug safety, insulin-independent glucose lowering
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Animals, Blood Glucose, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Kidney Tubules, Proximal, Treatment Outcome, Sodium-Glucose Transporter 1, Sodium-Glucose Transporter 2, Molecular Targeted Therapy, Renal Reabsorption, Renal Elimination
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