Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition
Open accessAbstract
Healthy kidneys filter ∼160 g/day of glucose (∼30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ∼450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule. In the absence or with inhibition of SGLT2, the renal reabsorptive capacity for glucose declines to ∼80 g/day (the residual capacity of SGLT1), i.e. the safety valve opens at a lower threshold, which makes it relevant to glucose homeostasis from day-to-day. Several SGLT2 inhibitors are now approved glucose lowering agents for individuals with type 2 diabetes and preserved kidney function. By inducing glucosuria, these drugs improve glycaemic control in all stages of type 2 diabetes, while their risk of causing hypoglycaemia is low because they naturally stop working when the filtered glucose load falls below ∼80 g/day and they do not otherwise interfere with metabolic counterregulation. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. Because SGLT2 reabsorbs sodium along with glucose, SGLT2 blockers are natriuretic and antihypertensive. Also, because they work in the proximal tubule, SGLT2 inhibitors increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure. This mitigates glomerular hyperfiltration, reduces the kidney's demand for oxygen and lessens albuminuria. For reasons that are less well understood, SGLT2 inhibitors are also uricosuric. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.
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Restoration of tubuloglomerular feedback occurs as a consequence of increased sodium chloride delivery to the macula densa.
“Restoration of tubuloglomerular feedback occurs as a consequence of increased sodium chloride delivery to the macula densa (19,20).”
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 [20]
When sodium chloride enters the macula densa, vasoactive substances such as adenosine are locally formed and released.
“When sodium chloride enters the macula densa, vasoactive substances such as adenosine are locally formed and released.”
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 [20]
SGLT2 inhibitors suppress glomerular hyperfiltration, likely reflecting reduced intraglomerular pressure in response to reduced proximal tubule Na reabsorption.
“SGLT2 inhibitors (SGLT2i) suppress glomerular hyperfiltration, likely reflecting reduced intraglomerular pressure in response to reduced PT Na ϩ reabsorption (38,39).”
From Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data (2018) · cites this paper as [39]
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- Authors
- Vallon, V., & Thomson, S. C.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Vallon, Volker
- Venue
- Diabetologia
- Published
- 2016-11-22
- Volume
- 60
- Issue
- 2
- Pages
- 215-225
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC5884445
- OpenAlex
- W2553261268
- Cited by
- 635
- References
- 85
- Citations by year
- 2026: 75 · 2025: 63 · 2024: 50 · 2023: 73 · 2022: 80 · 2021: 65 · 2020: 73 · 2019: 60 · 2018: 62 · 2017: 32 · 2015: 2
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Boehringer Ingelheim
- U.S. Department of Veterans Affairs
- National Institutes of Health (R01DK56248)
- Bristol-Myers Squibb
- 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, renal glucose reabsorption, hyperglycemia, type 2 diabetes, glycosuria, SGLT1, proximal tubule, sodium excretion, antihypertensive effect, tubuloglomerular feedback, glomerular hyperfiltration, albuminuria, uricosuric effect, empagliflozin, chronic kidney disease
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Diabetes Mellitus, Type 2, Glucose, Humans, Hyperglycemia, Insulin Resistance, Kidney, Phlorhizin, Sodium-Glucose Transporter 2
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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