title: Beyond Glycosuria: Exploring the intrarenal effects of SGLT₋₂ inhibition in diabetes.
abstract: For millennia, the syndrome that has become known as diabetes was considered to be primarily a disease of the urinary system and, by association, of dysfunction in the kidneys (recognized as the source of urine). In the last decade, there has been renewed interest in the role of the kidneys in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodiumglucose cotransporter 2 (SGLT-2) as a means to control glucose levels and augment calorie-wasting leading to weight loss. However, beyond actions on glycaemic control, inhibition of proximal glucose absorption via SGLT-2 has significant direct effects to attenuate hyperfiltration and reduce renal hypertrophy. Increased distal sodium delivery may also act to suppress the intrarenal renin-angiotensin-aldosterone system, although systemic activity may be modestly increased due to osmotic diuresis. Reducing proximal glucose reabsorption may also protect the tubular cells from exposure to excess glucose and glucose-induced reactive oxygen species. On the other hand, distal glucose delivery following inhibition of SGLT-2 may increase glycogen deposition, the significance of which is unclear. However, subjects with familial glycosuria appear to have a benign renal prognosis. Some studies have demonstrated significant reductions in albumin excretion in various experimental models and as post-hoc observations in clinical trials. Whether these reflect renoprotection or are simply the result of intraglomerular haemodynamic changes remains unclear. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress.
authors.affiliation: Baker IDI Heart & Diabetes Institute, 75 Commercial Rd, Melbourne, Australia, 3004; Monash University, Dept. of Epidemiology and Preventive Medicine, Melbourne, Australia. Electronic address: amerlin.thomas@bakeridi.edu.au.
authors.forename: M C
authors.initials: MC
authors.lastname: Thomas
authors.affiliation: Baker IDI Heart & Diabetes Institute, 75 Commercial Rd, Melbourne, Australia, 3004.
authors.forename: K
authors.initials: K
authors.lastname: Jandeleit-Dahm
authors.affiliation: Inserm UMR 991, service endocrinologie-diabétologie, CHU Rennes, université Rennes 1, 2 rue du Thabor, CS 46510, 35065 Rennes cedex, FRANCE.
authors.forename: F
authors.initials: F
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D049990:Membrane Transport Modulators / Q000009:adverse effects / Q000627:therapeutic use*; D065667:Renal Elimination / Q000187:drug effects; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D049990:Membrane Transport Modulators; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
keywords: Diabetes; Glycosuria; Hyperfiltration; Kidney; SGLT inhibitors