The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2012-01, Vol.14 (1), p.5-14
• Main Authors: DeFronzo, R. A., Davidson, J. A., Del Prato, S.
• Format: Article
• Language: English
• Subjects: Adipocytes; Affinity; Animals; Beta cells; Blood glucose; Blood Glucose - drug effects; Blood Glucose - metabolism; clinical trials; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Glucose; glucose homeostasis; Glucose transport; Glucose Transport Proteins, Facilitative - drug effects; Glucose Transport Proteins, Facilitative - metabolism; glycosuria; Homeostasis; Homeostasis - drug effects; Humans; hyperglycaemia; Hyperglycemia; Hypoglycemic Agents - therapeutic use; Insulin; Kidney - drug effects; Kidney - metabolism; Kidneys; Liver; Neuroendocrine system; Protein transport; Rats; Reabsorption; renal glucose transport; SGLT2; SGLT2 inhibitors; Sodium-glucose cotransporter; sodium-glucose cotransporters; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Sodium-Glucose Transporter 2 - metabolism
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2011.01511.x

The maintenance of normal glucose homeostasis requires a complex, highly integrated interaction among the liver, muscle, adipocytes, pancreas and neuroendocrine system. Recent studies have showed that the kidneys also play a central role in glucose homeostasis by reabsorbing all the filtered glucose, an adaptive mechanism that ensures sufficient energy is available during fasting periods. This mechanism becomes maladaptive in diabetes, however, as hyperglycaemia augments the expression and activity of the sodium–glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney. As a result, glucose reabsorption may be increased by as much as 20% in individuals with poorly controlled diabetes. SGLT2 is a low‐affinity, high‐capacity glucose transport protein that reabsorbs 90% of filtered glucose, while the high‐affinity, low‐capacity SGLT1 transporter reabsorbs the remaining 10%. SGLT2 represents a novel target for the treatment of diabetes. In animal studies, SGLT2 inhibition reduces plasma glucose levels, resulting in improved β‐cell function and enhanced insulin sensitivity in liver and muscle. Human studies have confirmed the efficacy of SLGT2 inhibitors in improving glucose control and reducing the A1c. Because the mechanism of SGLT2 inhibition is independent of circulating insulin levels or insulin sensitivity, these agents can be combined with all other antidiabetic classes, including exogenous insulin. Although the long‐term efficacy and safety of SGLT2 inhibitors remain under study, the class represents a novel therapeutic approach with potential for the treatment of both type 2 and 1 diabetes.