Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus.
OBJECTIVE
To review the renal handling of glucose and the role of inhibition of a sodium-glucose transporter (SGLT2) in the treatment of type 2 diabetes mellitus (T2DM).


METHODS
We review the published data about (1) the filtration and reabsorption of glucose by the kidneys in normal subjects and patients with diabetes; (2) the deleterious effects of long-term elevation of plasma glucose levels on muscle and hepatic insulin sensitivity and beta cell function (that is, glucotoxicity); (3) the effect of inhibiting the SGLT2 transporter on the induction of glycosuria, glycemic control, insulin resistance, and beta cell dysfunction in animals and humans with diabetes; and (4) the safety of SGLT2 inhibition as a therapeutic modality to treat human T2DM.


RESULTS
Studies in animal models of diabetes document the efficacy of the SGLT2 inhibitors in inducing glycosuria, decreasing both fasting and postprandial glucose levels, augmenting beta cell function, and enhancing hepatic and muscle insulin sensitivity. In human T2DM, short-term studies with dapagliflozin (12 weeks) and sergliflozin (2 weeks) have confirmed the efficacy of these agents in improving glycemic control. Excessive urinary electrolyte or water loss, plasma electrolyte disturbances, and hypoglycemia were not observed.


CONCLUSIONS
SGLT2 inhibitors represent a promising approach to the treatment of T2DM. They have the potential to be used as monotherapy, as well as in combination with all approved antidiabetic agents. Because their mechanism of action is independent of the severity of beta cell dysfunction or insulin resistance, efficacy should not decline with progressive beta cell failure or in the presence of severe insulin resistance.
Abdul-Ghani
Muhammad A
MA
Division of Diabetes, University of Texas Health Science Center, San Antonio, TX 78229, USA.
DeFronzo
Ralph A
RA
D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D001786:Blood Glucose; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D005947:Glucose