The Role of Kidney in Glucose Homeostasis — SGLT2 Inhibitors, a New Approach in Diabetes Treatment

Vasileios Andrianesis; John Doupis


Expert Rev Clin Pharmacol. 2013;6(5):519-539. 

In This Article

Abstract and Introduction


The role of the kidney in blood glucose-level regulation was until recently underestimated. Renal gluconeogenesis, renal glucose uptake and tubular glucose reabsorption are the three ways of renal involvement in glucose homeostasis. In the postabsorptive state, 20% of total glucose release is attributed to renal gluconeogenesis. Tubular glucose reabsorption is performed by the combined action of Na+/D-glucose SGLTs co-transporters and GLUT-facilitated diffusion glucose transporters. SGLT2 inhibitors are a new family of agents, which occlude the path of SGLT2 glucose reabsorption and cause glucosuria. Efficacy of SGLT2 inhibitors includes reduction of HbA1c, fasting and postprandial blood glucose level and slight body weight and systolic blood pressure decrease. The most common adverse events of them are genital mycotic and urinary tract infections. Dapagliflozin and canagliflozin are the first agents of this class, approved from the European Medicine Agency and FDA, respectively.


According to the Center for Disease Control and Prevention, diabetes presents features of an epidemic: it is common, disabling and deadly. Approximately 25.8 million people in the USA (8.3% of the population) have been diagnosed with diabetes.[101] It is the leading cause of blindness, kidney failure and non-traumatic foot amputation, and it has been reported as the seventh leading cause of death as listed on the US death certificates in 2007. It has been estimated that incase the current trend continue, one of three US adults will have diabetes by 2050.[101] From the financial point of view, the total cost (direct and indirect) of diabetes in 2007 was $174 billion of which $116 billion was direct medical cost.[101]

Given the high importance of diabetes, the glucose homeostasis in human body has been deeply analyzed and investigated. It is characterized by a complex and highly integrated interaction among pancreas, liver, muscle, adipocytes and neuroendocrine system. The role of kidney in this procedure was until recently underestimated. The involvement of kidney in glucose regulation involves three different pathways: glucose release from renal cortex via gluconeogenesis; glucose uptake and glycolysis from renal medulla for satisfying kidney energy needs; and glucose reabsorption from proximal convoluted tubule.[1] The purpose of this review paper is to analyze the role of the kidney in glucose homeostasis, emphasizing in SGLT2 inhibition as a new therapeutic target for diabetes management.