The role of kidney in glucose homeostasis – SGLT2 inhibitors, a new approach in diabetes treatment

Abstract

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.

Keywords::

• canagliflozin
• dapagliflozin
• glucosuria
• renal gluconeogenesis
• SGLT2 Na⁺/D-glucose co-transporters
• SGLT2 inhibitors

Financial & competing interests disclosure

J Doupis is a member of Janssen diabetes experts committee having received honoraria for expert and advisory board meetings on canagliflozin. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Three ways of renal involvement in glucose homeostasis: 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.

• • In the post absorptive state, renal gluconeogenesis contribution to the total glucose release is ~20%. During 60-h fasting increases about 2.5-times more than in the post absorptive state and at postprandial state renal glucose release increases to over 50% of total endogenous glucose release.

• • Renal glucose reabsorption involves two transporter families: the SGLTs secondary active Na⁺/D-glucose co-transporters located at the brush border of tubular cells (SGLT2 and SGLT1) and the GLUTs facilitated diffusion glucose transporters located at the basolateral membrane of tubular cells (GLUT2 and GLUT1).

• • Transport maximum for glucose tubular transport system in adult humans is about 375 mg/min and the excess glucose is not reabsorbed and passes into urine. Normally, filtered glucose is about 125 mg/min.

• • Main action of SGLT2 inhibitors is the induction of glucosuria and osmotic diuresis. SGLT2 inhibitors reduce effectively fasting and postprandial blood glucose, insulin and glycosylated hemoglobin levels. Slight body weight and systolic blood pressure reduction are important beneficial effects.

• • Main adverse events of SGLT2 inhibitors are genital mycotic and urinary tract infections.

• • Dapagliflozin is the first agent of this family that completed Phase III clinical program. EMA and the European commission approved dapagliflozin in November 2012.

• • Canagliflozin is the second agent of this family that completes Phase III clinical trials and the first agent that takes the approval of US FDA in March 2013.