From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus

ABSTRACT

Background: Elevated glucose blood levels are the key criteria for diagnosing diabetes mellitus (DM). Hyperglycaemia contributes to the pathophysiology associated with DM, including microvascular and possibly macrovascular disease. In spite of a wide range of pharmacological options available to reduce hyperglycaemia in DM, epidemiological studies suggest that glucose levels remain high in a substantial proportion of patients. This supports the need for additional strategies for the treatment of hyperglycaemia.

Scope: This review focuses on the role of the kidney in glucose reabsorption and explores inhibition of renal glucose reabsorption as a novel approach to treat type 2 DM. A literature search to August 2008 using PubMed was used to compile data for review. Abstracts and presentations from the American Diabetes Association and the European Association for the Study of Diabetes, the American Society of Nephrology, and the International Society of Nephrology Annual Meetings were also searched for relevant studies.

Findings: Glucose filtered by the kidney is normally reabsorbed into the proximal renal tubule. Data from animal models suggest that approximately 90% of this reabsorption occurs through the sodium-coupled glucose cotransporter (SGLT) 2, which is a protein expressed almost exclusively in the proximal tubule of the kidney. Inhibition of SGLT2, and thus inhibition of renal glucose reabsorption, has the potential to reduce hyperglycaemia in patients with DM. Patients with familial renal glucosuria, a genetic disorder of SGLT2, do not appear to have adverse clinical consequences related to impaired renal reabsorption of glucose, which suggests that SGLT2 might be both an effective and safe treatment target for hyperglycaemia. In animal models of DM, pharmaceutical inhibition of SGLT2 reduces hyperglycaemia, and may improve insulin resistance.

Conclusion: Reduction of renal glucose reabsorption is a novel approach to DM treatment that potentially provides improvements in glucose lowering. Various SGLT2 inhibitors are currently in development in human trials.

Key words: :

• Diabetes mellitus, type 2
• Glucose
• Renal glucose excretion
• SGLT2 inhibitors
• Sodium-glucose cotransporter

Acknowledgements

Declarations of interest: The author would like to thank Mark Davies (Wolters Kluwer Health) who provided medical writing support on behalf of Bristol-Myers Squibb and AstraZeneca. The author is solely responsible for the interpretation of the evidence and views expressed in this review article, which may or may not be shared by Bristol-Myers Squibb and AstraZeneca (who are jointly developing the investigational drug dapagliflozin). The author has served as a consultant, speaker, and/or advisor to several companies, including AstraZeneca, Bristol-Myers Squibb, Merck, Merck/Schering Plough, Roche, sanofi-aventis, SmithKline Beecham and Takeda, and as a clinical investigator and/or research grant recipient from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck, Merck/Schering Plough, Roche and several other companies. No honorarium was provided for the writing of this review.