Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus

ABSTRACT

Introduction: Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium–glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential.

Areas covered: This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart.

Expert opinion: SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition.

KEYWORDS:

• Diabetes mellitus
• hyperglycemia
• sodium glucose cotransporter
• glucose transport
• kidney
• intestine
• heart
• LX4211
• GSK-1614235

Article highlights

1. The sodium glucose cotransporter SGLT1 is strongly expressed in the apical brush border of the small intestine and the late proximal tubule of the kidney, where it is critical for absorption/reabsorption of glucose into the blood stream.

2. Inhibition of SGLT1 and combined inhibition of SGLT1/SGLT2 is an interesting new anti-hyperglycemic concept.

3. SGLT1 inhibition improves glucose homeostasis in diabetic patients by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1.

4. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased when more glucose is delivered to SGLT1 in the late proximal tubule, as shown in mice during inhibition of SGLT2 and as can occur in diabetes.

5. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe and not associated with increased rates of hypoglycemia or clinical relevant gastrointestinal side effects.

6. More data is needed on long-term clinical efficacy and outcome, and to determine whether SGLT1 and/or dual SGLT1/SGLT2 inhibitors are safe, with particular focus on intestine, brain, lung, and heart.

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Declaration of interest

P Song’s work was supported by China Scholarship Council (CSC); A Onishi’s work was supported by Japan Heart Foundation and the Bayer Yakuhin Research Grant Abroad; V Vallon’s work was supported by the National Institutes of Health (R01DK56248, R01DK106102, P30DK079337) and the Department of Veterans Affairs. V Vallon has served as a consultant and received honoraria from Boehringer Ingelheim, Janssen Pharmaceutical, and Intarcia Therapeutics. V Vallon’s work was supported by investigator-initiated research grants by Bristol-Myers Squibb, Astra-Zeneca, and Boehringer Ingelheim, Biberach. 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.