Improved glycemic control in mice lacking Sglt1 and Sglt2

Area of Science:

• Metabolic diseases
• Renal physiology
• Pharmacology

Background:

• Sodium-glucose cotransporter 2 (SGLT2) is the main transporter for renal glucose reabsorption, while SGLT1 is minor.
• SGLT2 inhibitors improve glycemic control in diabetic patients by increasing urinary glucose excretion (UGE).

Purpose of the Study:

• To investigate the roles of SGLT1 and SGLT2 in glucose reabsorption and glycemic control.
• To compare the effects of SGLT1 and SGLT2 knockout (KO) on glucose homeostasis.
• To evaluate the potential of combined SGLT1 and SGLT2 inhibition for type 2 diabetes treatment.

Main Methods:

• Generation of Sglt1 KO, Sglt2 KO, and Sglt1/Sglt2 double-KO (DKO) mice.
• Assessment of oral and intraperitoneal glucose tolerance tests.
• Measurement of urinary glucose excretion (UGE) and circulating glucagon-like peptide-1 (GLP-1) levels.

Main Results:

• Sglt2 KO mice showed improved glucose tolerance and diabetes resistance.
• DKO mice exhibited significantly higher UGE and lower fasting blood glucose compared to Sglt2 KO mice.
• Sglt1 KO mice on a glucose-free high-fat diet displayed delayed intestinal glucose absorption and increased GLP-1.

Conclusions:

• SGLT2 is the major renal glucose transporter, but SGLT1 compensates significantly when SGLT2 is absent.
• Mice lacking SGLT2 show improved glucose tolerance, with DKO mice demonstrating even better glycemic control.
• Combined inhibition of SGLT1 and SGLT2 may offer superior glycemic control for type 2 diabetes patients compared to SGLT2 inhibition alone.