Improved glycemic control in mice lacking Sglt1 and Sglt2

Abstract

Sodium-glucose cotransporter 2 (SGLT2) is the major, and SGLT1 the minor, transporter responsible for renal glucose reabsorption. Increasing urinary glucose excretion (UGE) by selectively inhibiting SGLT2 improves glycemic control in diabetic patients. We generated Sglt1 and Sglt2 knockout (KO) mice, Sglt1/Sglt2 double-KO (DKO) mice, and wild-type (WT) littermates to study their relative glycemic control and to determine contributions of SGLT1 and SGLT2 to UGE. Relative to WTs, Sglt2 KOs had improved oral glucose tolerance and were resistant to streptozotocin-induced diabetes. Sglt1 KOs fed glucose-free high-fat diet (G-free HFD) had improved oral glucose tolerance accompanied by delayed intestinal glucose absorption and increased circulating glucagon-like peptide-1 (GLP-1), but had normal intraperitoneal glucose tolerance. On G-free HFD, Sglt2 KOs had 30%, Sglt1 KOs 2%, and WTs <1% of the UGE of DKOs. Consistent with their increased UGE, DKOs had lower fasting blood glucose and improved intraperitoneal glucose tolerance than Sglt2 KOs. In conclusion, 1) Sglt2 is the major renal glucose transporter, but Sglt1 reabsorbs 70% of filtered glucose if Sglt2 is absent; 2) mice lacking Sglt2 display improved glucose tolerance despite UGE that is 30% of maximum; 3) Sglt1 KO mice respond to oral glucose with increased circulating GLP-1; and 4) DKO mice have improved glycemic control over mice lacking Sglt2 alone. These data suggest that, in patients with type 2 diabetes, combining pharmacological SGLT2 inhibition with complete renal and/or partial intestinal SGLT1 inhibition may improve glycemic control over that achieved by SGLT2 inhibition alone.

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

“…However, maximally effective SGLT2 inhibitor doses typically prevent ;50% of the filtered glucose from being reabsorbed, suggesting that SGLT1 has considerably greater capacity for glucose reabsorption than expected based on the commonly quoted 90% value for SGLT2. This is supported by data from genetic models, since SGLT2 KO mice exhibit only about 30% of the UGE observed in SGLT1/SGLT2 double KO mice (17). These data, combined with human care.diabetesjournals.orgdata showing that phlorizin can block virtually all renal glucose reabsorption (19), suggest that dual SGLT1/2 renal inhibitors might achieve considerably greater UGE than selective SGLT2 inhibitors.…”

“…In humans, familial renal glucosuria is a rare, benign condition arising from SGLT2 mutations that reduce renal glucose reabsorption and lead to UGE ranging from 1 to 170 g/day, whereas SGLT1 mutations only mildly increase UGE (17). Similarly, only minimal UGE is observed in SGLT1 knockout (KO) mice, whereas high UGE is seen in SGLT2 KO mice (17,18).…”

“…SGLT1 KO mice exhibited elevated glucose in the distal small intestine and colon and decreased cecal pH when challenged with a meal containing glucose (17,20). Reductions in serum total glucagon-like peptide 1 (GLP-1) have been reported 5 min after a meal challenge (17,20), but serum GLP-1 was increased from 30 min to 6 h after the meal (20), indicating that SGLT1 may be required for the early GLP-1 response and that there is a second more predominant phase of GLP-1 release that does not require SGLT1 and is enhanced in the absence of SGLT1. The increased GLP-1 seen in SGLT1 KO mice may be due to increased glucose reaching the distal small intestine and colon where it, or its metabolites, can trigger GLP-1 release (21,22).…”

Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor

“…These effects were not observed in SGLT2 knockout mice, confirming that they were the result of decreased SGLT1 and not SGLT2. 10 The experience with SGLT1 knockout mice also provided a perspective on safety. SGLT1 knockout mice maintained on a diet containing glucose and galactose exhibited unformed or watery stools, decreased food intake and reduced weight gain, which provided additional evidence that complete inhibition of intestinal SGLT1 might not be desirable.…”

Novel Agents for the Treatment of Type 2 Diabetes

“…However, recent studies in combined SGLT-1/SGLT-2 knockout mice suggest that SGLT-1 is responsible for a much greater reabsorption of the filtered glucose load than previously appreciated. 83 Studies in mice treated with the nonabsorbable SGLT-1 inhibitor LX 2761 (Lexicon) demonstrated reductions in FPG and PPG and a reduction in A1C of 0.7% with no GI side effects, no increase in glucosuria, and an increase in circulating levels of GLP-1 and peptide YY (PYY), hormones that suppress the appetite. 84 With respect to the increase in GLP-1, reduced GI absorption of glucose leads to increased distal delivery of glucose and short-chain fatty acids (produced by bacterial metabolism of glucose in the GI tract), both of which enhance GLP-1 and PYY secretion by the L-cell.…”