LX4211 Increases Serum Glucagon-Like Peptide 1 and Peptide YY Levels by Reducing Sodium/Glucose Cotransporter 1 (SGLT1)–Mediated Absorption of Intestinal Glucose

Powell, David R.; Smith, Melinda; Greer, Jennifer; Harris, Angela L.; Zhao, Sharon; DaCosta, Christopher M.; Mseeh, Faika; Shadoan, Melanie K.; Sands, Arthur; Zambrowicz, Brian; Ding, Zhi‐Ming

doi:10.1124/jpet.113.203364

Cited by 161 publications

(178 citation statements)

References 60 publications

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“…Glucose-stimulated GLP1 and GIP secretion in vitro is prevented by pharmacological inhibition of SGLT1 (33), and Sglt1-deficient mice exhibit impaired GLP1 and GIP secretion immediately following oral glucose administration (34). At later time points after glucose gavage, plasma GLP1 was paradoxically increased in Sglt1 knockout mice (35), perhaps because reduced glucose absorption in the upper small intestine results in increased nutrient delivery to the L cell-rich distal gut, where an SGLT1-independent pathway may play a more important role.…”

Section: Molecular Mechanisms Underlying Gut Chemosensingmentioning

confidence: 99%

Gut chemosensing mechanisms

Psichas¹,

Reimann²,

Gribble³

2015

J. Clin. Invest.

209

176

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Section: Molecular Mechanisms Underlying Gut Chemosensingmentioning

confidence: 99%

Gut chemosensing mechanisms

Psichas¹,

Reimann²,

Gribble³

2015

J. Clin. Invest.

209

176

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“…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).…”

Section: Role Of Sglt1 In Intestinal Glucose Absorptionmentioning

confidence: 99%

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

et al. 2015

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Type 2 diabetes is a chronic disease with disabling micro-and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium-glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to reductions in plasma glucose concentrations. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors.It took nearly 200 years from the isolation of phlorizin, a chemical found in apple tree bark that inhibits sodium-glucose cotransporters (SGLTs) (1), to the approval of the first medications inhibiting SGLTs for treatment of type 2 diabetes (T2D). During this time, several SGLTs were discovered and the roles of SGLT1 and SGLT2 in intestinal and renal glucose reabsorption have been elucidated in studies in genetically manipulated rodents, humans with SGLT gene mutations, healthy humans, and humans with diabetes (Fig. 1). This review provides an overview of the basic and clinical research that led to the translation of the initial findings of increased glucosuria with phlorizin to the development and approval of SGLT inhibitors and a summary of the clinical trial results obtained to date. Identification, Distribution, and In Vitro Characterization of the SGLT InhibitorsIn the 1980s and 1990s, Wright and colleagues cloned SGLT1 (2) and SGLT2 (2,3) and did much of the in vitro characterization, demonstrating that SGLT1 has a higher affinity for glucose than SGLT2 (K m for glucose ;0.4 mmol/L and 2 mmol/L, respectively), whereas SGLT2 has a higher capacity (4). SGLT1 is expressed at high levels in the intestine and is also expressed in the kidney, heart, and skeletal muscle, whereas SGLT2 is expressed almost exclusively in the kidney (4). Renal SGLT2 expression is increased in hyperglycemic rodents (5,6) and in humans with T2D (7). Intestinal SGLT1 expression is regulated by diet and other factors (8) and is

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“…These results were associated with significant reductions in postprandial glucose. 12,13 Initial phase 1 studies of sotagliflozin…”

Section: Preclinical Studies Of Sotagliflozinmentioning

confidence: 99%

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

Lapuerta

Zambrowicz

Strumph

et al. 2015

Diabetes and Vascular Disease Research

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110

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The sodium-dependent glucose transporter 2 (SGLT2) inhibitors are an important emerging class for the treatment of diabetes. Development of SGLT2 inhibitors has been oriented around a desire for high selectivity for the SGLT2 protein relative to the SGLT1 protein. More recently, genetic and pharmacology research in mice has indicated that gastrointestinal SGLT1 inhibition may also be an appropriate therapeutic target to treat diabetes. Combining SGLT1 and SGLT2 inhibition in a single molecule would provide complementary insulin-independent mechanisms to treat diabetes. Therefore, sotagliflozin (LX4211) has been developed as a dual inhibitor of SGLT1 and SGLT2. The differentiating clinical features of dual inhibitor of SGLT1 and SGLT2 include a large postprandial glucose reduction, elevation of glucagon-like peptide 1 and modest urinary glucose excretion. These features may have clinical implications for the use of sotagliflozin in the treatment of both type 1 and type 2 diabetes.

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LX4211 Increases Serum Glucagon-Like Peptide 1 and Peptide YY Levels by Reducing Sodium/Glucose Cotransporter 1 (SGLT1)–Mediated Absorption of Intestinal Glucose

Cited by 161 publications

References 60 publications

Gut chemosensing mechanisms

Gut chemosensing mechanisms

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

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

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