Effects of LX4211, a Dual Sodium-Dependent Glucose Cotransporters 1 and 2 Inhibitor, on Postprandial Glucose, Insulin, Glucagon-like Peptide 1, and Peptide Tyrosine Tyrosine in a Dose-Timing Study in Healthy Subjects

Zambrowicz, Brian; Ogbaa, Ike; Frazier, Kenneth; Banks, Phillip; Turnage, Anne; Freiman, Joel; Boehm, Kristi A.; Ruff, Dennis; Powell, David R.; Sands, Arthur

doi:10.1016/j.clinthera.2013.06.011

Cited by 65 publications

(51 citation statements)

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“…It is a specific SGLT1 inhibitor compared with other molecules that primarily inhibit renal glucose reabsorption via SGLT2 (4) or have dual effects on SGLT1 and SGLT2 (40,41). This report presents the first set of nonclinical and clinical studies that have determined the effects of selective SGLT1 inhibitors in animal models and confirmed their translation to normal human physiology.…”

mentioning

confidence: 61%

Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release

Dobbins

Greenway

Chen

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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GSK-1614235 and KGA-2727 are potent, selective inhibitors of the SGLT1 sodium-dependent glucose transporter. Nonclinical (KGA-2727) and clinical (GSK-1614235) trials assessed translation of SGLT1 inhibitor effects from rats to normal human physiology. In rats, KGA-2727 (0.1 mg/kg) or vehicle was given before oral administration of 3-O-methyl-α-d-glucopyranose (3-O-methylglucose, 3-OMG) containing 3-[3H]OMG tracer. Tracer absorption and distribution were assessed from plasma, urine, and fecal samples. SGLT1 inhibition reduced urine 3-OMG recovery and increased fecal excretion. SGLT1 inhibitor effects on plasma glucose, insulin, gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were also measured during a standard meal. Incremental glucose, insulin, and GIP concentrations were decreased, indicating downregulation of β-cell and K cell secretion. Minimal effects were observed in the secretion of the L cell product, GLP-1. With the use of a three-way, crossover design, 12 healthy human subjects received placebo or 20 mg GSK-1614235 immediately before or after a meal. Five minutes into the meal, 3-OMG was ingested. Postmeal dosing had little impact, yet premeal dosing delayed and reduced 3-OMG absorption, with an AUC0-10 of 231±31 vs. 446±31 μg·h(-1)·ml(-1), for placebo. Recovery of tracer in urine was 1.2±0.7 g for premeal dosing and 2.2±0.1 g for placebo. Incremental concentrations of insulin, C-peptide, and GIP were reduced for 2 h with premeal GSK-1614235. Total GLP-1 concentrations were significantly increased, and a trend for increased peptide YY (PYY) was noted. SGLT1 inhibitors block intestinal glucose absorption and reduce GIP secretion in rats and humans, suggesting SGLT1 glucose transport is critical for GIP release. Conversely, GLP-1 and PYY secretion are enhanced by SGLT1 inhibition in humans.

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mentioning

confidence: 61%

Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release

Dobbins

Greenway

Chen

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Growing evidence suggests that SGLT1 transport plays a role in entero-endocrine hormone release. In human studies, treatment with sotagliflozin increased GLP-1 and PYY levels after meals and reduced blood GIP levels after breakfast in patients with T2D (31) and increased GLP-1 and PYY in healthy subjects (61). Similar gut hormone changes have been seen in healthy subjects after single 300-mg doses of canagliflozin (14).…”

Section: Gi Effects Of Dual Sglt1/2 Inhibitorsmentioning

confidence: 85%

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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“…The latter suggests that a threshold of duodenal glucose delivery of about 2 kcal/min is required to allow for the interaction with L cells located in the relatively distal region of the gut. Furthermore, the inhibition of glucose flow in the duodenum by hyoscine attenuated the secretion of GIP and GLP-1 (Chaikomin et al 2007), and the blockade of glucose absorption from the proximal small intestine by sodium glucose co-transport-1 (SGLT-1) inhibitors resulted in a delayed, but overall substantially increased, GLP-1 response to oral glucose ingestion Zambrowicz et al 2013) -a phenomenon also seen when the malabsorption of a non-glucose carbohydrate is induced by α-glucosidase inhibitors (e.g. acarbose and miglitol) (Arakawa et al 2008;Enc et al 2001;Qualmann et al 1995).…”

Section: Regulation Of Incretin Hormone Secretionmentioning

confidence: 99%

Incretins

Wu¹,

Rayner²,

Horowitz³

2015

Metabolic Control

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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the known incretin hormones in humans, released predominantly from the enteroendocrine K and L cells within the gut. Their secretion is regulated by a complex of integrated mechanisms involving direct contact for the activation of different chemo-sensors on the brush boarder of K and L cells and several indirect neuro-immuno-hormonal loops. The biological actions of GIP and GLP-1 are fundamental determinants of islet function and blood glucose homeostasis in health and type 2 diabetes. Moreover, there is increasing recognition that GIP and GLP-1 also exert pleiotropic extra-glycaemic actions, which may represent therapeutic targets for human diseases. In this review, we summarise current knowledge of the biology of incretin hormones in health and metabolic disorders and highlight the therapeutic potential of incretin hormones in metabolic regulation.

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Effects of LX4211, a Dual Sodium-Dependent Glucose Cotransporters 1 and 2 Inhibitor, on Postprandial Glucose, Insulin, Glucagon-like Peptide 1, and Peptide Tyrosine Tyrosine in a Dose-Timing Study in Healthy Subjects

Cited by 65 publications

References 21 publications

Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release

Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release

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

Incretins

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