Brian Zambrowicz

Lexicon Pharmaceuticals, The Woodlands, Texas, United States

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Publications (81)597.24 Total impact

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    ABSTRACT: WNT signaling, involving WNTs, FZDs, LRPs, Sclerostin, DKK1 and SFRP4, plays a key role in bone formation and identification of additional genes in this pathway can provide novel therapeutic approaches to treat osteoporosis. NOTUM is a secreted enzyme that inactivates WNTs by removing a palmitoleic acid group essential for activity. Male and female Notum KO mice have normal soft tissue histology, bone length and trabecular bone parameters, but elevated cortical bone thickness (9 cohorts, total KO N=165) with increased strength. Enzymatic and cell-based assays of NOTUM activity were employed to screen both a chemical library and antibodies generated against mouse NOTUM. Neutralizing antibody 2.78.33 had IC50 potencies of 37 and 4 nM in enzymatic and cell-based assays, respectively. Small molecule (SM) LP-935001 had IC50 potencies of 0.4 and 12 nM in enzymatic and cell-based assays, respectively. Exposure of differentiating MC3TC-E1 osteoblasts to NOTUM conditioned medium prevented mineralization, which was reversed by cotreatment with SM inhibitors. Eight weeks following surgery, sham-surgery and OVX mice were treated with Ab 2.78.33 (10 mg/kg weekly) for 4 weeks starting at 24 weeks of age. Treatment increased cortical thickness (P < 0.01) similarly in sham and OVX mice in midshaft femur (12%), vertebral body (9%) and femoral neck (6%). Triple fluorochrome labeling on days 7 (calcein), 14 (alizarin) and 21 (demeclocycline) showed 3-fold elevations in midshaft femur endocortical MS at 7 and 14 days but minimal activity at 21 days. BFR was elevated 4-fold between 7 and 14 days. Sixty-three weeks following surgery, OVX rats were treated with LP-935001 (daily oral gavage at 1 and 5 mg/kg) for 12 weeks starting at 80 weeks of age. High dose treatment increased (P < 0.02) cortical bone thickness in midshaft femur (6%), distal tibia (9%), pelvis (12%). vertebral body (7%) and femoral neck (6%). Bone strength was elevated (P < 0.01) in midshaft femur (13%), midshaft tibia (7%) and femoral neck (15%). Two courses of double fluorochrome labeling showed 3.6- and 3.2-fold elevations in distal tibia endocortical BFR during 1 to 3 weeks (alizarin) and 9 to 11 weeks (calcein) of treatment, respectively. These findings demonstrate NOTUM is a WNT inhibitory factor reducing bone formation. As a secreted enzyme inhibitable by neutralizing antibodies and orally active SMs, NOTUM is a potential drug target for stimulating endocortical bone formation and treating osteoporosis.
    Full-text · Conference Paper · Oct 2015

  • No preview · Article · Sep 2015
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    ABSTRACT: To assess the safety and efficacy of dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes. We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment. In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70-180 mg/dL (3.9-10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group. As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Preview · Article · Jun 2015 · Diabetes Care
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    ABSTRACT: After creating >4,650 knockouts (KOs) of independent mouse genes, we screened them by high-throughput phenotyping and found that cannabinoid receptor 1 (Cnr1) KO mice had the same lean phenotype published by others. We asked if our KOs of DAG lipase α or β (Dagla or Daglb), which catalyze biosynthesis of the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG), or Napepld, which catalyzes biosynthesis of the EC anandamide, shared the lean phenotype of Cnr1 KO mice. We found that Dagla KO mice, but not Daglb or Napepld KO mice, were among the leanest of 3651 chow-fed KO lines screened. In confirmatory studies, chow- or high fat diet-fed Dagla and Cnr1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 47 and 45% lower in Dagla and Cnr1 KO mice, respectively, relative to WT values. By contrast, neither Daglb nor Napepld KO mice were lean. Weanling Dagla KO mice ate less than WT mice and had body weight (BW) similar to pair-fed WT mice, and adult Dagla KO mice had normal activity and VO2 levels, similar to Cnr1 KO mice. Our Dagla and Cnr1 KO mice also had low fasting insulin, triglyceride, and total cholesterol levels, and after glucose challenge had normal glucose but very low insulin levels. Dagla and Cnr1 KO mice also showed similar responses to a battery of behavioral tests. These data suggest: (1) the lean phenotype of young Dagla and Cnr1 KO mice is mainly due to hypophagia; (2) in pathways where ECs signal through Cnr1 to regulate food intake and other metabolic and behavioral phenotypes observed in Cnr1 KO mice, Dagla alone provides the 2-AG that serves as the EC signal; and (3) small molecule Dagla inhibitors with a pharmacokinetic profile similar to that of Cnr1 inverse agonists are likely to mirror the ability of these Cnr1 inverse agonists to lower BW and improve glycemic control in obese patients with type 2 diabetes, but may also induce undesirable neuropsychiatric side-effects.
    Full-text · Article · Jun 2015 · Frontiers in Endocrinology

  • No preview · Article · May 2015

  • No preview · Article · Apr 2015 · Journal of the American Society of Hypertension
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    ABSTRACT: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents that improve glycemic control by inhibiting SGLT2-mediated renal glucose reabsorption. Currently available agents increase urinary glucose excretion (UGE) to <50% of maximal values because they do not inhibit SGLT1, which reabsorbs >50% of filtered glucose when SGLT2 is completely inhibited. This led us to test whether LP-925219, a small molecule dual SGLT1/SGLT2 inhibitor, increases UGE to maximal values in wild-type (WT) mice. We first tested LP-925219 inhibition of glucose transport by HEK293 cells expressing SGLT1 or SGLT2, and then characterized LP-925219 pharmacokinetics. We found that LP-925219 was a potent inhibitor of mouse SGLT1 (IC50 = 22.6 nmol/L) and SGLT2 (IC50 = 0.5 nmol/L), and that a 10 mg/kg oral dose was bioavailable (87%) with a long half-life (7 h). We next delivered LP-925219 by oral gavage to WT, SGLT1 knockout (KO), SGLT2 KO, and SGLT1/SGLT2 double KO (DKO) mice and measured their 24-h UGE. We found that, in vehicle-treated mice, DKO UGE was maximal and SGLT2 KO, SGLT1 KO, and WT UGEs were 30%, 2%, and 0.2% of maximal, respectively; we also found that LP-925219 dosed at 60 mg/kg twice daily increased UGE of SGLT1 KO, SGLT2 KO, and WT mice to DKO UGE levels. These findings show that orally available dual SGLT1/SGLT2 inhibitors can maximize 24-h UGE in mammals, and suggest that such agents merit further evaluation for their potential, in diabetic patients, to achieve better glycemic control than is achieved using selective SGLT2 inhibitors.
    Full-text · Article · Apr 2015
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    Pablo Lapuerta · Brian Zambrowicz · Paul Strumph · Arthur Sands
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    ABSTRACT: 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. © The Author(s) 2015.
    Full-text · Article · Mar 2015 · Diabetes & Vascular Disease Research
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    ABSTRACT: Oral agents are needed that improve glycemic control without increasing hypoglycemic events in patients with type 1 diabetes (T1D). Sotagliflozin may meet this need, because this compound lowers blood glucose through the insulin-independent mechanisms of inhibiting kidney SGLT2 and intestinal SGLT1. We examined the effect of sotagliflozin on glycemic control and rate of hypoglycemia measurements in T1D mice maintained on a low daily insulin dose, and compared these results to those from mice maintained in better glycemic control with a higher daily insulin dose alone. Nonobese diabetes-prone mice with cyclophosphamide-induced T1D were randomized to receive one of four daily treatments: 0.2 U insulin/vehicle, 0.05 U insulin/vehicle, 0.05 U insulin/2 mg/kg sotagliflozin or 0.05 U insulin/30 mg/kg sotagliflozin. Insulin was delivered subcutaneously by micro-osmotic pump; the day after pump implantation, mice received their first of 22 once-daily oral doses of sotagliflozin or vehicle. Glycemic control was monitored by measuring fed blood glucose and hemoglobin A1c levels. Blood glucose levels decreased rapidly and comparably in the 0.05 U insulin/sotagliflozin-treated groups and the 0.2 U insulin/vehicle group compared to the 0.05 U insulin/vehicle group, which had significantly higher levels than the other three groups from day 2 through day 23. A1c levels were also significantly higher in the 0.05 U insulin/vehicle group compared to the other three groups on day 23. Importantly, the 0.2 U insulin/vehicle group had, out of 100 blood glucose measurements, 13 that were <70 mg/dL compared to one of 290 for the other three groups combined. Sotagliflozin significantly improved glycemic control, without increasing the rate of hypoglycemia measurements, in diabetic mice maintained on a low insulin dose. This sotagliflozin-mediated improvement in glycemic control was comparable to that achieved by raising the insulin dose alone, but was not accompanied by the increased rate of hypoglycemia measurements observed with the higher insulin dose.
    Full-text · Article · Feb 2015 · Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
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    ABSTRACT: Context: Carcinoid syndrome (CS) is associated with elevated serotonin, diarrhea, flushing and increased risk of valvular heart disease. Many patients respond to somatostatin analogs (SSAs) initially; but response diminishes in most patients. Additional options are needed. Objective: To assess whether telotristat etiprate (TE) can reduce gastrointestinal (GI) symptoms in CS and reduce urinary 5-HIAA (a biomarker of serotonin). Design: Prospective, exploratory, dose-escalating 12-week, open-label, multicenter study of TE with efficacy and safety analyses Setting: Multicenter study Patients: Eligible patients had metastatic, well-differentiated, neuroendocrine tumors and CS with ≥4 bowel movements (BMs)/day. SSA use was allowed. Interventions: Telotristat etiprate, a novel oral inhibitor of peripheral serotonin synthesis. Main Outcome Measures: Primary: Safety. Secondary: Daily BMs, stool form, urinary 5-hydroxyindoleacetic acid (u5-HIAA) Results: Fifteen patients were enrolled and 14 completed the treatment period. All patients experienced reductions in BMs/day (mean decrease 43.5%). A 74.2% mean reduction in u5-HIAA, the main metabolite of serotonin, was observed, with generally greater reductions in patients with greater reductions in BMs/day. Nine (75%) patients reported "adequate relief" of GI symptoms at 12-weeks, compared with 2 (17%) at baseline. Stool form and flushing also improved. AEs were mostly gastrointestinal (n=10, 67%), consistent with underlying illness; 3 AEs were serious (abdominal pain, diarrhea, and gastroenteritis), but judged unrelated. Conclusion: TE was generally safe and well tolerated. Patients experienced substantial improvement in CS and reductions in u5-HIAA, consistent with TE's mechanism of action. These results support further evaluation in Phase 3 studies.
    No preview · Article · Jan 2015 · Journal of Clinical Endocrinology & Metabolism
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    ABSTRACT: We sought to assess the efficacy and safety profile of LX4211, a dual inhibitor of sodium-glucose cotransporter1 (SGLT1) and SGLT2, in patients with type 2 diabetes and renal impairment. Thirty-one patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) were randomly assigned to receive 400 mg of LX4211 or placebo for 7 days. The primary end point was the change from baseline to day 7 in postprandial glucose (PPG) levels. Other end points included changes in fasting plasma glucose levels, glucagon-like peptide 1 levels, urinary glucose excretion (UGE), and blood pressure. LX4211 therapy significantly reduced PPG levels relative to placebo in the total population and in patients with an eGFR <45 mL/min/1.73 m(2), with a placebo-adjusted decrease in incremental AUCpredose-4 of 73.5 mg·h/dL (P = 0.009) and 137.2 mg·h/dL (P = 0.001) for the total population and the eGFR <45 mL/min/1.73 m(2) subgroup, respectively. There was a significant reduction in fasting plasma glucose levels relative to baseline of -27.1 mg/dL (P < 0.001). Total and active glucagon-like peptide 1 levels were significantly elevated relative to placebo with LX4211 dosing, and UGE was significantly elevated with placebo-subtracted measures of 38.7, 53.5, and 20.4 g/24 h (P ≤ 0.007 for all 3) in the total population, eGFR 45 to 59 mL/min/1.73 m(2), and eGFR <45 mL/min/1.73 m(2) subgroups, respectively. The PPG effects were maintained in patients with an eGFR <45 mL/min/1.73 m(2) despite the expected reduction in UGE, suggesting that dual SGLT1 and SGLT2 inhibition with LX4211 could prove useful for the treatment of patients with type 2 diabetes and renal impairment. identifier: NCT01555008. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.
    Full-text · Article · Dec 2014 · Clinical Therapeutics
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    P Vogel · R Read · G M Hansen · L C Freay · B P Zambrowicz · A T Sands

    Full-text · Dataset · Nov 2014
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    ABSTRACT: Screening gene function in vivo is a powerful approach to discover novel drug targets. We present high-throughput screening (HTS) data for 3 762 distinct global gene knockout (KO) mouse lines with viable adult homozygous mice generated using either gene-trap or homologous recombination technologies. Bone mass was determined from DEXA scans of male and female mice at 14 weeks of age and by microCT analyses of bones from male mice at 16 weeks of age. Wild-type (WT) cagemates/littermates were examined for each gene KO. Lethality was observed in an additional 850 KO lines. Since primary HTS are susceptible to false positive findings, additional cohorts of mice from KO lines with intriguing HTS bone data were examined. Aging, ovariectomy, histomorphometry and bone strength studies were performed and possible non-skeletal phenotypes were explored. Together, these screens identified multiple genes affecting bone mass: 23 previously reported genes (Calcr, Cebpb, Crtap, Dcstamp, Dkk1, Duoxa2, Enpp1, Fgf23, Kiss1/Kiss1r, Kl (Klotho), Lrp5, Mstn, Neo1, Npr2, Ostm1, Postn, Sfrp4, Slc30a5, Slc39a13, Sost, Sumf1, Src, Wnt10b), five novel genes extensively characterized (Cldn18, Fam20c, Lrrk1, Sgpl1, Wnt16), five novel genes with preliminary characterization (Agpat2, Rassf5, Slc10a7, Slc26a7, Slc30a10) and three novel undisclosed genes coding for potential osteoporosis drug targets.
    Full-text · Article · Oct 2014
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    ABSTRACT: Objective: To assess the dose-ranging efficacy and safety of LX4211, a dual inhibitor of sodium-glucose cotransporter (SGLT) 1 and SGLT2, in type 2 diabetes. Research design and methods: Type 2 diabetic patients inadequately controlled on metformin were randomly assigned to 75 mg once daily, 200 mg once daily, 200 mg twice daily, or 400 mg once daily of LX4211 or placebo. Primary end point was A1C change from baseline to week 12. Secondary end points included changes in blood pressure (BP) and body weight. Results: Baseline characteristics in 299 patients randomly assigned to LX4211 or placebo in this 12-week dose-ranging study were similar: mean age 55.9 years, A1C 8.1% (65 mmol/mol), BMI 33.1 kg/m(2), and BP 124/79 mmHg. LX4211 significantly reduced A1C to week 12 in a dose-dependent manner by 0.42% (4.6 mmol/mol), 0.52% (5.7 mmol/mol), 0.80% (8.7 mmol/mol), and 0.92% (10.0 mmol/mol), respectively (P < 0.001 each), compared with 0.09% (1.0 mmol/mol) for placebo. Greater A1C reductions were produced by 400 mg once a day than 200 mg once a day LX4211 without higher urinary glucose excretion, suggesting a contribution of SGLT1 inhibition. Significant reductions were seen in body weight (-1.85 kg; P < 0.001) and systolic BP (-5.7 mmHg; P < 0.001), but diastolic BP was unchanged (-1.6; P = 0.164). Adverse events with LX4211 were mild to moderate and similar to placebo, including urinary tract infections and gastrointestinal-related events; genital infections were limited to LX4211 groups (0-5.0%). No hypoglycemia occurred. Conclusions: Dual inhibition of SGLT1/SGLT2 with LX4211 produced significant dose-ranging improvements in glucose control without dose-increasing glucosuria and was associated with reductions in weight and systolic BP in metformin-treated patients with type 2 diabetes.
    No preview · Article · Sep 2014 · Diabetes Care
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    ABSTRACT: Serotonin produced by neuroendocrine tumors is believed to be a principal cause of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with diarrhea associated with carcinoid syndrome. In this prospective, randomized study, patients with evidence of carcinoid tumor and ≥4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot therapy were enrolled in sequential, escalating, cohorts of 4 patients/cohort. In each cohort, 1 patient was randomly assigned to placebo and 3 patients to telotristat etiprate, at 150, 250, 350, or 500 mg 3x/day (tid). In a subsequent cohort, 1 patient was assigned to placebo and 6 patients to telotristat etiprate 500 mg tid. Patients were assessed for safety, BM frequency (daily diary), 24-hour urinary 5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients were treated; 18 received telotristat etiprate and 5 received placebo. Adverse events were generally mild. Among evaluable telotristat etiprate-treated patients, 5/18 (28%) experienced a >30% reduction in BM frequency for >2 weeks, 9/16 (56%) experienced biochemical response (>50% reduction or normalization in 24-hour u5-HIAA) at Week 2 or 4, and 10/18 (56%) reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was not observed in placebo-treated patients. Telotristat etiprate was well tolerated. Our observations suggest that telotristat etiprate has activity in controlling diarrhea associated with carcinoid syndrome. Further studies confirming these findings are warranted.
    Preview · Article · Jul 2014 · Endocrine Related Cancer
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    Full-text · Dataset · Jun 2014
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    ABSTRACT: Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4+ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1-/- B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1-/- CD4+ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4+ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.
    Full-text · Article · May 2014 · PLoS ONE
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    ABSTRACT: Treatments which lower blood glucose levels and body weight should benefit patients with type 2 diabetes mellitus (T2DM). We developed LX4211, an orally available small molecule that decreases postprandial glucose excursions by inhibiting intestinal SGLT1 and increases urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies of patients with T2DM, LX4211 appears to act through dual SGLT1/SGLT2 inhibition to improve glycemic control and promote weight loss. Here, we present preclinical studies which explored the ability of LX4211 to improve glycemic control and promote weight loss. We found: 1) LX4211 inhibited in vitro glucose transport mediated by mouse, rat and dog SGLT1 and SGLT2; 2) a single daily LX4211 dose markedly increased UGE for > 24 hours in mouse, rat and dog; and 3) in the KKA(y) mouse model of T2DM, LX4211 lowered A1C and postprandial glucose concentrations while increasing postprandial GLP-1 concentrations. Also, long-term LX4211 treatment: 1) decreased OGTT glucose excursions, increased OGTT 30 minute insulin concentrations and increased pancreatic insulin content in KKA(y) mice; and 2) decreased weight gain in dogs and rats but not in KKA(y) mice, while increasing food consumption in dogs, rats and KKA(y) mice; in these KKA(y) mice, calories lost through UGE were completely offset by calories gained through hyperphagia. These findings suggest that LX4211 improves glycemic control by dual SGLT1/SGLT2 inhibition in mice as in humans, and that the LX4211-mediated weight loss observed in patients with T2DM may be attenuated by LX4211-mediated hyperphagia in some of these individuals.
    Full-text · Article · May 2014 · Journal of Pharmacology and Experimental Therapeutics

  • No preview · Conference Paper · Jan 2014
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    ABSTRACT: LX4211 is a first-in-class dual inhibitor of sodium-dependent glucose cotransporters 1 and 2 (SGLT1 and SGLT2). SGLT1 is the primary transporter for glucose absorption from the gastrointestinal tract, and SGLT2 is the primary transporter for glucose reabsorption in the kidney. SGLT1 inhibition reduces postprandial glucose (PPG) levels and increases the release of gastrointestinal peptides such as glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY), whereas SGLT2 inhibition results in increased urinary glucose excretion (UGE).
    No preview · Article · Jul 2013 · Clinical Therapeutics

Publication Stats

5k Citations
597.24 Total Impact Points


  • 2008-2015
    • Lexicon Pharmaceuticals
      The Woodlands, Texas, United States
  • 2014
    • American College of Pathologists
      American Canyon, California, United States
  • 2013
    • Columbia University
      • Department of Pathology & Cell Biology
      New York, New York, United States
  • 2002
    • Washington University in St. Louis
      • Department of Ophthalmology and Visual Sciences
      San Luis, Missouri, United States
  • 2001
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States
  • 1995-1997
    • Fred Hutchinson Cancer Research Center
      • Division of Basic Sciences
      Seattle, Washington, United States
  • 1993-1994
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States