Brian Zambrowicz

Lexicon Pharmaceuticals, The Woodlands, Texas, United States

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Publications (67)479.11 Total impact

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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.
    04/2015; 3(2). DOI:10.1002/prp2.129
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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.
    Diabetes & Vascular Disease Research 03/2015; 12(2):101-10. DOI:10.1177/1479164114563304 · 3.04 Impact Factor
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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.
    Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 02/2015; 8:121-7. DOI:10.2147/DMSO.S76342
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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.
    Journal of Clinical Endocrinology &amp Metabolism 01/2015; 100(4):jc20142247. DOI:10.1210/jc.2014-2247 · 6.31 Impact Factor
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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. ClinicalTrials.gov identifier: NCT01555008. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.
    Clinical Therapeutics 12/2014; 37(1). DOI:10.1016/j.clinthera.2014.10.026 · 2.59 Impact Factor
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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.
    10/2014; DOI:10.1038/boneres.2014.34
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    ABSTRACT: To assess the dose-ranging efficacy and safety of LX4211, a dual inhibitor of sodium glucose cotransporter 1 (SGLT1) and SGLT2, in type 2 diabetes.
    Diabetes Care 09/2014; 38(3). DOI:10.2337/dc14-0890 · 8.57 Impact Factor
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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.
    Endocrine Related Cancer 07/2014; DOI:10.1530/ERC-14-0173 · 4.91 Impact Factor
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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.
    PLoS ONE 05/2014; 9(5):e98151. DOI:10.1371/journal.pone.0098151 · 3.53 Impact Factor
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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.
    Journal of Pharmacology and Experimental Therapeutics 05/2014; 350(2). DOI:10.1124/jpet.114.214304 · 3.86 Impact Factor
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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). This study evaluated how timing of dose relative to meals changes the pharmacodynamic (PD) effects of LX4211 treatment, including effects on UGE, fasting plasma glucose, PPG, insulin, total and active GLP-1, and PYY. The safety and tolerability of LX4211 in healthy subjects were also assessed. This was a randomized, double-blind, placebo-controlled, multiple-dose study to determine the PD effects of LX4211 dose timing relative to meals in 12 healthy subjects. Blood and urine were collected for the analysis of PD variables. Twelve healthy subjects 30 to 51 years of age were enrolled and treated. Treatment with LX4211 resulted in significant elevation of total and active GLP-1, and PYY while significantly decreasing PPG levels relative to placebo, likely by reducing SGLT1-mediated intestinal glucose absorption. Comparisons performed among the dosing schedules indicated that dosing immediately before breakfast maximized the PD effects of LX4211 on both SGLT1 and SGLT2 inhibition. The comparative results suggested distinct SGLT1 effects on GLP-1, PYY, glucose, and insulin, which were separate from SGLT2-mediated effects, indicating that SGLT1 inhibition with LX4211 may be clinically meaningful. All treatments were well tolerated with no evidence of diarrhea with LX4211 treatment. This clinical study indicates that dosing of LX4211 immediately before breakfast maximized the PD effects of both SGLT1 and SGLT 2 inhibition and provided a convenient dosing schedule for future trials. LX4211 was safe and well tolerated and, due to its SGLT1 inhibition, produced strong PPG reductions and low UGE relative to selective SGLT2 inhibitors. LX4211 may provide a promising new therapy for patients with type 2 diabetes mellitus. The potential long-term clinical benefits and safety of LX4211 treatment will need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01334242.
    Clinical Therapeutics 07/2013; DOI:10.1016/j.clinthera.2013.06.011 · 2.59 Impact Factor
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    ABSTRACT: Sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) are the major cellular transporters responsible for gastrointestinal (GI) glucose absorption and renal glucose reabsorption, respectively. LX4211, a dual inhibitor of SGLT1 and SGLT2, reduces glucose absorption from the GI tract and enhances urinary glucose excretion. Although several SGLT2-selective inhibitors have been tested in large phase 2 studies, dual inhibition of SGLT1 and SGLT2 is novel at this stage of drug development, and it has implications for clinical-trial design. In this article, we describe the design and rationale of a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of LX4211 in subjects with type 2 diabetes mellitus who have inadequate glycemic control on metformin monotherapy. The primary endpoint is the change in glycated hemoglobin A1c from baseline to week 12. Secondary endpoints include the proportion of subjects achieving a glycated hemoglobin A1c value of <7%, change from baseline in fasting plasma glucose and postprandial glucose (as part of an oral glucose tolerance test), body weight, and blood pressure. Safety is evaluated with particular focus on hypoglycemia, GI symptoms, and incidence of genitourinary tract infections.
    Clinical Cardiology 07/2013; 36(7). DOI:10.1002/clc.22125 · 2.23 Impact Factor
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    ABSTRACT: OBJECTIVE: Enterochromaffin cell-derived serotonin (5-HT) promotes intestinal inflammation. We tested hypotheses that peripheral tryptophan hydroxylase (TPH) inhibitors, administered orally, block 5-HT biosynthesis and deplete 5-HT from enterochromaffin cells sufficiently to ameliorate intestinal inflammation; moreover, peripheral TPH inhibitors fail to enter the murine enteric nervous system (ENS) or central nervous systems and thus do not affect constitutive gastrointestinal motility. DESIGN: Two peripheral TPH inhibitors, LP-920540 and telotristat etiprate (LX1032; LX1606) were given orally to mice. Effects were measured on 5-HT levels in the gut, blood and brain, 5-HT immunoreactivity in the ENS, gastrointestinal motility and severity of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Quantitation of clinical scores, histological damage and intestinal expression of inflammation-associated cytokines and chemokines with focused microarrays and real-time reverse transcriptase PCR were employed to evaluate the severity of intestinal inflammation. RESULTS: LP-920540 and LX1032 reduced 5-HT significantly in the gut and blood but not in the brain. Neither LP-920540 nor LX1032 decreased 5-HT immunoreactive neurons or fibres in the myenteric plexus and neither altered total gastrointestinal transit time, colonic motility or gastric emptying in mice. In contrast, oral LP-920540 and LX1032 reduced the severity of TNBS-induced colitis; the expression of 24% of 84 genes encoding inflammation-related cytokines and chemokines was lowered at least fourfold and the reduced expression of 17% was statistically significant. CONCLUSIONS: Observations suggest that that peripheral TPH inhibitors uncouple the positive linkage of enterochromaffin cell-derived 5-HT to intestinal inflammation. Because peripheral TPH inhibitors evidently do not enter the murine ENS, they lack deleterious effects on constitutive intestinal motility in mice.
    Gut 06/2013; 63(6). DOI:10.1136/gutjnl-2013-304901 · 13.32 Impact Factor
  • Gastroenterology 05/2013; 144(5):S-360. · 13.93 Impact Factor
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    ABSTRACT: LX4211, a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide (GLP)-1 and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2 -/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1 -/- mice had increased levels of plasma GLP-1, plasma PYY and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area-under-the-curve (AUC) values, whereas SGLT2 -/- mice showed no response. LX4211-treated mice and SGLT1 -/- mice also had increased GLP-1 AUC, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice, and were decreased in SGLT1 -/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels five minutes after oral glucose. These data suggest LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.
    Journal of Pharmacology and Experimental Therapeutics 03/2013; DOI:10.1124/jpet.113.203364 · 3.86 Impact Factor
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    ABSTRACT: BACKGROUND: Combination therapy is required to provide adequate glycemic control in many patients with type 2 diabetes mellitus (T2DM). Because sodium-dependent glucose transporter (SGLT)-1 inhibition results in an increased release of glucagon-like peptide (GLP)-1, and because dipeptidyl peptidase (DPP)-4 inhibitors prevent its inactivation, the 2 mechanisms together provide an intriguing potential combination therapy. OBJECTIVES: This combination was explored in preclinical models and then tested in patients with T2DM to compare the effects of single-dose LX4211 400 mg and sitagliptin 100 mg, administered as monotherapy or in combination, on GLP-1, peptide tyrosine tyrosine (PYY), gastric inhibitory peptide (GIP), glucose, and insulin. METHODS: Preclinical: Obese male C57BL6J mice were assigned to 1 of 4 treatment groups: LX4211 60 mg/kg, sitagliptin 30 mg/kg, LX4211 + sitagliptin, or inactive vehicle. Clinical: This 3-treatment, 3-crossover, randomized, open-label study was conducted at a single center. Patients on metformin monotherapy were washed out from metformin and were randomly assigned to receive sequences of single-dose LX4211, sitagliptin, or the combination. In both studies, blood was collected for the analysis of pharmacodynamic variables (GLP-1, PYY, GIP, glucose, and insulin). In the clinical study, urine was collected to assess urinary glucose excretion. RESULTS: Preclinical: 120 mice were treated and assessed (5/time point/treatment group). With repeat daily dosing, the combination was associated with apparently synergistic increases in active GLP-1 relative to monotherapy with either agent; this finding was supported by findings from an additional 14-day repeated-dose experiment. Clinical: 18 patients were enrolled and treated (mean age, 49 years; 56% male; 89% white). The LX4211 + sitagliptin combination was associated with significantly increased active GLP-1, total GLP-1, and total PYY; with a significant reduction in total GIP; and with a significantly improved blood glucose level, with less insulin, compared with sitagliptin monotherapy. LX4211 was associated with a significant increase in total GLP-1 and PYY and a reduced total GIP, likely due to a reduction in SGLT1-mediated intestinal glucose absorption, whereas sitagliptin was associated with suppression of all 3 peptides relative to baseline. All treatments were well tolerated, with no evidence of diarrhea with LX4211 treatment. CONCLUSIONS: The findings from the preclinical studies suggest that the LX4211 + sitagliptin combination produced synergistic increases in active GLP-1 after a meal challenge containing glucose. These initial clinical results also suggest that a LX4211 + DPP-4 inhibitor combination may provide an option in patients with T2DM. The potential long-term clinical benefits of such combination treatment need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01441232.
    Clinical Therapeutics 02/2013; DOI:10.1016/j.clinthera.2013.01.010 · 2.59 Impact Factor
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    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 wildtype (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 tolerance to intraperitoneal glucose. On G-free HFD, Sglt2 KOs had 30%, Sglt1 KOs 2% and WTs < 1% of the UGE of DKO mice. Consistent with their increased UGE, DKOs had lower fasting blood glucose, and improved tolerance to intraperitoneal glucose, compared to Sglt2 KO mice. In conclusion, 1) Sglt2 is the major renal glucose transporter, however Sglt1 reabsorbs 70% of filtered glucose if Sglt2 is absent; 2) mice lacking Sglt2 display improved glucose tolerance despite UGE that is at best 30% of maximum; 3) Sglt1 KO mice respond to oral glucose with increased circulating GLP-1; and 4) mice lacking Sglt1 and Sglt2 have improved glycemic control over mice lacking Sglt2 alone. These data suggest that dual SGLT1/SGLT2 inhibition is an approach that may further improve glycemic control over SGLT2 inhibition alone in patients with type 2 diabetes.
    AJP Endocrinology and Metabolism 11/2012; 304(2). DOI:10.1152/ajpendo.00439.2012 · 4.09 Impact Factor
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    ABSTRACT: Recent advances have suggested that aberrations in glutamate signaling play a part in the pathophysiology of a number of mood disorders. To better understand the molecular underpinnings of depression and anxiety, agnostic to extant hypotheses, we screened a collection of mouse knockout lines through a battery of behavioral assays. One line, LG809, demonstrated antidepressive and anxiolytic phenotypes in a range of behavioral paradigms, including the Forced Swim Test, Tail Suspension Test, Open Field Test, Elevated Plus Maze, Zero Maze, and Novelty-induced Digging Test. This line carried an ablation of the Slc25a18 gene, which encodes the mitochondrial glutamate carrier, GC2. The two mitochondrial glutamate carriers, GC1 and GC2, function to shuttle glutamate into and out of the mitochondria, and are the only known mechanism to export net glutamate into the cytosol. We found that GC2 was expressed primarily in astrocytes rather than in neurons. Astrocytes synthesize glutamate de novo in their mitochondria and transport it into the cytosol, where it is converted to glutamine; glutamine is then shuttled to neurons, where it is converted back to glutamate. An inability of glia to transport mitochondrial glutamate into the cytosol would prevent its conversion to glutamine and ultimately result in reduced glutamate in neurons. Indeed, we found that glutamate and glutamine levels were decreased in cortical tissue of GC2 knockout animals. Since glutamate levels measured in tissue reflect mostly neuronal glutamate, these observations suggest a deficit in glutamine cycling from astrocytes to neurons. Taken together, our results point to a model in which astrocytes modulate glutamate levels available to neurons in a GC2-dependent manner, and such regulation affects anxiety and depressive behaviors. This model is consistent with the pathophysiology of major depressive disorder, in which both dysregulation of glutamatergic tone and glial pathology are observed. The antidepressive and anxiolytic phenotypes of the GC2 knockout animals suggest that pharmacological inhibition of GC2 may have therapeutic effects in depressive and anxiety disorders.
    Society for Neuroscience, New Orleans, LA; 10/2012

Publication Stats

4k Citations
479.11 Total Impact Points

Institutions

  • 2008–2015
    • Lexicon Pharmaceuticals
      The Woodlands, Texas, United States
  • 2010–2014
    • American College of Pathologists
      American Canyon, California, United States
  • 2013
    • Columbia University
      • Department of Pathology & Cell Biology
      New York, New York, United States
  • 2004
    • National Human Genome Research Institute
      Maryland, United States
    • Incyte Corporation
      Wilmington, Delaware, United States
  • 2001
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States
  • 1997
    • Fred Hutchinson Cancer Research Center
      • Division of Basic Sciences
      Seattle, Washington, United States
  • 1994
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • University of Pennsylvania
      • School of Veterinary Medicine
      Philadelphia, PA, United States
  • 1993
    • University of Washington Seattle
      • Department of Biochemistry
      Seattle, Washington, United States