ABSTRACT
BACKGROUND: Nutritional agents have modest efficacy in reducing weight and blood glucose in animal models and humans, but combinations are less well characterized. GSK2890457 (GSK457) is a combination of 4 nutritional agents, discovered by the systematic assessment of 16 potential components using the diet-induced obese mouse model, which was subsequently evaluated in a human study. NONCLINICAL RESULTS: In the diet-induced obese mouse model, GSK457 (15% w/w in chow) given with a long-acting glucagon-like peptide -1 receptor agonist, exendin-4 AlbudAb, produced weight loss of 30.8% after 28 days of treatment. In db/db mice, a model of diabetes, GSK457 (10% w/w) combined with the exendin-4 AlbudAb reduced glucose by 217 mg/dL and HbA1c by 1.2% after 14 days. CLINICAL RESULTS: GSK457 was evaluated in a 6 week randomized, placebo-controlled study that enrolled healthy subjects and subjects with type 2 diabetes to investigate changes in weight and glucose. In healthy subjects, GSK457 well tolerated when titrated up to 40 g/day, and it reduced systemic exposure of metformin by ~ 30%. In subjects with diabetes taking liraglutide 1.8 mg/day, GSK457 did not reduce weight, but it slightly decreased mean glucose by 0.356 mmol/L (95% CI: -1.409, 0.698) and HbAlc by 0.065% (95% CI: -0.495, 0.365), compared to placebo. In subjects with diabetes taking metformin, weight increased in the GSK457-treated group [adjusted mean % increase from baseline: 1.26% (95% CI: -0.24, 2.75)], and mean glucose and HbA1c were decreased slightly compared to placebo [adjusted mean glucose change from baseline: -1.22 mmol/L (95% CI: -2.45, 0.01); adjusted mean HbA1c change from baseline: -0.219% (95% CI: -0.910, 0.472)]. CONCLUSIONS: Our data demonstrate remarkable effects of GSK457 in rodent models of obesity and diabetes, but a marked lack of translation to humans. Caution should be exercised with nutritional agents when predicting human efficacy from rodent models of obesity and diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01725126.
Subject(s)
Biological Factors/pharmacology , Blood Glucose/drug effects , Body Weight/drug effects , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/physiopathology , Adolescent , Adult , Aged , Animals , Diabetes Mellitus, Type 2/metabolism , Female , Glucagon-Like Peptide 1/metabolism , Healthy Volunteers , Humans , Hypoglycemic Agents/pharmacology , Liraglutide/pharmacology , Male , Metformin/pharmacology , Mice , Mice, Inbred C57BL , Middle Aged , Weight Loss/drug effects , Young AdultABSTRACT
The gastrointestinal tract microbiome has been suggested as a potential therapeutic target for metabolic diseases such as obesity and Type 2 diabetes mellitus (T2DM). However, the relationship between changes in microbial communities and metabolic disease-phenotypes are still poorly understood. In this study, we used antibiotics with markedly different antibacterial spectra to modulate the gut microbiome in a diet-induced obesity mouse model and then measured relevant biochemical, hormonal and phenotypic biomarkers of obesity and T2DM. Mice fed a high-fat diet were treated with either ceftazidime (a primarily anti-Gram negative bacteria antibiotic) or vancomycin (mainly anti-Gram positive bacteria activity) in an escalating three-dose regimen. We also dosed animals with a well-known prebiotic weight-loss supplement, 10% oligofructose saccharide (10% OFS). Vancomycin treated mice showed little weight change and no improvement in glycemic control while ceftazidime and 10% OFS treatments induced significant weight loss. However, only ceftazidime showed significant, dose dependent improvement in key metabolic variables including glucose, insulin, protein tyrosine tyrosine (PYY) and glucagon-like peptide-1 (GLP-1). Subsequently, we confirmed the positive hyperglycemic control effects of ceftazidime in the Zucker diabetic fatty (ZDF) rat model. Metagenomic DNA sequencing of bacterial 16S rRNA gene regions V1-V3 showed that the microbiomes of ceftazidime dosed mice and rats were enriched for the phylum Firmicutes while 10% OFS treated mice had a greater abundance of Bacteroidetes. We show that specific changes in microbial community composition are associated with obesity and glycemic control phenotypes. More broadly, our study suggests that in vivo modulation of the microbiome warrants further investigation as a potential therapeutic strategy for metabolic diseases.
Subject(s)
Anti-Bacterial Agents/pharmacology , Diabetes Mellitus, Type 2/microbiology , Gastrointestinal Microbiome/drug effects , Obesity/microbiology , Animals , Ceftazidime/pharmacology , Diet/adverse effects , Disease Models, Animal , Male , Mice , Obesity/etiology , Phenotype , Prebiotics , RatsABSTRACT
This report explores aspects of developing obesity in two captive populations of common marmosets (Callithrix jacchus), a small primate with a short lifespan that may be of value in modeling chronic aspects of obesity acquisition and its lifetime effects. Two populations were examined. In study 1, body composition, lipid parameters, and glucose metabolic parameters were measured in a population of 64 adult animals. Animals classified as obese (>80th percentile relative fat based on sex) displayed both dyslipidemia (higher triglyceride and very low-density lipoprotein (VLDL)) and altered glucose metabolism (higher fasting glucose and HbA(1c)). Using operational definitions of atypical values for factors associated with metabolic syndrome in humans, five subjects (7.8%) had at least three atypical factors and five others had two atypical factors. A previously unreported finding in these normally sexually monomorphic primates was higher body weight, fat weights, and percent fat in females compared to males. In a second study, longitudinal weight data for a larger population (n = 210) were analyzed to evaluate the development of high weight animals. Differences in weights for animals that would exceed the 90th percentile in early adulthood were evident from infancy, with a 15% difference in weight between future-large weight vs. their future-normal weight litter mates as early as 4-6 months of age. The marmoset, therefore, demonstrates similar suites of obesity-related alterations to those seen in other primates, including humans, suggesting that this species is worthy of consideration for obesity studies in which its fast maturity, high fertility, relatively short lifespan, and small size may be of advantage.
Subject(s)
Obesity/diagnosis , Obesity/physiopathology , Animals , Body Composition , Body Weight , Callithrix , Female , Glucose/metabolism , Lipid Metabolism , Lipids/chemistry , Lipoproteins, VLDL/metabolism , Longitudinal Studies , Male , Models, Biological , Obesity/metabolism , Phenotype , Time FactorsABSTRACT
The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Aniline Compounds/chemistry , Ethanolamine/chemistry , Ethanolamine/pharmacology , Receptors, Adrenergic, beta-3/metabolism , Animals , Blood Glucose/metabolism , Cell Line , Cricetinae , Cyclic AMP/metabolism , Dogs , Ethanolamine/chemical synthesis , Glycosylation/drug effects , Hemoglobins/metabolism , Humans , Male , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3), beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.