Strengths and Weaknesses

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Strengths and Weaknesses

  1. 1. Strengths and Weaknesses Lisa Joseph Sophie Harris
  2. 2. Strengths <ul><li>Original study </li></ul><ul><li>Clear objectives which they achieved </li></ul><ul><li>Used a wide range of techniques </li></ul><ul><ul><li>Used more than 1 method to show same result </li></ul></ul><ul><ul><li>Results reproducible (n=3/4) </li></ul></ul>
  3. 3. <ul><li>Good statistical significance in majority of results (p<0.01) </li></ul><ul><li>Valuable research </li></ul><ul><ul><li>Potential to develop new therapeutic drugs </li></ul></ul>
  4. 4. Weaknesses <ul><li>Statistically significant results often achieved at glucose concentrations higher than normal </li></ul><ul><li>A lot of data not shown </li></ul><ul><li>Need to analyse direct interactions between FFA’S and GPR40. </li></ul>
  5. 5. Points for Discussion <ul><li>Are the results reliable/reproducible? </li></ul><ul><ul><li>2 other separate studies (Briscoe CP et al [2003], Kotarsky K et al [2003]) </li></ul></ul><ul><ul><li>Different cells, different concentrations </li></ul></ul><ul><ul><li>Disparate EC 50 values </li></ul></ul><ul><li>Are the conditions physiological? </li></ul><ul><li>Is the research valuable? </li></ul><ul><ul><li>Drugs already exist that may target this pathway (Kotarsky et al [2003]) </li></ul></ul>
  6. 6. Result reliability/reproducibility? Itoh Y et al CHO-hGPR40 <300µM Briscoe CP et al HEK293-hGPR40 >1µM Kotarsky K et al HFF11-R10 ‘ appropriate’ Capric acid (C6) 43±2.2 4.85±0.06 12.6±0.4 γ -linolenic acid 4.6±1.6 5.05±0.12 28.5±2.6 Oleic acid 2.0±0.3 4.39 123.1±12
  7. 7. Physiological conditions? <ul><li>Murine pancreatic β -cell lines – why the differences in GPR40 expression? </li></ul><ul><li>FFA concentrations and albumin </li></ul><ul><ul><li>Concentration unbound 1-10nM </li></ul></ul><ul><ul><li>EC 50 for activation higher than this level </li></ul></ul><ul><ul><li>?Local levels higher than plasma levels </li></ul></ul><ul><li>Glucose concentration </li></ul>
  8. 8. Intracellular metabolism or GPR40? Poitout 2003
  9. 9. Is it valuable? <ul><li>Kotarsky K et al: </li></ul><ul><ul><li>Thiazolidinedione drugs/anti-obesity drug(e.g. rozaglitazone) strongly activate this receptor </li></ul></ul><ul><ul><li>Mechanism of action? </li></ul></ul><ul><ul><li>Remaining therapeutic potential? </li></ul></ul>
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