title: Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus.
abstract: BACKGROUND
  The stepwise hyperglycemic clamp procedure (SHCP) is the gold standard for measuring the renal threshold for glucose excretion (RT(G)), but its use is limited to small studies in specialized laboratories.
  
  
  OBJECTIVE
  The objective of the study was to validate a new method for determining RT(G) using data obtained during a mixed-meal tolerance test (MMTT) in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  This was an open-label study with 2 sequential parts.
  
  
  METHODS
  The study was performed at a single center in Germany.
  
  
  METHODS
  Twenty-eight subjects with T2DM were studied.
  
  
  METHODS
  No treatment intervention was given in part 1. In part 2, subjects were treated with canagliflozin 100 mg/d for 8 days. In each part, subjects underwent an MMTT and a 5-step SHCP on consecutive days.
  
  
  METHODS
  For both methods, RT(G) was estimated using measured blood glucose (BG) and urinary glucose excretion (UGE); estimated glomerular filtration rates were also used to determine RT(G) during the MMTT. The methods were compared using the concordance correlation coefficient and geometric mean ratios.
  
  
  RESULTS
  In untreated and canagliflozin-treated subjects, the relationship between UGE rate and BG was well described by a threshold relationship. Good agreement was obtained between the MMTT-based and SHCP-derived RT(G) values. The concordance correlation coefficient (for all subjects) was 0.94; geometric mean ratios (90% confidence intervals) for RT(G) values (MMTT/SHCP) were 0.93 (0.89-0.96) in untreated subjects and 1.03 (0.78-1.37) in canagliflozin-treated subjects. Study procedures and treatments were generally well tolerated in untreated and canagliflozin-treated subjects.
  
  
  CONCLUSIONS
  In both untreated and canagliflozin-treated subjects with T2DM, RT(G) can be accurately estimated from measured BG, UGE, and estimated glomerular filtration rates using an MMTT-based method.
authors.affiliation: Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. DPolido1@its.jnj.com
authors.forename: David
authors.initials: D
authors.lastname: Polidori
authors.forename: Sue
authors.initials: S
authors.lastname: Sha
authors.forename: Atalanta
authors.initials: A
authors.lastname: Ghosh
authors.forename: Leona
authors.initials: L
authors.lastname: Plum-Mörschel
authors.forename: Tim
authors.initials: T
authors.lastname: Heise
authors.forename: Paul
authors.initials: P
authors.lastname: Rothenberg
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use*; D006029:Glycosuria / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D049990:Membrane Transport Modulators / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D050177:Overweight / Q000150:complications; D019518:Postprandial Period; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D049990:Membrane Transport Modulators; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin