title: Dapagliflozin improves insulin resistance and glucose intolerance in a novel transgenic rat model of chronic glucose overproduction and glucose toxicity.
abstract: To determine whether the excretion of glucose improves insulin resistance, impaired insulin secretion or both.
  
  
  
  Appropriate methods were used to assess insulin sensitivity (euglycaemic-hyperinsulinaemic clamp) and insulin secretion (hyperglycaemic clamp) in insulin-resistant and hyperglycaemic phosphoenolpyruvate carboxykinase (PEPCK) transgenic rats after treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin.
  
  
  
  In 14-week-old rats with hyperglycaemia, insulin resistance and glucose intolerance, 6 weeks of dapagliflozin treatment resulted in lower weight gain, plasma glucose and insulin levels, and improved glucose tolerance, associated with enhanced insulin sensitivity (rate of glucose disappearance: 51.6 ± 2.3 vs 110.6 ± 3.9 µmol/min/kg; P < .005) and glucose uptake in muscle (0.9 ± 0.1 vs 1.7 ± 0.3 µmol/min/100 g; P < .05) and fat (0.23 ± 0.04 vs 0.55 ± 0.10 µmol/min/100 g, P < .05). Additionally, adipose tissue GLUT4 protein levels were increased (0.78 ± 0.05 vs 1.20 ± 0.09 arbitrary units; P < .05), adipocyte count was higher (221.4 ± 17.7 vs 302.3 ± 21.7 per mm2fat area; P < .05) and adipocyte size was reduced (4631.8 ± 351.5 vs 3397.6 ± 229.4 µm2, P < .05). There was no improvement, however, in insulin secretion. To determine whether earlier intervention is necessary, 5-week-old PEPCK transgenic rats were treated with dapagliflozin for 9 weeks and insulin secretion assessed. Dapagliflozin resulted in improved plasma glucose and insulin levels, and lower weight gain but, again, insulin secretion was not improved.
  
  
  
  In this transgenic model of low-grade chronic hyperglycaemia, SGLT2 inhibitor treatment resulted in reduced blood glucose and insulin levels and enhanced glucose tolerance, associated with improved muscle and fat insulin resistance but not improved insulin secretory function.
authors.affiliation: Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Christos N
authors.initials: CN
authors.lastname: Joannides
authors.affiliation: Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Salvatore P
authors.initials: SP
authors.lastname: Mangiafico
authors.affiliation: Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Waters
authors.affiliation: Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Lamont
authors.affiliation: Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria, Australia.
authors.forename: Sofianos
authors.identifier: 0000-0002-8932-8592
authors.initials: S
authors.lastname: Andrikopoulos
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D048429:Cell Size / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051275:Glucose Transporter Type 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000517:prevention & control*; D006946:Hyperinsulinism / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D055647:Rats, Transgenic; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001559:Benzhydryl Compounds; D051275:Glucose Transporter Type 4; D005960:Glucosides; D007004:Hypoglycemic Agents; D007328:Insulin; D049990:Membrane Transport Modulators; C495694:Slc2a4 protein, rat; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C529054:dapagliflozin; D010729:Phosphoenolpyruvate Carboxykinase (GTP)
keywords: SGLT2 inhibitor; antidiabetic drug; dapagliflozin; glucose metabolism; insulin resistance; insulin secretion