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Dapagliflozin improves insulin resistance and glucose intolerance in a novel transgenic rat model of chronic glucose overproduction and glucose toxicity
Author(s) -
Joannides Christos N.,
Mangiafico Salvatore P.,
Waters Matthew F.,
Lamont Benjamin J.,
Andrikopoulos Sofianos
Publication year - 2017
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12923
Subject(s) - medicine , endocrinology , dapagliflozin , insulin resistance , insulin , glucose clamp technique , glut4 , adipocyte , glucose uptake , glucose transporter , adipose tissue , diabetes mellitus , pancreatic hormone , type 2 diabetes
Aim To determine whether the excretion of glucose improves insulin resistance, impaired insulin secretion or both. Materials and methods 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. Results 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 mm 2 fat area; P < .05) and adipocyte size was reduced (4631.8 ± 351.5 vs 3397.6 ± 229.4 µm 2 , 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. Conclusions 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.