title: Independent effects of circulating glucose, insulin and NEFA on cardiac triacylglycerol accumulation and myocardial insulin resistance in a swine model.
abstract: OBJECTIVE
  Cardiac steatosis and myocardial insulin resistance elevate the risk of cardiac complications in obesity and diabetes. We aimed to disentangle the effects of circulating glucose, insulin and NEFA on myocardial triacylglycerol (TG) content and myocardial glucose uptake.
  
  
  METHODS
  Twenty-two pigs were stratified according to four protocols: low NEFA + low insulin (nicotinic acid), high NEFA + low insulin (fasting) and high insulin + low NEFA ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia-euglycaemia). Positron emission tomography, [U-(13)C]palmitate enrichment techniques and tissue biopsies were used to assess myocardial metabolism. Heart rate and rate-pressure product (RPP) were monitored.
  
  
  RESULTS
  Myocardial glucose extraction was increased by NEFA suppression and was similar in the hyperinsulinaemia-hypergylcaemia, hyperinsulinaemia-euglycaemia and nicotinic acid groups. Hyperglycaemia enhanced myocardial glucose uptake due to a mass action. Myocardial TG content was greatest in the fasting group, whereas hyperinsulinaemia had a mild effect. Heart rate and RPP increased in hyperinsulinaemia-euglycaemia, in which cardiac glycogen content was reduced. Heart rate correlated with myocardial TG and glycogen content.
  
  
  CONCLUSIONS
  Elevated NEFA levels represent a powerful, self-sufficient promoter of cardiac TG accumulation and are a downregulator of myocardial glucose uptake, indicating that the focus of treatment should be to 'normalise' adipose tissue function to lower the risk of cardiac TG accumulation and myocardial insulin resistance. The observation that hyperinsulinaemia and nicotinic acid led to myocardial fuel deprivation provides a potential explanation for the cardiovascular outcomes reported in recent intensive glucose-lowering and NEFA-lowering clinical trials.
authors: Institute of Clinical Physiology, National Research Council (CNR), Via Moruzzi 1, 56124, Pisa, Italy.
authors: Maria Angela
authors: MA
authors: Guzzardi
authors: Leanne
authors: L
authors: Hodson
authors: Letizia
authors: L
authors: Guiducci
authors: Elena
authors: E
authors: Sanguinetti
authors: Pietro
authors: P
authors: Di Cecco
authors: Tiziana
authors: T
authors: Liistro
authors: Cristina
authors: C
authors: Vassalle
authors: Silvia
authors: S
authors: Pardini
authors: Lucia
authors: L
authors: Giorgetti
authors: Piero A
authors: PA
authors: Salvadori
authors: Silvia
authors: S
authors: Burchielli
authors: Patricia
authors: P
authors: Iozzo
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D007328:Insulin; D007333:Insulin Resistance / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D013552:Swine; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D014280:Triglycerides