Independent effects of circulating glucose, insulin and NEFA on cardiac triacylglycerol accumulation and myocardial insulin resistance in a swine model

Abstract

Aims/hypothesis 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 hyperinsulinaemiahypergylcaemia, 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/interpretation 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 glucoselowering and NEFA-lowering clinical trials.

Pericardial- Rather than Intramyocardial Fat Is Independently Associated with Left Ventricular Systolic Heart Function in Metabolically Healthy Humans

“…Our results indicate that even in metabolically healthy subjects cardiac fat depots affect heart function, without being confounded by elevated circulating plasma substrate concentrations. This is of special interest, since the influence of circulating substrates or underlying metabolic disease on cardiac lipid stores is well established in animal models [ 25 ] as well as in humans [ 12 – 14 ]. Therefore we decided to include only metabolically healthy volunteers, to primarily elucidate the role of different cardiac fat depots as such.…”

“…Of note, the lack of a significant correlation between MYCL and parameters of LV heart function might most likely be explained by the low amount of ectopic lipids in a metabolically healthy lean population. MYCL develops on the background of hyperglycemia and hyperinsulinemia [ 13 ] combined with increased FFA concentrations [ 25 ], a metabolic condition that is not present in insulin sensitive normal weight subjects. On the other hand, PERI extends over a much broader range compared to MYCL in healthy volunteers, wherefore associations can be detected earlier.…”

Biomarkers and prediction of myocardial triglyceride content in non-diabetic men

“…In line with previous reports [2,3] we showed that hyperglycemia was linked to cardiac steatosis. Interestingly, data from recent animal study [25] indicate that hyperglycemia increases myocardial glucose uptake by glucose mass action independently of insulin. Notably, in a recent study including subjects with and without the metabolic syndrome, myocardial steatosis was unrelated to antilipolytic and glucoregulatory actions of insulin [26].…”

Seven-Day Caloric and Saturated Fat Restriction Increases Myocardial Dietary Fatty Acid Partitioning in Impaired Glucose-Tolerant Subjects

“…In subjects with type 2 diabetes, a 3-day very lowcalorie diet (471 kcal/day, but with SFA .13%) induced an increase in myocardial TG levels and reduced diastolic function, but with no change in LVEF measured by MRI (41). Fatty acid uptake by the heart is essential for intramyocellular TG repletion and the maintenance of cardiac function (42,43). It is therefore premature to postulate that enhanced cardiac DFA partitioning can be mechanistically linked to a reduction in LVEF in the current study.…”