Short-Term Hyperinsulinemia and Hyperglycemia Increase Myocardial Lipid Content in Normal Subjects

Abstract

Increased myocardial lipid content (MYCL) recently has been linked to the development of cardiomyopathy in diabetes. In contrast to steatosis in skeletal muscle and liver, previous investigations could not confirm a link between MYCL and insulin resistance. Thus, we hypothesized that cardiac steatosis might develop against the background of the metabolic environment typical for prediabetes and early type 2 diabetes: combined hyperglycemia and hyperinsulinemia. Therefore, we aimed to prove the principle that acute hyperglycemia (during a 6-h clamp) affects MYCL and function (assessed by 1H magnetic resonance spectroscopy and imaging) in healthy subjects (female subjects: n = 8, male subjects: n = 10; aged 28 ± 5 years; BMI 22.4 ± 2.6 kg/m2). Combined hyperglycemia (202.0 ± 10.6 mg/dL) and hyperinsulinemia (110.6 ± 59.0 μU/mL) were, despite insulin-mediated suppression of free fatty acids, associated with a 34.4% increase in MYCL (baseline: 0.20 ± 0.17%, clamp: 0.26 ± 0.22% of water signal; P = 0.0009), which was positively correlated with the area under the curve of insulin (R = 0.59, P = 0.009) and C-peptide (R = 0.81, P < 0.0001) during the clamp. Furthermore, an increase in ejection fraction (P < 0.0001) and a decrease in end-systolic volume (P = 0.0002) were observed, which also were correlated with hyperinsulinemia. Based on our findings, we conclude that combined hyperglycemia and hyperinsulinemia induce short-term myocardial lipid accumulation and alterations in myocardial function in normal subjects, indicating that these alterations might be directly responsible for cardiac steatosis in metabolic diseases.

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

“…Similarly, in fasting conditions, glycogen depots tended to be lower and RPP was higher. In line with our findings, elevations in HR and RPP have been observed in patients with type 2 diabetes or those fed a high-fat diet [1,16] while no change in haemodynamic variables has been observed following an acute exposure to isolated hyperglycaemia [38] or combined hyperinsulinaemiahyperglycaemia [34].…”

“…Our results indicate that exposure to physiologically elevated NEFA levels may be a key mechanism in promoting TG accumulation in the myocardium, which appears to have a dynamic lipid depot that is responsive to acute metabolic changes [13,34]. Prolonged fasting (~20 h) was associated with a rise in plasma NEFA concentrations and appearance rates.…”

“…Hammer et al [38] reported that 24 h of hyperglycaemia achieved by partial insulin deprivation in patients with type 1 diabetes did not affect the myocardial TG content. In contrast, Winhofer et al [34] demonstrated that combined hyperglycaemia and hyperinsulinaemia induced myocardial lipid accumulation in normal individuals, independent of insulin resistance and while plasma NEFA were suppressed; the authors suggested that insulinaemia rather than glycaemia was responsible. Our data extend this line of evidence by separating the effect of hyperglycaemia from that of hyperinsulinaemia and comparing these with control conditions.…”

Failing Heart of Patients With Type 2 Diabetes Mellitus Can Adapt to Extreme Short-term Increases in Circulating Lipids and Does Not Display Features of Acute Myocardial Lipotoxicity

“…This indicates that MyLC 24 than that observed in previous studies of non-HF patients, and it is in accordance with findings of a high myocardial FFA uptake in case of impaired glucose tolerance. 35 FFA, triglyceride levels, and MyLC correlated positively.…”

“…Winhofer et al 24 report that hyperglycemic clamp and hyperinsulinemia cause an increase in MyLC in normal subjects. We found that MyLC was lowest during hyperinsulinemic-euglycemic clamping (low FFA).…”