Participants with diabetes have less augmentation in cardiac function and energetics in response to increased supply of fatty acid
Authors: Green P , Watson W.D , Herring N , Neubauer S , Rider O.J 
Published: November 2020

Abstract

Introduction
The Phosphocreatine (PCR)/ATP ratio is an established indicator of cardiac energetic status. Measurement of the Creatine Kinase pseudo-first order rate constant (CKkf) provides a more sensitive measure of cardiac energetics, and allows calculation of ATP delivery rate through the creatine kinase shuttle (CK flux). The normal heart is metabolically flexible, and so should maintain energetics and cardiac output regardless of substrate available (fat or glucose). This flexibility may be impaired in diabetes mellitus (DM), which may contribute to diabetic cardiomyopathy. It is unknown to what extent flexibility can be influenced by artificially altering the substrate available for metabolism.

Purpose
To compare cardiac function and energetics between diabetic and non-diabetic participants clamped on either fatty acid (FA) or glucose metabolism.

Methods
Participants with non-insulin dependent diabetic mellitus (NIDDM) and without DM (NoDM) were recruited and received intravenous infusions of either 20% fat emulsion (60ml/hr) or insulin/dextrose 20% (GLUC, variable rate) at 2 visits at least 1 week apart, before undergoing multi-parametric cardiac MRI at 3 Tesla. Cardiac volume and function, PCR/ATP ratio and CKkf (s–1) were assessed. CK flux was calculated as CKkf x PCR/ATP x 5.7 μmol (g wet weight)–1 (assumed ATP concentration).

Results
Ten NoDM participants (3 male, age 41.3±19.7 years) and 11 NIDDM participants (10 male, age 59.2±6.8 years) were recruited. Left ventricular ejection fraction (LVEF) was higher on FA in both groups (NoDM FA 63.0±3.4%; GLUC 58.1±3.8%, p=0.01; NIDDM FA 64.3±4.2%; GLUC 61.9±5.0%, p=0.05) but the increase in absolute terms was less in the NIDDM group (2.4% vs 4.9%). NoDM participants had a significantly higher CKkf on FA than GLUC (FA 0.31±0.10 s–1; GLUC 0.21±0.09 s–1, p=0.02), which did not occur in NIDDM participants (FA 0.15±0.07 s–1; GLUC 0.18±0.09 s–1, p=0.28). This was associated with a trend towards an increase in CK flux in the NoDM group which did not reach statistical significance (FA 3.50±0.99 μmol (g wet weight)–1 s–1; GLUC 2.61±1.01 μmol (g wet weight)–1 s–1, p=0.06; NIDDM FA 1.60±0.79 μmol (g wet weight)–1 s–1; GLUC 1.85±0.90 μmol (g wet weight)–1 s–1, p=0.32). There was no difference in PCR/ATP between infusions in either group (NoDM: FA 1.98±0.34; GLUC 2.05±0.30, p=0.57; NIDDM: FA 1.84±0.36; GLUC 1.85±0.24, p=0.93).

Conclusion
Increasing FA supply results in an increase in LVEF in participants with and without diabetes, but this is lower in absolute terms in diabetic participants. In non-diabetic participants this is associated with an increase in CKkf and a trend towards increased CK flux, but not in participants with NIDDM. This may reflect maximal baseline FA metabolism in participants with NIDDM and so impaired flexibility and an inability for further upregulation.
LVEF and CKkf

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): British Heart Foundation