Glycaemic Variability Identified as a Critical Determinant of Myocyte Dysfunction and Risk for Myocardial Injury in Preclinical Models of Diabetes

Abstract

This study evaluates mechanisms of glycaemic stress underpinning cardiovascular risk in diabetes. Using in vitro and in vivo models, we demonstrate that glycaemic variability rather than hyperglycaemia alone is a dominant risk factor for heart muscle dysfunction and myocardial injury sensitivity in diabetes. These findings provide new preclinical models for mechanistic and drug discovery studies and inform strategies for managing cardiovascular outcomes in patients with diabetes.

Note:
Funding Information: This work has been supported by grant funding from the NHMRC (MRFCDDM000033 to NP and KS and 2007625 to NP as well as 2007919 and 1159959 to KRS), the Ian Potter Foundation (31111380 to NP), and the National Heart Foundation of Australia (106721 to NP).

Declaration of Interests: NJP is co-founder and equity holder in Infensa Bioscience, developing therapeutics for ischaemic heart disease.

No other conflicts declared.

Ethical Approval Statement: All human pluripotent stem cell studies were carried out in accordance with consent from The University of Queensland’s Institutional Human Research Ethics approval (HREC#: 2015001434). Human serum sample collection and iPSC modelling was approved by Mater Research Ethics Committee 206 (HREC/MML/55151 V2) and the University of Queensland Ethics Committee (2019/HE002522).

All animal experiments were approved by the University of Queensland Animal Ethics Committee (2022/AE000203).

Keywords: Glycaemic Variability, Myocardial Infarction, Ischaemia-Reperfusion Injury, Human Induced Pluripotent Stem Cell, Cardiomyocytes, Maturation, Contractility, metabolism, Cardiac Cell Death, Mortality, UK Biobank Cohort