Recurrent hypoglycaemia promotes cardiomyopathy and cardiac vulnerability in a rodent model of type 1 diabetes

TL;DR

Recurrent low blood sugar episodes in type 1 diabetes worsen heart function and structure in mice, highlighting a new risk factor for heart disease.

Contribution

This study is the first to show in vivo how repeated hypoglycaemia worsens diabetic heart disease through molecular and physiological changes.

Findings

Recurrent hypoglycaemia worsens microvascular dysfunction in type 1 diabetic mice.

Chronic hypoglycaemia leads to early dilated cardiomyopathy in type 1 diabetic mice.

Hypoglycaemia increases cardiac vulnerability and alters gene expression related to heart function.

Abstract

CVD remains the leading cause of mortality in individuals with type 1 diabetes over the age of 40 years. Although intensive insulin therapy lowers chronic hyperglycaemia and improves cardiovascular outcomes, it also increases the frequency of hypoglycaemic episodes, an emerging but poorly understood contributor to CVD risk. The mechanisms by which recurrent hypoglycaemia exacerbates cardiovascular pathology in type 1 diabetes are unknown.

Using a C57BL/J streptozocin-induced male mouse model of type 1 diabetes, combined with detailed physiological and molecular assessments, we investigated the impact of recurrent hypoglycaemia (<3.0 mmol/l) on cardiovascular structure and function using laser Doppler imaging with iontophoresis and ultrasound imaging.

Type 1 diabetes induces significant microvascular endothelial dysfunction, which is worsened by recurrent hypoglycaemia. Chronic exposure to hypoglycaemia (60 episodes over 20 weeks) resulted in compensatory shifts in cardiac haemodynamics, which in type 1 diabetic mice but not non-diabetic mice resulted in early dilated cardiomyopathy. In both type 1 diabetic and non-diabetic mice, recurrent hypoglycaemia resulted in impaired systolic function during a subsequent hypoglycaemic challenge, indicating increased cardiac vulnerability despite any compensatory changes. Transcriptomic profiling of left ventricular tissue revealed that recurrent hypoglycaemia induces distinct gene expression changes involving ion homeostasis, repolarisation dynamics and microvascular signalling—molecular alterations characteristic of early diabetic cardiomyopathy.

These findings provide the first in vivo evidence that recurrent hypoglycaemia synergises with hyperglycaemia to accelerate microvascular dysfunction and adverse cardiac remodelling in type 1 diabetes. This work identifies a novel mechanistic link between hypoglycaemia and diabetic heart disease, underscoring the need for therapeutic strategies that mitigate glycaemic variability without increasing the hypoglycaemic burden.

Transcriptomic data are available as supplementary data.

The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-025-06574-5.

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