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

Calum Forteath; Heather J Merchant; Cyril Kocherry; Colin E Murdoch; Jennifer Kerr; Jennifer R Gallagher; Mark L Evans; Bernard Thorens; Ulrik Pedersen-Bjergaard; Bastiaan E de Galan; Rory J McCrimmon; Alison D McNeilly; Hypo‐RESOLVE Consortium

doi:10.1007/s00125-025-06574-5

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

Calum Forteath, Heather J Merchant, Cyril Kocherry, Colin E Murdoch, Jennifer Kerr, Jennifer R Gallagher, Mark L Evans, Bernard Thorens, Ulrik Pedersen-Bjergaard, Bastiaan E de Galan, Rory J McCrimmon^*, Alison D McNeilly^*, Hypo‐RESOLVE Consortium

^*Corresponding author for this work

Department of Endocrinology and Nephrology

Abstract

AIMS/HYPOTHESIS: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS/INTERPRETATION: 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.

DATA AVAILABILITY: Transcriptomic data are available as supplementary data.

Original language	English
Journal	Diabetologia
Volume	69
Issue number	2
Pages (from-to)	515-528
Number of pages	14
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-025-06574-5
Publication status	Published - Feb 2026

Keywords

Animals
Diabetes Mellitus, Experimental/complications
Diabetes Mellitus, Type 1/complications
Diabetic Cardiomyopathies/etiology
Disease Models, Animal
Hypoglycemia/complications
Male
Mice
Mice, Inbred C57BL
Hypoglycaemia
Cardiovascular disease
Left ventricle
Dilated cardiomyopathy
Type 1 diabetes
Microvascular dysfunction

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Forteath, C., Merchant, H. J., Kocherry, C., Murdoch, C. E., Kerr, J., Gallagher, J. R., Evans, M. L., Thorens, B., Pedersen-Bjergaard, U., de Galan, B. E., McCrimmon, R. J., McNeilly, A. D., & Hypo‐RESOLVE Consortium (2026). Recurrent hypoglycaemia promotes cardiomyopathy and cardiac vulnerability in a rodent model of type 1 diabetes. Diabetologia, 69(2), 515-528. https://doi.org/10.1007/s00125-025-06574-5

Forteath, C, Merchant, HJ, Kocherry, C, Murdoch, CE, Kerr, J, Gallagher, JR, Evans, ML, Thorens, B, Pedersen-Bjergaard, U, de Galan, BE, McCrimmon, RJ, McNeilly, AD & Hypo‐RESOLVE Consortium 2026, 'Recurrent hypoglycaemia promotes cardiomyopathy and cardiac vulnerability in a rodent model of type 1 diabetes', Diabetologia, vol. 69, no. 2, pp. 515-528. https://doi.org/10.1007/s00125-025-06574-5

@article{4127eb184fe54392b4ccf0e4d3d37a6a,

title = "Recurrent hypoglycaemia promotes cardiomyopathy and cardiac vulnerability in a rodent model of type 1 diabetes",

abstract = "AIMS/HYPOTHESIS: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS/INTERPRETATION: 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.DATA AVAILABILITY: Transcriptomic data are available as supplementary data.",

keywords = "Animals, Diabetes Mellitus, Experimental/complications, Diabetes Mellitus, Type 1/complications, Diabetic Cardiomyopathies/etiology, Disease Models, Animal, Hypoglycemia/complications, Male, Mice, Mice, Inbred C57BL, Hypoglycaemia, Cardiovascular disease, Left ventricle, Dilated cardiomyopathy, Type 1 diabetes, Microvascular dysfunction",

author = "Calum Forteath and Merchant, \{Heather J\} and Cyril Kocherry and Murdoch, \{Colin E\} and Jennifer Kerr and Gallagher, \{Jennifer R\} and Evans, \{Mark L\} and Bernard Thorens and Ulrik Pedersen-Bjergaard and \{de Galan\}, \{Bastiaan E\} and McCrimmon, \{Rory J\} and McNeilly, \{Alison D\} and \{Hypo‐RESOLVE Consortium\}",

note = "{\textcopyright} 2025. The Author(s).",

year = "2026",

month = feb,

doi = "10.1007/s00125-025-06574-5",

language = "English",

volume = "69",

pages = "515--528",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "2",

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TY - JOUR

T1 - Recurrent hypoglycaemia promotes cardiomyopathy and cardiac vulnerability in a rodent model of type 1 diabetes

AU - Forteath, Calum

AU - Merchant, Heather J

AU - Kocherry, Cyril

AU - Murdoch, Colin E

AU - Kerr, Jennifer

AU - Gallagher, Jennifer R

AU - Evans, Mark L

AU - Thorens, Bernard

AU - Pedersen-Bjergaard, Ulrik

AU - de Galan, Bastiaan E

AU - McCrimmon, Rory J

AU - McNeilly, Alison D

AU - Hypo‐RESOLVE Consortium

PY - 2026/2

Y1 - 2026/2

N2 - AIMS/HYPOTHESIS: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS/INTERPRETATION: 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.DATA AVAILABILITY: Transcriptomic data are available as supplementary data.

AB - AIMS/HYPOTHESIS: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS/INTERPRETATION: 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.DATA AVAILABILITY: Transcriptomic data are available as supplementary data.

KW - Animals

KW - Diabetes Mellitus, Experimental/complications

KW - Diabetes Mellitus, Type 1/complications

KW - Diabetic Cardiomyopathies/etiology

KW - Disease Models, Animal

KW - Hypoglycemia/complications

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Hypoglycaemia

KW - Cardiovascular disease

KW - Left ventricle

KW - Dilated cardiomyopathy

KW - Type 1 diabetes

KW - Microvascular dysfunction

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U2 - 10.1007/s00125-025-06574-5

DO - 10.1007/s00125-025-06574-5

M3 - Journal article

C2 - 41212210

SN - 0012-186X

VL - 69

SP - 515

EP - 528

JO - Diabetologia

JF - Diabetologia

IS - 2

ER -

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

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