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

Calum Forteath  ¹ , Heather J Merchant  ¹ , Cyril Kocherry  ¹ , Colin E Murdoch  ² , Jennifer Kerr  ¹ , Jennifer R Gallagher  ¹ , Mark L Evans  ³ , Bernard Thorens  ⁴ , Ulrik Pedersen-Bjergaard  ^{5   6} , Bastiaan E de Galan  ^{7   8   9} , Rory J McCrimmon  ¹⁰ , Alison D McNeilly  ¹¹ ; Hypo-RESOLVE Consortium

• Diabetologia. 2025 Nov 10. doi: 10.1007/s00125-025-06574-5. Online ahead of print.
• . 2025 Nov 10.
• doi: 10.1007/s00125-025-06574-5.

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.

The sleep-wake history contributes to rhythmic BMAL1 chromatin binding in the cerebral cortex but not in the live

Carlos Neves  ¹ , Charlotte N Hor  ¹ , Sonia Jimenez  ¹ , Paul Franken  ¹

Proc Natl Acad Sci U S A. 2025 Dec 2;122(48):e2515047122. doi: 10.1073/pnas.2515047122. Epub 2025 Nov 26.

• PMID: 41296730
• DOI: 10.1073/pnas.2515047122

Abstract

The timing and quality of sleep is regulated by circadian- and sleep-wake-driven processes. The core clock gene Bmal1 not only affects the circadian timing of sleep, but also the response to sleep deprivation (SD), which, in turn, causes long-term changes in cortical Bmal1 expression. We aimed at separating the circadian- and sleep-wake-driven contributions to BMAL1 binding to its target genes in the cerebral cortex by scheduling 6 SDs at 4 h intervals across the daily 12 h light/12 h dark cycle. We show that BMAL1 rhythmically bound its tissue-specific targets with tissue-specific dynamics, reaching peak binding 2 to 4 h later in the cortex than in the liver, while trough times did not differ. The SDs affected BMAL1 binding most significantly in the cortex, causing 80% of rhythmically bound regions to lose rhythmicity, suggesting BMAL1 binding has a prominent sleep-wake-driven component in this tissue. Analyses of the promoters of other core clock-genes indicate that BMAL1 binding to Bhlhe41 and Nr2d1 have a strong sleep-wake-driven component, while for Per2 two binding regions were identified one with circadian- and the other with sleep-wake-driven binding dynamics. Our results attest to a nonadditive interaction of time-of-day and time-spent-awake affecting the core molecular circadian circuitry. It further highlights that rhythms in gene expression in peripheral tissues are an emergent property of molecular interactions beyond that of the core molecular clock circuitry.

Gamete fusion triggers cytosolic functions and P-body recruitment of the RNA-binding protein Mei2 to drive fission yeast zygotic development

Ayokunle Araoyinbo ^{#  1} , Clàudia Salat-Canela ^{#  1} , Aleksandar Vještica  ²

Genes Dev. 2025 Nov 26. doi: 10.1101/gad.353201.125. Online ahead of print.

• PMID: 41298081
• DOI: 10.1101/gad.353201.125

Abstract

Compartmentalized regulation of RNAs is emerging as a key driver of developmental transitions, with RNA-binding proteins performing specialized functions in different subcellular compartments. The RNA-binding protein Mei2, which arrests mitotic proliferation and drives zygotic development in fission yeast, was shown to function in the nucleus to trigger meiotic divisions. Here, using compartment-restricted alleles, we report that Mei2 functions in the cytosol to arrest mitotic growth and initiate development. We found that Mei2 is a zygote-specific component of P-bodies that inhibits the translation of tethered mRNAs. Importantly, we show that P-bodies are necessary for Mei2-driven development. Phosphorylation of Mei2 by the inhibitory Pat1 kinase impedes P-body recruitment of both Mei2 and its target RNA. Finally, we establish that Mei2 recruitment to P-bodies and its cytosolic functions, including translational repression of tethered RNAs, depend on the RNA-binding domain of Mei2 that is dispensable for nuclear Mei2 roles. Collectively, our results dissect how distinct pools of an RNA-binding protein control developmental stages and implicate P-bodies as key regulators of gamete-to-zygote transition.

Evolution of taste processing shifts dietary preference

Enrico Bertolini  ^{1   2} , Daniel Münch ^{#  3   4} , Justine Pascual ^{#  1   2} , Noemi Sgammeglia  ² , Matteo Bruzzone  ² , Carlos Ribeiro  ³ , Thomas O Auer  ^{5   6   7}

Nature. 2025 Nov 26. doi: 10.1038/s41586-025-09766-6. Online ahead of print.

• PMID: 41299173
• DOI: 10.1038/s41586-025-09766-6

Abstract

Food choice is an important driver of speciation and invasion of novel ecological niches. However, we know little about the mechanisms leading to changes in dietary preference. Here we use three closely related species, Drosophila sechellia (Dsec), Drosophila simulans and Drosophila melanogaster, to study taste circuit¹ and food choice evolution. Dsec, a host specialist, feeds exclusively on a single fruit (Morinda citrifolia; noni), whereas the other two are generalists living on diverse diets². Using quantitative feeding assays, we recapitulate the preference for noni in Dsec and detect conserved sweet but altered bitter sensitivity by means of calcium imaging in peripheral taste neurons. Noni activates bitter-sensing neurons more strongly in Dsec than in the other two species owing to a small deletion in a single gustatory receptor. Using volumetric calcium imaging in the ventral brain³, we show that instead of peripheral physiology, species-specific processing of noni and sucrose signals in sensorimotor circuits recapitulates differences in dietary preference. Our data indicate that altered food choice may not be explained by peripheral receptor changes alone but rather by modifications in how sensory information is transformed into feeding motor commands.

The adiponectin agonist AdipoRon accelerates osteoporosis development in two different models and modulates adipocyte differentiation

Julia Halper  ¹ , Sarah Nicolas  ² , Federica Gilardi  ³ , Carine Winkler  ⁴ , Maria Materozzi  ⁵ , Mariano Schiffrin  ⁴ , Jean-Yves Jouzeau  ⁶ , Claudine Blin-Wakkach  ⁵ , Beatrice Desvergne  ⁴ , Joelle Chabry  ² , Didier F Pisani  ⁵ , David Moulin  ⁷

Bone. 2025 Dec:201:117628. doi: 10.1016/j.bone.2025.117628. Epub 2025 Sep 3.

• PMID: 40912669
• DOI: 10.1016/j.bone.2025.117628

Free article

Abstract

Osteoporosis is an increasing concern in the aging population worldwide, culminating in increased economic concerns and diminished quality of life. Similarly, disturbances of lipid metabolism and adipocytes accumulate more and more in western societies and need solutions. Adipocytes have recently attracted much interest in relation to their endocrine products, one of which is adiponectin, normally associated with beneficial effects on cardiovascular health, inflammation, and cancer. In this study, we have investigated the effect of AdipoRon, an adiponectin receptor agonist with reported anti-osteoclastic properties, on the development of osteoporosis in two different preclinical models. Contrasting to our initial hypothesis, AdipoRon treatment accelerated metabolic changes and bone loss in both models. However, AdipoRon rescued bone marrow adipocytes presence induced by glucocorticoids. Investigations on adipocyte differentiation revealed that AdipoRon potently changes adipocyte identity, by exerting opposite effects on adipocyte-gene induction depending on the time point and duration of stimulation. In conclusion, adipocyte-derived Adiponectin deserves further investigation as an autocrine mediator in musculoskeletal research.

Optimization of Gastruloid Pre-culture Conditions for Reproducible Germ Layer Composition

Marloes Blotenburg  ¹ , Beril Esin  ² , Shruthi Buddharaju  ² , Peter Zeller  ³

Methods Mol Biol. 2025 Oct 11. doi: 10.1007/7651_2025_667. Online ahead of print.

• PMID: 41071232
• DOI: 10.1007/7651_2025_667

Abstract

Gastruloids are an in vitro model that mimics key aspects of gastrulation and can be used to study implantation-stage embryonic development. Even though current protocols have contributed significantly to our understanding of developmental biology, further improvements in terms of consistency and reproducibility are still required. In this chapter, we present a detailed pre-culture protocol optimized for the generation of gastruloids from 129S1/SvImJ/ C57BL/6 mouse embryonic stem cells (mESCs). Additionally, we provide information on the steps of the protocol open to optimization and present a workflow for selecting optimal conditions and evaluating the gastruloid formation outcome when using different cell lines. Overall, this workflow facilitates a step-by-step approach toward generating gastruloids from any cell line in a highly reproducible manner by optimizing the mESC pre-culture conditions.