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Bridging the Gap Between Diabetes and Stroke in Search of High Clinical Relevance Therapeutic Targets

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Abstract

Diabetes affects more than 425 million people worldwide, a scale approaching pandemic proportion. Diabetes represents a major risk factor for stroke, and therefore is actively addressed for stroke prevention. However, how diabetes affects stroke severity has not yet been extensively considered, which is surprising given the evident but understudied common mechanistic features of both pathologies. The increase in number of diabetic people, incidence of stroke in the presence of this specific risk factor, and the exacerbation of ischemic brain damage in diabetic conditions (at least in animal models) warrants the need to integrate this comorbidity in preclinical studies of brain ischemia to develop novel therapeutic approaches. Therefore, a better understanding of the commonalties involved in the course of both diseases would offer the promise of discovering novel neuroprotective pathways that would be more appropriated to clinical scenarios. In this article, we will review the relevant mechanisms that have been identified as common traits of both pathologies and that could be, to our knowledge, potential targets in both pathologies.

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Abbreviations

ACE inhibitors:

Angiotensin converting enzyme inhibitors

ADA:

American diabetes association

Akt:

Serine–threonine kinase

ARBs:

Angiotensin II receptor blockers

ATF3:

Activating transcription factor 3

ATP:

Adenosine triphosphate

CamK:

Ca2+/calmodulin kinase

CaMKK:

CaM kinase kinase

cAMP:

Cyclic adenosine monophosphate

CNS:

Central nervous system

CREB:

C-AMP response element-binding protein

CRP:

C-reactive protein

DPP-4:

Dipeptidyl peptidase-4

FFA:

Free fatty acid

GLP-1:

Glucagon-like peptide-1

HbA1c:

Hemoglobin A1c

HDL:

High-density lipoproteins

ICER:

Inducible cAMP early repressor

IL1-β:

Interleukin1-beta

JNKs:

c-Jun N-terminal kinases

LDL:

Low-density lipoproteins

NGF:

Nerve growth factor

NMDA:

N-methyl-D-aspartate

PDE:

Phosphodiesterase

PKA:

Protein kinase A

PKB:

Protein kinase B

PKCδ:

Protein kinase Cdelta

ROS:

Reactive oxygen species

SGLT-2:

Sodium-glucose co-transporter-2

STAIR:

Stroke therapy academic industry roundtable

TNF:

Tumor necrosis factor

VADT:

Veterans affairs diabetes trial

VLDL:

Very low-density lipoproteins

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Acknowledgements

The authors thank all their past and present team members and collaborators who have contributed to the data discussed in the review. We would like to express our gratitude to Drs. Heurteaux and Mazzela for their cordial support, valuable information, and guidance, which helped us in completing this review.

Funding

This work was funded by the Centre National de la Recherche Scientifique - CNRS.

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Correspondence to Thierry Coppola or Nicolas Blondeau.

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The authors declare that they have no conflict of interest.

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Coppola, T., Beraud-Dufour, S., Lebrun, P. et al. Bridging the Gap Between Diabetes and Stroke in Search of High Clinical Relevance Therapeutic Targets. Neuromol Med 21, 432–444 (2019). https://doi.org/10.1007/s12017-019-08563-5

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  • DOI: https://doi.org/10.1007/s12017-019-08563-5

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