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Early microvascular complications of prediabetes in mice with impaired glucose tolerance and dyslipidemia

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Abstract

Microvascular complications are an important cause of morbidity in diabetic patients and can be detected in a significant number of patients at the time of diabetes diagnosis. However, little is known about the alterations in the microvasculature previous to the clinical manifestation of diabetes mellitus type 2. To obtain more insights into the early microvascular deterioration resulting from prediabetes, morphological and functional microvascular parameters were monitored using intravital fluorescence microscopy through a dorsal skin-fold chamber preparation in the uncoupling promotor-driven diphtheria toxin A chain (UCP1/DTA) mice. At the age of 12 weeks, the UCP1/DTA-mice were characterized by impaired glucose tolerance with concurrent unchanged fasting glucose, as well as dyslipidemia, hyperinsulinemia, hypertension and obesity. Prediabetic mice displayed combined hypertriglyceridemia and hypercholesterinemia. Associated with these prediabetic metabolic alterations, we demonstrate that microvascular density showed a dramatic decrease due to a reduction in perfused small vessels. A reduction in vascular density combined with unaltered blood flow in single vessels resulted in impaired tissue perfusion. Endothelial dysfunction with subsequently increased microvascular permeability and leukocyte–endothelium interactions were found. Our results of profound microvascular alterations at stages of normal fasting glucose underline the importance of early screening for prediabetes and associated microvascular complications.

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Abbreviations

UCP1/DTA:

Uncoupling protein diphtheria toxin A chain

FITC:

Fluorescein-isothiocyanate

TRITC:

Tetramethylrhodamine

LEI:

Leukocyte–endothelium interactions

VRBC :

Red blood cell velocity

BFR:

Blood flow rate

LDL:

Low density lipoproteins

HDL:

High density lipoproteins

VLDL:

Very low density lipoproteins

ROS:

Reactive oxygen species

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Acknowledgments

This work was supported by a Werner-Otto Stiftung research grant to N. H.-A. We thank B. Schwarzloh for outstanding technical support.

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Authors and Affiliations

  1. Spine Center, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Christian Schaefer, Malte Schroeder, Ina Fuhrhop & Nils Hansen-Algenstaedt

  2. Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Christian Schaefer, Malte Schroeder, Ina Fuhrhop, Andreas Niemeier, Wolfgang Rüther & Nils Hansen-Algenstaedt

  3. Department of Trauma-, Hand- and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Tanja Biermann

  4. Endocrinology, Department of Internal Medicine III, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany

    Petra Algenstaedt

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  1. Christian Schaefer
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Corresponding author

Correspondence to Christian Schaefer.

Additional information

C. Schaefer and T. Biermann have contributed equally to this study.

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Schaefer, C., Biermann, T., Schroeder, M. et al. Early microvascular complications of prediabetes in mice with impaired glucose tolerance and dyslipidemia. Acta Diabetol 47 (Suppl 1), 19–27 (2010). https://doi.org/10.1007/s00592-009-0114-7

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  • DOI: https://doi.org/10.1007/s00592-009-0114-7

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