Reduced skeletal-muscle perfusion and impaired ATP release during hypoxia and exercise in individuals with type 2 diabetes

  • Martin B. Groen
  • Trine A. Knudsen
  • Stine H. Finsen
  • Bente K. Pedersen
  • Ylva Hellsten
  • Stefan P. MortensenEmail author



Plasma ATP is a potent vasodilator and is thought to play a role in the local regulation of blood flow. Type 2 diabetes is associated with reduced tissue perfusion. We aimed to examine whether individuals with type 2 diabetes have reduced plasma ATP concentrations compared with healthy control participants (case–control design).


We measured femoral arterial and venous plasma ATP levels with the intravascular microdialysis technique during normoxia, hypoxia and one-legged knee-extensor exercise (10 W and 30 W) in nine participants with type 2 diabetes and eight control participants. In addition, we infused acetylcholine (ACh), sodium nitroprusside (SNP) and ATP into the femoral artery to assess vascular function and ATP signalling.


Individuals with type 2 diabetes had a lower leg blood flow (LBF; 2.9 ± 0.1 l/min) compared with the control participants (3.2 ± 0.1 l/min) during exercise (p < 0.05), in parallel with lower venous plasma ATP concentration (205 ± 35 vs 431 ± 72 nmol/l; p < 0.05). During systemic hypoxia, LBF increased from 0.35 ± 0.04 to 0.54 ± 0.06 l/min in control individuals, whereas it did not increase (0.25 ± 0.04 vs 0.31 ± 0.03 l/min) in the those with type 2 diabetes and was lower than in the control individuals (p < 0.05). Hypoxia increased venous plasma ATP levels in both groups (p < 0.05), but the increase was higher in control individuals (90 ± 26 nmol/l) compared to those with type 2 diabetes (18 ± 5 nmol/l). LBF and vascular conductance were lower during ATP (0.15 and 0.4 μmol min−1 [kg leg mass]−1) and ACh (100 μg min−1 [kg leg mass]−1) infusion in individuals with type 2 diabetes compared with the control participants (p < 0.05), whereas there was no difference during SNP infusion.


These findings demonstrate that individuals with type 2 diabetes have lower plasma ATP concentrations during exercise and hypoxia compared with control individuals, and this occurs in parallel with lower blood flow. Moreover, individuals with type 2 diabetes have a reduced vasodilatory response to infused ATP. These impairments in the ATP system are both likely to contribute to the reduced tissue perfusion associated with type 2 diabetes.

Trial registration NCT02001766.


Exercise Human Metabolic physiology in vivo Microvascular disease 





Inwardly rectifying potassium channels


Leg blood flow


Leg vascular conductance


Mean arterial pressure


Nitric oxide


Sodium nitroprusside


Contribution statement

MBG was responsible for acquisition of data, analysis and interpretation of the data and drafting the manuscript. TAK and SHF were responsible for acquisition of data, analysis and interpretation of the data and revision of the manuscript. BKP analysed and interpretated the data and revised the manuscript. YH was responsible for conception and design, acquisition of data, analysis and interpretation of the data and revision of the manuscript. SPM was responsible for conception and design, acquisition of data, analysis and interpretation of the data and drafting the manuscript. All authors approved the final version of the manuscript. SPM is responsible for the integrity of the data.


This study was supported by the Capitol Region of Denmark. The Centre for Physical Activity Research (CFAS) is supported by a grant from TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). CIM/CFAS is a member of DD2 - the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grant no. 09-067009 and 09-075724).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4790_MOESM1_ESM.pdf (855 kb)
ESM 1 (PDF 854 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cardiovascular and Renal Research, Institute of Molecular MedicineUniversity of Southern DenmarkOdenseDenmark
  2. 2.Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, University of Copenhagen, RigshospitaletCopenhagenDenmark
  3. 3.Department of Nutrition, Exercise and SportsUniversity of CopenhagenCopenhagenDenmark

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