Effects of equivalent sympathetic activation during hypoglycemia on endothelial function and pro-atherothrombotic balance in healthy individuals and obese standard treated type 2 diabetes

Metabolism. 2016 Dec;65(12):1695-1705. doi: 10.1016/j.metabol.2016.09.001. Epub 2016 Sep 12.


Objective: Recent studies in type 2 diabetes have reported an association between hypoglycemia and severe cardiovascular adverse events, which are relatively increased in standard versus intensively treated individuals. The aim of this study was to determine the effects of equivalent sympathetic nervous system (SNS) activity during moderate hypoglycemia on in-vivo endothelial function, pro-inflammatory, pro-atherothrombotic, and pro-coagulant responses in healthy and standard treated type 2 diabetes individuals.

Research design and methods: Eleven type 2 diabetes and 16 healthy individuals participated in single 2day studies. Day 1 involved a 2h hyperinsulinemic/euglycemic clamp and day 2, a 2h hyperinsulinemic/hypoglycemic clamp of 3.2±1mmol/L in type 2 diabetes and (2.9±0.1mmol/L) in healthy individuals.

Results: ICAM-1, VCAM-1, P-selectin, PAI-1, VEGF and endothelin-1 (ET-1) fell during hyperinsulinemic euglycemia but increased during hypoglycemia in type 2 diabetes and healthy individuals. Epinephrine and norepinephrine levels were equivalent during hypoglycemia in type 2 DM and healthy individuals. However, despite similar SNS drive but milder and hypoglycemia there were greater ICAM-1, VCAM-1, PAI-1, VEGF and ET-1 responses in the type 2 diabetes group. Endogenous and exogenous nitric oxide mediated arterial vasodilation were also impaired only during hypoglycemia in type 2 diabetes.

Conclusion: We conclude that, milder hypoglycemia but equivalent SNS activation results in more diffuse endothelial dysfunction and a greater pro-inflammatory, pro-atherothrombotic and pro-coagulant state in standard treated type 2 diabetes as compared to healthy individuals.

Keywords: Atherothrombosis; Endothelial function; Hypoglycemia; Sympathetic nervous system; Type 2 diabetes.

MeSH terms

  • Adult
  • Atherosclerosis / blood
  • Blood Coagulation
  • Case-Control Studies
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications*
  • Endothelin-1 / blood
  • Endothelium, Vascular / physiology*
  • Female
  • Humans
  • Hypoglycemia / etiology
  • Hypoglycemia / physiopathology*
  • Hypoglycemic Agents / pharmacology
  • Inflammation / blood
  • Intercellular Adhesion Molecule-1 / blood
  • Male
  • Middle Aged
  • Obesity
  • P-Selectin / blood
  • Plasminogen Activator Inhibitor 1 / blood
  • Sympathetic Nervous System / metabolism*
  • Vascular Cell Adhesion Molecule-1 / blood
  • Vascular Endothelial Growth Factor A / blood


  • Endothelin-1
  • Hypoglycemic Agents
  • P-Selectin
  • Plasminogen Activator Inhibitor 1
  • Vascular Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • Intercellular Adhesion Molecule-1