ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO

  • Shiuchi T
  • Cui T
  • Wu L
 et al. 
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Abstract

Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. Mice treated with temocapril showed a smaller plasma glucose increase after glucose load. We demonstrated that temocapril treatment significantly enhanced 2-[3H]-deoxy-D-glucose (2-DG) uptake in skeletal muscle but not in white adipose tissue. Administration of a bradykinin B2 receptor antagonist, Hoe140, or an NO synthase inhibitor, L-NAME, attenuated the enhanced glucose uptake by temocapril. Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin. These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation.

Author-supplied keywords

  • *Insulin Resistance
  • *Muscle Proteins
  • Angiotensin-Converting Enzyme Inhibitors/*pharmaco
  • Animals
  • Biological Transport/drug effects
  • Blood Glucose/analysis
  • Bradykinin/*physiology
  • Cell Line
  • Deoxyglucose/metabolism
  • Diabetes Mellitus, Type 2/drug therapy/*metabolism
  • Glucose Transporter Type 4
  • Kinetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monosaccharide Transport Proteins/metabolism
  • Muscle, Skeletal/drug effects/metabolism
  • Nitric Oxide/*physiology
  • Phosphoproteins/metabolism
  • Phosphorylation
  • Protein Transport/drug effects
  • Research Support, Non-U.S. Gov't
  • Thiazepines/*pharmacology

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Authors

  • T Shiuchi

  • T X Cui

  • L Wu

  • H Nakagami

  • Y Takeda-Matsubara

  • M Iwai

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