Enhancement of muscle glucose uptake by the vasopeptidase inhibitor, omapatrilat, is independent of insulin signaling and the AMP kinase pathway.
Omapatrilat (OMA), a vasopeptidase inhibitor (VPI), presently being tested in clinical trials for its antihypertensive properties, inhibits both angiotensin-converting enzyme and neutral endopeptidase, and raises tissue bradykinin levels. Recent studies from our laboratory and those of others have demonstrated that VPIs enhance muscle glucose uptake in animal models, and this effect is mediated by the bradykinin-nitric oxide pathway. The mechanism of the effect of OMA on muscle glucose uptake, however, is presently unknown. To investigate the effect of OMA on insulin signaling, soleus muscle was isolated 2 or 5 min after an i.v. bolus of insulin or saline from male Zucker fatty rats (8-10 weeks of age), following a 5-day treatment period of oral OMA (15 mg/kg per day) or drug vehicle (placebo). OMA resulted in significantly lower systolic blood pressure compared with the placebo-treated group (84.4+/- 7.52 mmHg in OMA vs 112+/-2.18 mmHg in controls, P<0.01). Immunoprecipitation and Western blot analysis of insulin receptor substrate 1 (IRS-1) revealed no changes in protein mass with OMA treatment. OMA did not enhance basal or insulin-stimulated IRS-1 tyrosine phosphorylation or its subsequent association with the p85 regulatory subunit of phosphatidylinositol 3-kinase. Under basal and insulin-stimulated conditions, OMA treatment did not alter the protein mass or the phosphorylation of Akt/protein kinase B, p42/44 extracellular signal-regulated kinase or adenosine monophosphate-activated protein kinase, or GLUT4 protein expression. We conclude that the ability of OMA to enhance whole body and specifically muscle glucose uptake in Zucker fatty rats is not mediated by enhancing insulin or AMPK signaling. Future studies should examine whether hemodynamic effects of the drug, independent of insulin signaling, enhance glucose uptake in insulin-resistant skeletal muscle.
Wong
Victor
V
Department of Medicine, Division of Endocrinology and Metabolism and the Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Szeto
Linda
L
Uffelman
Kristine
K
Fantus
I George
IG
Lewis
Gary F
GF
D000263:Adenylate Kinase / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000032:analysis; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000502:physiology*; D013841:Thiazepines / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D011725:Pyridines; C495694:Slc2a4 protein, rat; D013841:Thiazepines; C106266:omapatrilat; D019869:Phosphatidylinositol 3-Kinases; D000263:Adenylate Kinase; D005947:Glucose