Graded occlusion of perfused rat muscle vasculature decreases insulin action.
Insulin increases capillary recruitment in vivo and impairment of this may contribute to muscle insulin resistance by limiting either insulin or glucose delivery. In the present study, the effect of progressively decreased rat muscle perfusion on insulin action using graded occlusion with MS (microspheres; 15 mum in diameter) was examined. EC (energy charge), PCr/Cr (phosphocreatine/creatine ratio), AMPK (AMP-activated protein kinase) phosphorylation on Thr(172) (P-AMPKalpha/total AMPK), oxygen uptake, nutritive capacity, 2-deoxyglucose uptake, Akt phosphorylation on Ser(473) (P-Akt/total Akt) and muscle 2-deoxyglucose uptake were determined. Arterial injection of MS (0, 9, 15 and 30 x 10(6) MS/15 g of hindlimb muscle, as a bolus) into the pump-perfused (0.5 ml x min(-1) x g(-1) of wet weight) rat hindlimb led to increased pressure (-0.5+/-0.8, 15.9+/-2.1, 28.7+/-4.6 and 60.3+/-9.4 mmHg respectively) with minimal changes in oxygen uptake. Nutritive capacity was decreased from 10.6+/-1.0 to 3.8+/-0.9 micromol x g(-1) of muscle x h(-1) (P<0.05) with 30 x 10(6) MS. EC was unchanged, but PCr/Cr was decreased dose-dependently to 61% of basal with 30 x 10(6) MS. Insulin-mediated increases in P-Akt/total Akt decreased from 2.15+/-0.35 to 1.41+/-0.23 (P<0.05) and muscle 2-deoxyglucose uptake decreased from 130+/-19 to 80+/-12 microg x min(-1) x g(-1) of dry weight (P<0.05) with 15 x 10(6) MS; basal P-AMPKalpha in the absence of insulin was increased, but basal P-Akt/total Akt and muscle 2-deoxyglucose uptake were unaffected. In conclusion, partial occlusion of the hindlimb muscle has no effect on basal glucose uptake and marginally impacts on oxygen uptake, but markedly impairs insulin delivery to muscle and, thus, insulin-mediated Akt phosphorylation and glucose uptake.
Vollus
Georgie C
GC
Department of Biochemistry, University of Tasmania Medical School, Private Bag 58, 7001, Hobart, Tasmania, Australia.
Bradley
Eloise A
EA
Roberts
Merren K
MK
Newman
John M B
JM
Richards
Stephen M
SM
Rattigan
Stephen
S
Barrett
Eugene J
EJ
Clark
Michael G
MG
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000378:metabolism* / Q000503:physiopathology; D015153:Blotting, Western / Q000379:methods; D002196:Capillaries; D005947:Glucose / Q000378:metabolism; D006614:Hindlimb; D007004:Hypoglycemic Agents / Q000378:metabolism*; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D007333:Insulin Resistance; D008863:Microspheres; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow
D007004:Hypoglycemic Agents; D007328:Insulin; D051057:Proto-Oncogene Proteins c-akt; D000263:Adenylate Kinase; D005947:Glucose; D010100:Oxygen