Muscle contraction, but not insulin, increases microvascular blood volume in the presence of free fatty acid-induced insulin resistance.
OBJECTIVE
Insulin and contraction each increase muscle microvascular blood volume (MBV) and glucose uptake. Inhibiting nitric oxide synthase blocks insulin's but not contraction's effects. We examined whether contraction could augment the MBV increase seen with physiologic hyperinsulinemia and whether free fatty acid (FFA)-induced insulin resistance differentially affects contraction- versus insulin-mediated increases in MBV.


METHODS
Rats were fasted overnight. Plasma FFAs were increased by intralipid/heparin infusion (3 h), insulin was increased with a euglycemic clamp (3 mU x min(-1) x kg(-1)), and hindlimb muscle contraction was electrically stimulated. Muscle MBV was measured using contrast-enhanced ultrasound. Insulin transport into muscle was measured using (125)I-insulin. BQ-123 (0.4 mg/h) was used to block the endothelin-1 (ET-1) receptor A.


RESULTS
Superimposing contraction on physiologic hyperinsulinemia increased MBV within 10 min by 37 and 67% for 0.1 or 1 Hz, respectively (P < 0.01). FFA elevation alone did not affect MBV, whereas 0.1 Hz stimulation doubled MBV (P < 0.05) and increased muscle insulin uptake (P < 0.05) despite high FFA. Physiologic hyperinsulinemia during FFA elevation paradoxically decreased MBV (P < 0.05). This MBV decrease was reversed by either 0.1 Hz contraction or ET-1 receptor A antagonism, and the combination raised MBV above basal.


CONCLUSIONS
Contraction recruits microvasculature beyond that seen with physiologic hyperinsulinemia by a distinct mechanism that is not blocked by FFA-induced vascular insulin resistance. The paradoxical MBV decline seen with insulin plus FFA may result from differential inhibition of insulin-stimulated nitric oxide-dependent vasodilation relative to ET-1 vasoconstriction. Our results implicate ET-1 as a potential mediator of FFA-induced vascular insulin resistance.
Inyard
April C
AC
University of Virginia, Charlottesville, Virginia, USA.
Chong
Daniel G
DG
Klibanov
Alexander L
AL
Barrett
Eugene J
EJ
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001810:Blood Volume / Q000187:drug effects / Q000502:physiology*; D003847:Deoxyglucose / Q000378:metabolism; D004558:Electric Stimulation; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D006614:Hindlimb; D006946:Hyperinsulinism / Q000503:physiopathology; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007457:Iodine Radioisotopes; D003847:Deoxyglucose; D055372:AMP-Activated Protein Kinases
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