Graded occlusion of perfused rat muscle vasculature decreases insulin action

Abstract

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.

Activity restriction, impaired capillary function, and the development of insulin resistance in lean primates

“…In these previous studies, reduced glucose storage capacity was associated with a reduction in recruitable CBV, measured by capillary xanthine-oxidase activity or CEU, in obese and insulin-resistant animals and humans (4,5,32). Furthermore, the importance of capillary recruitment for both glucose uptake and insulin delivery is supported by the reduction in insulin-mediated glucose uptake and insulin receptor signaling after graded microsphere occlusion of skeletal muscle microcirculation without a change in basal glucose uptake and insulin receptor signaling (31). In aggregate, these studies together with our data suggest that microvascular dysfunction is not simply a downstream consequence of DM.…”

Losartan modulates muscular capillary density and reverses thiazide diuretic-exacerbated insulin resistance in fructose-fed rats

“…11, 12, 13, 33, 34, 35 Likewise, rodent studies have demonstrated a direct effect of capillarization on insulin action in skeletal muscles. 14, 15, 16, 36, 37 A decrease in CD is associated with a longer diffusion distance between the nutritional blood vessels and the skeletal muscle cells. This change would impede the delivery of glucose to the muscle cells and thereby decrease IS.…”

Microvascular dysfunction: a direct link among BMI, waist circumference and glucose homeostasis in young overweight/obese normoglycemic women?

“…[12][13][14][15] Results from experimental and human studies have suggested that insulin-mediated changes in muscle perfusion can modulate insulin-mediated glucose uptake. 11,35 The action of insulin, also seen in the skin, 36 can favor insulin itself and glucose availability to cells. MD seems to be inversely associated with insulin sensitivity in subjects with fasting hyperglycemia.…”

“…Experimentally, it has been shown that graded occlusion of perfused rat muscle vasculature markedly impaired insulin delivery, insulin-mediated Akt phosphorylation and glucose uptake, suggesting a pre-receptor defect in the insulin signaling pathway. 11 Although not yet fully established in a clinical setting, endothelial and MDs, characterized by decreased responses to endothelial-derived relaxing factors (essentially, but not only, nitric oxide) and alterations of hemodynamic parameters such as the number of perfused capillaries and baseline red blood cell velocity, respectively, have been hypothesized as primary causes of IR. [12][13][14][15] In type 2 diabetes mellitus, MD has been well characterized in the coronary bed 16 and the skin, 17 but in the young uncomplicated OW/obese persons, the extent of microvascular damage, tested by a non-invasive method, namely, the nailfold videocapillaroscopy, and its interrelationship with clinical-anthropometrical-laboratorial parameters remains to be determined.…”