Acute vasoconstriction-induced insulin resistance in rat muscle in vivo.

Abstract

Insulin-mediated changes in blood flow are associated with altered blood flow distribution and increased capillary recruitment in skeletal muscle. Studies in perfused rat hindlimb have shown that muscle metabolism can be regulated by vasoactive agents that control blood flow distribution within the hindlimb. In the present study, the effects of a vasoconstrictive agent that has no direct effect on skeletal muscle metabolism but that alters perfusion distribution in rat hindlimb was investigated in vivo to determine its effects on insulin-mediated vascular action and glucose uptake. We measured the effects of alpha-methylserotonin (alpha-met5HT) on mean arterial blood pressure, heart rate, femoral blood flow, hindlimb vascular resistance, and glucose uptake in control and euglycemic insulin-clamped (10 mU x min(-1) x kg(-1)) anesthetized rats. Blood flow distribution within the hindlimb muscles was assessed by measuring the metabolism of 1-methylxanthine (1-MX), an exogenously added substrate for capillary xanthine oxidase. Alpha-met5HT (20 microg x min(-1) x kg(-1)) infusion alone increased mean arterial blood pressure by 25% and increased hindlimb vascular resistance but caused no change in femoral blood flow. These changes were associated with decreased hindlimb 1-MX metabolism indicating less capillary flow. Insulin infusion caused decreased hindlimb vascular resistance that was associated with increased femoral blood flow and 1-MX metabolism. Treatment with alpha-met5HT infusion commenced before insulin infusion prevented the increase in femoral blood flow and inhibited the stimulation of 1-MX metabolism. Alpha-met5HT infusion had no effect on hindlimb glucose uptake but markedly inhibited the insulin stimulation of glucose uptake (P < 0.05) and was associated with decreased glucose infusion rates to maintain euglycemia (P < 0.05). A significant correlation (P < 0.05) was observed between 1-MX metabolism and hindlimb glucose uptake but not between femoral blood flow and glucose uptake. The results indicate that in vivo, certain types of vasoconstriction in muscle such as elicited by 5HT2 agonists, which prevent normal insulin recruitment of capillary flow, cause impaired muscle glucose uptake. Moreover, if vasoconstriction of this kind results from stress-induced increase in sympathetic outflow, then this may provide a clue as to the link between hypertension and insulin resistance that is often observed in humans.

Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment

“…We propose that glucosamine inhibits insulin signalling in as yet unidentified site(s), thereby blocking the increases in total flow and capillary recruitment. In so doing, impaired access for insulin and glucose may ensue, contributing to insulin resistance in a similar way to previous experimental situations, where capillary recruitment by insulin was blocked [12][13][14].…”

“…In Table 1 Arterial and venous plasma 1-MX concentrations, femoral arterial flow rate and calculated hind limb 1-MX metabolism for anaesthetised rats infused with saline, N-glucosamine, insulin or both N-glucosamine and insulin Data were collected 180 min after the commencement of the infusions as shown in Fig. 1 Values are means±SE for n=8 in each group *p<0.05 difference from saline; # p<0.05 difference from insulin contrast, there is growing evidence that insulin-mediated capillary recruitment may play a key role in muscle glucose uptake, particularly in animal models [18] and is impaired in animal models of muscle insulin resistance [12][13][14]41] and in obese humans [42,43]. Capillary recruitment is controlled independently of limb blood flow [17,18,21] and occurs in response to locally administered physiological insulin in human forearm in association with glucose uptake [44].…”

“…20 μmol/l. As noted previously [12,21] this was achieved by partly inhibiting the activity of xanthine oxidase with allopurinol [24] (10 μmol/kg), administered as a bolus dose 5 min prior to commencing the 1-MX infusion (Fig. 1).…”

“…However, it is also possible that there is a haemodynamic element with resultant impairment of both insulin-mediated limb blood flow and capillary recruitment. Inhibition of insulin's haemodynamic action has been shown to be associated with decreased insulin-mediated glucose uptake [12][13][14].…”

Physiological hyperinsulinaemia increases intramuscular microvascular reactive hyperaemia and vasomotion in healthy volunteers

“…In the rat hindlimb, insulin recruited capillary perfusion as shown by an in-crease in the metabolism of 1-methylxanthine. This capillary recruitment was related to changes in skeletal muscle glucose uptake independently of changes in total blood flow [2,3]. Furthermore, it has been shown that laser Doppler flow measurements in the constant-flow, erythrocyte-perfused rat hindlimb correlate with changes in muscle metabolism, indicating the ability of this technology to measure erythrocyte movement both proportional to nutritive flow and separate from total flow [4].…”