Glucose-stimulated insulin secretion causes an insulin-dependent nitric oxide–mediated vasodilation in the blood supply of the rat sciatic nerve

Abstract

This study tested the hypothesis that acute hyperglycemia reduces sciatic nerve blood flow in Sprague-Dawley rats. Anesthetized rats underwent cannulation of their right jugular vein (for anesthetic/nutrient/drug infusion) and right carotid artery (for continuous blood pressure measurement via pressure transducer). The left sciatic nerve was exposed and nerve blood velocity (NBV) was assessed from an arterial segment lying superficially along the sciatic nerve (Doppler ultrasound, 40 MHz). NBV and mean arterial pressure (MAP) values were collected, and an index of nerve vascular conductance (NVC) was established (NBV/MAP) at baseline and at 5, 10, 20, and 30 min (and 80 min for insulin) following 1) low glucose infusion, 1 g/kg (50% solution); 2) high glucose infusion, 3 g/kg; 3) high glucose infusion in the absence of a functioning pancreas; 4) euglycemic hyperinsulinemic clamp-insulin infusion (10 mU·kg⁻¹·min⁻¹; 0.4 IU/ml); 5) high glucose infusion + NG-nitro-L-arginine methyl ester (L-NAME) infusion (30 mg/kg); and 6) L-NAME alone followed 20 min later by high glucose infusion. High glucose infusion increased NVC by ~120% relative to baseline (P < 0.001), and this dilation was attenuated in rats without a functioning pancreas (i.e., without insulin secretion) (P = 0.004) and following L-NAME infusion (P = 0.011). Therefore, the vasodilation in rat sciatic nerve during glucose infusion was dependent upon the insulin response and acted through a nitric oxide synthase pathway.

Exercise training enhances insulin-stimulated nerve arterial vasodilation in rats with insulin-treated experimental diabetes

“…By intention, blood glucose values in the current study were maintained at a moderate hyperglycemic concentration and similar to clinical values observed in people with poorly controlled Type 1 diabetes mellitus (49). In study 1, compared with control and DX groups, sedentary rats with insulin-treated experimental diabetes had lower insulin sensitivity and attenuated vasa nervorum responsiveness during the insulin clamp.…”

“…Conceivably, in rats with experimental diabetes, insulin treatment may restore nerve blood flow and vasoreactivity partially through a NO-related mechanism. In addition to the effects of insulin treatment on basal nerve blood flow, acute insulin administration stimulates epineurial arterial vasorelaxation and increases sciatic nerve blood flow velocity (NBFV) in rats (24,49). It is uncertain what compounds mediate the insulin-induced dilation (21), but glucose-stimulated insulin-mediated dilation can be prevented by NO synthase (NOS) inhibition (49).…”

“…In addition to the effects of insulin treatment on basal nerve blood flow, acute insulin administration stimulates epineurial arterial vasorelaxation and increases sciatic nerve blood flow velocity (NBFV) in rats (24,49). It is uncertain what compounds mediate the insulin-induced dilation (21), but glucose-stimulated insulin-mediated dilation can be prevented by NO synthase (NOS) inhibition (49). The vasodilatory actions of insulin were documented over 70 years ago (1), and since then it has been established that insulin-mediated vasodilation occurs through the activation of the intracellular enzymes phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt), which phosphorylate and activate endothelial NOS (eNOS) (27,45).…”

Endurance, interval sprint, and resistance exercise training: impact on microvascular dysfunction in type 2 diabetes

“…The vasodilatory effects of insulin appear to operate following insulin infusion (140) as well as glucosestimulated insulin secretion (100,113). Whether insulin is infused or secreted in response to glucose, the vasodilation is NO dependent (114). Insulin-induced vasodilation may contribute to the maintenance of normoglycemia by augmenting insulin and glucose dispersal in skeletal muscle (21,26).…”

The relationship between blood pressure and sciatic nerve blood flow velocity in rats with insulin-treated experimental diabetes

“…8,9,11,12 Notably, in this study, rats were chronically exposed to insulin. Insulin exposure dilates healthy nerve arterioles, 32,33 and insulin treatment attenuates decrements in NBF following diabetes induction. 4,22 Also, unlike previous studies that document no change 2,3,12 or reduced 8,34 MAP in rats with chronic severe hyperglycaemia, the rats with ITED in this study had similar anaesthetized and higher conscious blood pressures.…”