Alterations to flowmotion have been observed with the development of insulin resistance and T2D; shown in studies of acute vasoconstriction in in vivo rat skeletal muscle (57), as well as in skin+SC of obese (215, 216) and T2D (217, 218) populations. Investigation into flowmotion dysfunction in insulin resistance has primarily been determined with spectral analysis of skin+SC LDF measures and aberrant changes in a number of the different component frequencies have been observed. In a study by de Jongh et. al. (219) blood flow in the skin+SC was measured by LDF on healthy and obese female subjects, with and without the introduction of insulin through iontophoresis. Total LDF flux was assessed to determine blood flow and spectral analysis was performed on the LDF data to give a measure of flowmotion. Local administration of insulin to the skin+SC (iontophoresis) produced a
30 vasodilatory response in the healthy women, but not in the obese. In the basal state, flowmotion as a whole (the contribution of the total frequency spectrum) as well as the endothelial and neurogenic activity of flowmotion was lower in the obese subjects. The authors surmised that obesity involves an impaired microvascular vasodilatory effects and decrease in skin+SC microvasculature flowmotion. A study by Montero et. al. (216) comparing lean and severely obese adolescent participants, also using insulin iontophoresis and LDF flux measures, showed a reduction in insulin-induced myogenic activity in the obese individuals. The authors suggested dysfunction in the myogenic response to insulin may be an early step in the development of insulin resistance and T2D. Studies describing disruption of vascular smooth muscle Ca2+ release and signalling resulting from hyperglycaemia (220) and in an
obese rat model (104) support the idea that the myogenic component of flowmotion (vasomotion) is disrupted in the development of T2D. Another study by Clough et. al. (215) measuring skin+SC flowmotion with LDF flux in participants with central obesity, showed an increased neurogenic input during a euglycemic hyperinsulinemic clamp as compared to previously reported healthy participants. Furthermore, an association study by de Boer et. al. (221) showed an inverse relationship between BMI and normalised neurogenic component of flowmotion. Additionally, the cardiac component of flowmotion was positively associated with BMI. These studies show a link between an obese state, which is known to be causative of insulin resistance, and changes in flowmotion patterns and contribution. The results are quite varied based on the technique and participant populations, highlighting the need for further study into the area to elucidate what changes in flowmotion may be occurring in different stages of disease progression.
Flowmotion studies in patients with clinically diagnosed type 2 diabetics show similar dysfunction in flowmotion frequency components. Most studies in this area focus on patients with clinically diagnosed T2D at the later stages of disease progression when complications such as neuropathy and retinopathy have manifested. Studies by Sun et. al. (217, 218) investigating flowmotion dysfunction in T2D patients with various severity of neuropathy, show changes (decreased input) in the endothelial
31 and neurogenic components of flowmotion in the early stages of neuropathy development. The two studies indicate dysfunction in these frequency components may be causative of disease development. These studies measured skin+SC flowmotion with LDF flux on the foot of participants, but skin+SC LDF measures are not the only means to investigate changes in flowmotion that occur in T2D. A study by Bek et. al. (72) examined changes in retinal arteriole flowmotion over 180seconds by applying spectral analysis to video recordings of vasomotion activity in healthy controls and T2D with increasing severity of retinopathy. The study found a significant reduction in spontaneous high frequency oscillations (attributed to changes to cardiac function) and noted a reduction in overall frequencies with increasing severity of disease. Studying the changes in flowmotion at different stages of disease development, from insulin resistance through to severe microvascular disease state such as retinopathy, nephropathy and neuropathy, in a number of different tissue types may greatly enhance knowledge about how T2D develops and progresses over time.
A key tissue in the development of T2D is skeletal muscle, but due to technique difficulties there are a limited number of studies on skeletal muscle flowmotion in insulin resistances states. A previous study by Newman et. al. (57) on flowmotion in anesthetised rat skeletal muscle during a 10mU/min/kg euglycemic hyperinsulinemic clamp found (using LDF wavelet transformation from an implanted probe) an increase in the myogenic component (vasomotion) of flowmotion. Newman et. al. (57) then induced an acute state of insulin resistance with the peripheral vasoconstrictor α-methylserotonin and found a reduction in insulin-mediated glucose uptake and blockade of the myogenic component of flowmotion. The authors suggested that insulin-mediated microvascular recruitment may in part involve action on the vasculature smooth muscle to increase vasomotion, thereby enhancing capillary perfusion and glucose uptake. A concept supported by the evidence for NO-dependent endothelial mediated control of vasomotion.
32 The numerous changes in overall flowmotion as well as input from the individual frequency components is widely reported in abhorrent disease states such as insulin resistance and T2D. These changes may contribute to the development of disease and advancement of adverse outcomes. However, the results are varied based upon the tissue type and technique used, highlighting a need to better define changes that occur over the progression of disease. Importantly, the actions of flowmotion in tissues such as skeletal muscle may play an important role in normal glucose metabolism and thus dysfunction could play a role in early disease progression. A study by de Boer et. al. (12) on healthy individuals concurrently measuring skin+SC microvascular flowmotion and capillary perfusion in the nailfold during a euglycemic hyperinsulinemia clamp, showed an increase in normalised neurogenic input was associated with increased capillary perfusion, with both increases also associated with enhanced glucose uptake. The study concluded that lower insulin-mediated capillary recruitment and glucose uptake was associated with a decreased in neurogenic input during infusion of physiological levels of insulin (1mU/kg/min clamp). This study thereby indicates the potential importance in insulin-mediated changes in flowmotion. However, as the study was performed in skin+SC and nailfold, thus the translation of these results to the more metabolically important tissue of skeletal muscle is yet to be investigated.