Subcutaneous Blood Flow Research Articles

Acute Effects of Nicotine and Smoking on Blood Flow, Tissue Oxygen, and Aerobe Metabolism of the Skin and Subcutis

Nicotine released from tobacco smoke causing reduction in blood flow has been suggested as causative for postoperative wound complications in smokers, but the mechanism remains unknown. In eight healthy male smokers and eight ex-smokers, the cutaneous and subcutaneous blood flow (QBF, SqBF) was assessed by Laser Doppler and 133Xe clearance. Tissue oxygen tension (TO(2)) was measured by a LICOX O(2)-electrode. Tissue glucose and lactate (Tgluc, Tlact) were assessed by microdialysis. The parameters were studied after intravenous infusion of 1.0 mg nicotine, smoking of one cigarette, arterial occlusion, and reperfusion. Nicotine infusion decreased SqBF from 4.2 +/- 2.0 to 3.1 +/- 1.2 mL/100 g tissue/min (P < 0.01), whereas QBF was 21.7 +/- 8.6 and 22.7 +/- 9.6 Arbitrary Units (AU), respectively (P = 0.21). TO(2) increased from 49.3 +/- 12.0 to 53.9 +/- 12.0 mm Hg (P = 0.01). Tgluc and Tlact remained unaffected. Smoking decreased SqBF from 4.2 +/- 2.0 to 2.7 +/- 1.2 mL/100 g tissue/min (P < 0.01). QBF decreased from 23.4 +/- 9.2 to 20.3 +/- 7.4 AU (P < 0.01), and TO(2) decreased from 53.9 +/- 12.0 to 48.4 +/- 11.1 mm Hg (P < 0.01). Following smoking, Tgluc decreased from 0.7 +/- 0.1 to 0.6 +/- 0.1 ng/mL (P < 0.01), and Tlact increased from 0.2 +/- 0.1 to 0.3 +/- 0.2 ng/mL (P < 0.01). The observed alterations were similar in smokers and ex-smokers. Nicotine has a limited vasoactive effect in the skin and subcutis unlikely to be explained by smoking, which distinctly decreases tissue blood flow, oxygen tension, and aerobe metabolism independent of smoking status.

Non-Invasive Estimation of Subcutaneous and Visceral Adipose Tissue Blood Flow by Using [15O]H2O PET with Image Derived Input Functions

Subcutaneous adipose tissue blood flow is finely regulated, and tuned with fat metabolism; little is known about visceral fat, which is less accessible in humans. In estimating blood flow with positron emission tomography (PET) and oxygen-15-labelled water (( 15 O)H2O), the input function is obtained invasively from arterial blood samples. The aim of the current study was to validate a non-invasive method to measure blood flow in adipose depots, by extracting input function curves from ( 15 O)H2O-PET images. Data of twenty subjects undergoing abdominal ( 15 O)H2O-PET were used. Images were reconstructed with filtered backprojection (FBP). Location, diameter, and inner radioactivity levels of the abdominal aorta were automatically determined. Image derived arterial curves (IDI) were compared to measured arterial blood data, as obtained by an online blood sampler (OSI). Blood flow in three adipose tissue depots was estimated using the autoradiographic method with OSI vs the FBP image derived input (F-IDI) function. Correlations between blood flow results obtained with OSI and IDI were significant (r 0.87, p<0.0001) in all regions. Estimates of the aortic diameter ranged between 10.7-17.2 mm. A good agreement was found between area under the curve (AUC) values of F-IDI and OSI curves; the AUCF-IDI/AUCOSI ratio was 0.97±0.10. Our results support the implementation of the current method for the non-invasive detection of the abdominal aorta input function from a dynamic ( 15 O)H2O PET image in the quantifica- tion of regional blood flow in low flow tissues. This method allows simultaneously examine subcutaneous and intra- abdominal fat depots.

Impaired Postprandial Blood Flow in Adipose Tissue May Be an Early Marker of Insulin Resistance in Type 2 Diabetes

We investigated the changes in subcutaneous adipose tissue blood flow (ATBF) after a meal in the various stages of type 2 diabetes. Five groups were examined: healthy control subjects, first-degree relatives of subjects with type 2 diabetes, subjects with impaired glucose tolerance (IGT), subjects with type 2 diabetes and postprandial hyperglycemia but normal fasting plasma glucose levels (diabetes group A [DMA]), and subjects with type 2 diabetes with both postprandial and fasting hyperglycemia (diabetes group B [DMB]). ATBF was measured with (133)Xe. ATBF was higher in control subjects (1,507 +/- 103 ml/100 cm(3) tissue x min) versus relatives and IGT, DMA, and DMB subjects (845 +/- 123, 679 +/- 69, 765 +/- 60, and 757 +/- 69 ml/100 cm(3) tissue x min, respectively; P < 0.001). Insulin sensitivity index (ISI) in control subjects (82 +/- 3 mg x l(2)/mmol x mU x min) was higher versus that for relatives and IGT, DMA, and DMB subjects (60 +/- 3, 45 +/- 1, 40 +/- 6, and 29 +/- 4 mg x l(2)/mmol x mU x min, respectively; P < 0.0001). ISI was positively associated with peak-baseline ATBF (beta coefficient 0.029 +/- 0.013, P = 0.03). After meal ingestion, insulin-stimulated ATBF was decreased in relatives and and IGT, DMA, and DMB subjects. This defect could be an early marker of insulin resistance that precedes the development of type 2 diabetes.

Effects of a 3‐day fast on regional lipid and glucose metabolism in human skeletal muscle and adipose tissue

Fasting is characterized by increased whole body lipolysis and lipid oxidation, decreased glucose oxidation and insulin resistance. To identify the regional sources and underlying mechanisms, we studied 10 healthy male volunteers post-absorptively and after 72 h of fasting. Each study comprised a 3-h basal period and a 3-h hyperinsulinaemic euglycaemic clamp and we used a combination of leg and forearm arteriovenous techniques, upper and lower body microdialysis and glucose and palmitate tracers. In the basal state, plasma levels, fluxes and oxidation rates of free fatty acids all roughly doubled after fasting. Palmitate fluxes across the forearm and leg also increased by two to threefold and interstitial leg muscle glycerol concentrations doubled. Subcutaneous femoral glycerol concentrations and blood flows were unaltered, but abdominal subcutaneous blood flow increased by 50% in the presence of unchanged glycerol concentrations, indicating stimulated abdominal lipolysis. During the clamp, we observed whole body insulin resistance and glucose uptake across the leg and forearm decreased by 60%. Our data show that fasting induces insulin resistance in upper and lower body muscles and suggest that increased lipolysis, is primarily due to the activation of lipolysis in muscle-associated fat (in the leg) and in upper body subcutaneous fat, whereas peripheral subcutaneous fat is spared.

Effect of spaceflight on the subcutaneous venoarteriolar reflex in the human lower leg

Whenever the legs are lowered in humans, a venoarteriolar reflex is activated by the hydrostatic distension of the venules. Through local axon reflexes, the adjacent arterioles are contracted to decrease blood flow and prevent formation of edema. Because the venoarteriolar reflex is activated by gravity, we tested the hypothesis that long-term weightlessness would attenuate it. The reduction in subcutaneous blood flow was measured by the (133)Xe washout technique just proximal to the ankle joint in dependent lower legs of eight supine astronauts, where the knee joint was passively bent by 90 degrees . The measurements were conducted before spaceflight and 3-6 h on landing following 4-6.5 mo in space. Activation of the venoarteriolar reflex reduced subcutaneous blood flow by 37 +/- 9% (P = 0.016) before flight and by 64 +/- 8% (P < 0.001) following landing with no statistical significant difference between the two reductions (P = 0.062). Therefore, our results show that the venoarteriolar reflex is not attenuated by weightlessness and therefore does not need the everyday stimulus of gravity to maintain efficiency.

Noninvasive Blood Flow Measurement over Acupuncture Points (Gb21): A Pilot Study

Noninvasive evaluation of the cutaneous (cBF) and subcutaneous (sBF) blood flow over the acupuncture point (AP) Gb21 to assess a characteristically increased microcirculation at AP. AP show several anatomic, histologic and physiologic peculiarities that indicate a specifically elevated microcirculation. Nevertheless cBF and sBF over AP have not yet been established by noninvasive measurements. The laser Doppler spectroscope O2C allows a direct and real-time detection of the local cBF (depth: 1 mm) and sBF (depth: 8 mm) in vivo. In 28 subjects (41.1+/-9.8 years) the glass fiber probes of the O2C were placed over Gb21 and an adjacent asymptomatic reference point (RP) at the Trapezius Muscle. The relative blood flow was measured over a period of 3 minutes in each case. Microcirculation comparisons over AP and RP were made using multivariate analysis of variance. The results showed significantly higher sBF compared to cBF over Gb21 (F = 89.95, p< 0.01) and RP (F = 88.47, p< 0.01). A significantly higher microcirculation was evaluated for all subjects over Gb21 compared to RP (cBF: F = 7.35, p< 0.05; sBF: F = 8.56, p< 0.01). The employment of the O2C permitted for the first time noninvasive evidence of a significantly increased cBF and sBF over AP (Gb21). This evaluation of an initial microcirculatory state of AP should be determined for several AP and larger sampling sizes. The results could be the basis for following controlled acupuncture trials. Regarding a close correlation of AP with myofascial trigger points (TP), further studies in patients with myoskeletal pain could quantify noninvasively a decreased perfusion in the area of TP that might indicate a pathologic condition. The findings of this study encourage the implementation of the laser Doppler spectroscope O2C as a reliable diagnostic tool for various pain syndromes in prevention, therapy, and rehabilitation.

The temporal effect of a high velocity thrust technique to the lumbar spine on cutaneous blood flow in the lower limb, comparing smokers and non-smokers

Background The lumbar high velocity low amplitude thrust technique (HVLAT) is a frequently used technique for the relief of spinal restriction and local somatic dysfunction. While this has generally been in order to achieve a local somatic correction and it is known to evoke a visceral response, 1,3 and a short term vascular response, 4 little has been published about the long term distal autonomic consequences. Smoking has a detrimental effect on the condition of blood vessels and the autonomic nervous system. 2,5 This experiment investigates the effect a lumbar HVLAT has on vascular perfusion in the lower limb over the period of an hour, and compares the effect of a lumbar HVLAT on non-smokers and smokers. Methods Thirty-six subjects received a unilateral HVLAT thrust at the lumbo-sacral junction. Twenty-six participated in the study, 15 non-smokers and 11 smokers. Five control subjects received no intervention. A laser Doppler Blood flow monitor measured subcutaneous blood flow in the dorsum of the foot in the L5 dermatome for a total of 60min. For statistical analysis the blood flow units were calculated as percentages with the baseline 5min reading being taken as 100% and subsequent 5min intervals being positive or negative. Results Following an HVT to the lumbo-sacral junction there was a significant difference ( P =0.02) in the 5min post-HVLAT period in the ipsilateral foot comparing smokers and non-smokers. There was no significant ( P >0.05) change in blood flow on the ipsilateral side of non-smokers. On the contralateral side there was a significant ( P =0.01) difference at 30min post-HVLAT and a significant difference ( P =0.006) at 55min post-HVLAT. In smokers there was a significant decrease ( P =0.02) in blood flow on the ipsilateral side in the 5min post-HVLAT period, which was also significant ( P =0.02) at 30min post-HVLAT but not at 55min. There was no significant change on the contralateral side of smokers. Conclusion This study indicates a difference in smoker and non-smoker response to the HVLAT. The author proposes that this is due to facilitation of the sympathetic nervous system in smokers causing a hyper-reactive predisposition.

Angiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans

We investigated the functional roles of circulating and locally produced angiotensin II (Ang II) in fasting and postprandial adipose tissue blood flow (ATBF) regulation and examined the interaction between Ang II and nitric oxide (NO) in ATBF regulation. Local effects of the pharmacological agents (or contralateral saline) on ATBF, measured with 133Xe wash-out, were assessed using the recently developed microinfusion technique. Fasting and postprandial (75 g glucose challenge) ATBF regulation was investigated in nine lean healthy subjects (age, 29 +/- 3 years; BMI, 23.4 +/- 0.7 kg m(-2)) using local Ang II stimulation, Ang II type 1 (AT1) receptor blockade, and angiotensin-converting enzyme (ACE) inhibition. Furthermore, NO synthase (NOS) blockade alone and in combination with AT1 receptor blockade was used to examine the interaction between Ang II and NO. Ang II induced a dose-dependent decrease in ATBF (10(-9)m: -16%, P = 0.04; 10(-7)m: -33%, P < 0.01; 10(-5)m: -53%P < 0.01). Fasting ATBF was not affected by ACE inhibition, but was increased by approximately 55% (P < 0.01) by AT(1) receptor blockade. NOS blockade induced a approximately 30% (P = 0.001) decrease in fasting ATBF. Combined AT1 receptor and NOS blockade increased ATBF by approximately 40% (P = 0.003). ACE inhibition and AT1 receptor blockade did not affect the postprandial increase in ATBF. We therefore conclude that circulating Ang II is a major regulator of fasting ATBF, and a major proportion of the Ang II-induced decrease in ATBF is NO independent. Locally produced Ang II does not appear to regulate ATBF. Ang II appears to have no major effect on the postprandial enhancement of ATBF.

The water-soluble extract of Illicium anisatum stimulates mouse vibrissae follicles in organ culture.

It is well known that reduced blood flow in the scalp is a cause of alopecia. We have shown previously that the extract of Illicium anisatum increases subcutaneous blood flow in mice. In the present study, we used an organ culture system to examine whether this extract promoted hair follicle elongation. B6C3HF1 mouse vibrissae follicles were cultured in serum-free medium for 7 days at 31 degrees C. Follicles treated with water-soluble (WS) extracts of the leaves, fruits and roots of Illicium anisatum or shikimic acid grew significantly longer than controls. In contrast, ethyl acetate-soluble (AS) extracts and n-hexane-soluble (HS) extracts of the leaves, fruits and roots of the plant inhibited hair follicles and shaft growth. Fractionation of the WS fruit extract showed that the number 1 and number 2 fractions possessed hair follicle elongation activity. GC/MS analysis revealed that the number 1 fraction contained shikimic acid, and that the number 2 fraction was a mixture of many components including glycosides and polysaccharides. Reverse transcription-polymerase chain reaction analysis demonstrated that shikimic acid also induced mRNA expression of insulin-like growth factor-1, keratinocyte growth factor, and vascular endothelial growth factor in the hair follicles. These results suggest that the WS extract of Illicium anisatum promotes hair growth and may be a useful additive in hair growth products.

Nitric oxide and beta-adrenergic stimulation are major regulators of preprandial and postprandial subcutaneous adipose tissue blood flow in humans.

Blood flow mediates the metabolic and endocrine roles of adipose tissue. We have previously shown that the postprandial adipose tissue blood flow (ATBF) increase is dependent on insulin sensitivity. However, subcutaneous local insulin delivery had no demonstrable effect on either preprandial or postprandial ATBF. We hypothesized that insulin may act indirectly via sympathetic activation, mainly in the postprandial period, and that nitric oxide may be an overall major regulator of subcutaneous ATBF. We investigated the endogenous preprandial and postprandial regulation of ATBF by applying local tissue blockade of beta-adrenergic (propranolol), alpha-adrenergic (phentolamine and yohimbine), and nitric oxide (NG-monomethyl-L-arginine, L-NMMA) regulation of blood flow. Healthy subjects (body mass index, 18 to 31 kg/m2) were challenged with 75 g glucose for endogenous stimulation of ATBF. We used the novel "microinfusion" technique, which allows for simultaneous local delivery of pharmacological agents (or contralateral saline) and measurement of ATBF with the 133Xe washout method. Compared with control, the preprandial ATBF was not affected by propranolol but was increased by 21% (P<0.013) and 15% (P=0.004) with phentolamine and yohimbine, respectively. A decrease of 42% (2.97+/-0.33 versus 4.75+/-0.47 mL x min(-1) x 100 g tissue(-1), P<0.01) was seen with L-NMMA. The postprandial response was blunted by 58% (0.81+/-0.42 versus 1.90+/-0.44 mL x min(-1) x 100 g tissue(-1), P<0.004) with propranolol, but neither phentolamine, yohimbine, or L-NMMA altered this response. Nitric oxide seems to determine the absolute level of ATBF, whereas a major proportion of the postprandial enhancement of ATBF is under beta-adrenergic regulation in vivo in humans.

Subcutaneous adipose tissue blood flow varies between superior and inferior levels of the anterior abdominal wall

Blood flow regulation is thought to mediate the metabolic functions of adipose tissue. Different depots, and even different layers within the subcutaneous adipose tissue, may vary in metabolic activity and blood flow. Therefore, we investigated if any differences in subcutaneous adipose tissue blood flow (ATBF) exist at different locations of the anterior abdominal wall. ATBF was measured 8-10 cm above or below the umbilicus, at 8-10 cm (both sides) from the midline, in 18 healthy subjects (BMI range 18-33 kg/m(2)). Measurements of ATBF were performed using (133)xenon washout, during a stable baseline period and after ingestion of 75 g of glucose. At baseline, ATBF was greater at the upper level compared to the lower level (4.4+/-0.3 vs 3.8+/-0.2 ml min(-1) 100 g tissue(-1), P=0.005), but was not different between the right and the left sides at either level. ATBF increased in response to oral glucose at all sites. The mean increase at the superior level was also greater than the inferior level (3.5+/-0.7 vs 2.2+/-0.6 ml min(-1) 100 g tissue(-1), P=0.001). Even at a constant depth and with only 16-20 cm difference between sites, there are significant differences in function of the same adipose depot. These findings have physiological and methodological implications for in vivo metabolic studies of human adipose tissue.

Systemic and microvascular responses to hemorrhagic shock and resuscitation with Hb vesicles.

A phospholipid vesicle encapsulating hemoglobin (Hb vesicle, HbV) has been developed to provide O(2)-carrying capacity to plasma expanders. Its ability to restore systemic and microcirculatory conditions after hemorrhagic shock was evaluated in the dorsal skinfold window preparation of conscious hamsters. The HbV was suspended in 8% human serum albumin (HSA) at Hb concentrations of 3.8 g/dl [HbV(3.8)/HSA] and 7.6 g/dl [HbV(7.6)/HSA]. Shock was induced by 50% blood withdrawal, and mean arterial pressure (MAP) at 40 mmHg was maintained for 1 h by the additional blood withdrawal. The hamsters receiving either HbV(3.8)/HSA or HbV(7.6)/HSA suspensions restored MAP to 93 +/- 14 and 93 +/- 10 mmHg, respectively, similar with those receiving the shed blood (98 +/- 13 mmHg), which were significantly higher by comparison with resuscitation with HSA alone (62 +/- 12 mmHg). Only the HSA group tended to maintain hyperventilation and negative base excess after the resuscitation. Subcutaneous microvascular blood flow reduced to approximately 10-20% of baseline during shock, and reinfusion of shed blood restored blood flow to approximately 60-80% of baseline, an effect primarily due to the sustained constriction of small arteries A(0) (diameter 143 +/- 29 microm). The HbV(3.8)/HSA group had significantly better microvascular blood flow recovery and nonsignificantly better tissue oxygenation than of the HSA group. The recovery of base excess and improved tissue oxygenation appears to be primarily due to the increased oxygen-carrying capacity of HbV fluid resuscitation.

Free fatty acids/triglycerides increase ocular and subcutaneous blood flow

Elevated plasma free fatty acids (FFA) induce skeletal muscle insulin resistance and impair endothelial function. The aim of this study was to characterize the acute hemodynamic effects of FFA in the eye and skin. A triglyceride (Intralipid 20%, 1.5 ml/min)/heparin (bolus: 200 IU; constant infusion rate: 0.2 IU. kg(-1). min(-1)) emulsion or placebo was administered to 10 healthy subjects. Measurements of pulsatile choroidal blood flow with laser interferometry, retinal blood flow with the blue field entoptic technique, peak systolic and end diastolic blood velocity (PSV, EDV) in the ophthalmic artery with Doppler sonography, and subcutaneous blood flow with laser Doppler flowmetry were performed during an euglycemic somatostatin-insulin clamp over 405 min. Plasma FFA/triglyceride elevation induced a rise in pulsatile choroidal blood flow by 25 +/- 3% (P < 0.001) and in retinal blood flow by 60 +/- 23% (P = 0.0125). PSV increased by 27 +/- 8% (P = 0.001), whereas EDV was not affected. Skin blood flow increased by 149 +/- 38% (P = 0.001). Mean blood pressure and pulse rate remained unchanged, whereas pulse pressure amplitude increased by 17 +/- 5% (P = 0.019). Infusion of heparin alone had no hemodynamic effect in the eye or skin. In conclusion, FFA/triglyceride elevation increases subcutaneous and ocular blood flow with a more pronounced effect in the retina than in the choroid, which may play a role for early changes of ocular perfusion in the insulin resistance syndrome.

Subcutaneous Perfusion and Oxygen During Acute Severe Isovolemic Hemodilution in Healthy Volunteers

Acute severe isovolemic anemia (to a hemoglobin [Hb] concentration of 50 g/L) does not decrease subcutaneous wound tissue oxygen tension (PsqO(2)). University hospital operating room and inpatient general clinical research center ward. Twenty-five healthy, paid volunteers. Subcutaneous oxygen tension and subcutaneous temperature (Tsq) were measured continuously during isovolemic hemodilution to an Hb level of 50 g/L. In 14 volunteers (initially well-perfused), "normal" perfusion (Tsq >34.4 degrees C) was achieved by hydration and systemic warming prior to starting isovolemic hemodilution, while in 11 volunteers (perfusion not controlled [PNC]), no attempt was made to control perfusion prior to hemodilution. Measurements of PsqO(2), Tsq, and relative subcutaneous blood flow (flow index). While PsqO(2), Tsq, and flow index were significantly lower in PNC vs well-perfused subjects at baseline, there was no significant difference between them at the Hb of 50 g/L (nadir). Subcutaneous PO(2) did not decrease significantly in either group. Arterial PO(2) was not different between the groups, and did not change significantly over time; Tsq and flow index increased significantly from baseline to nadir Hb in both groups. The level of PsqO(2) was maintained at baseline levels during hemodilution to Hb 50 g/L in healthy volunteers, whether they were initially well-perfused or mildly underperfused peripherally. Given the significant increase in Tsq and flow index, this resulted from a compensatory increase in subcutaneous blood flow sufficient to maintain oxygen delivery. Wound healing depends to a large extent on tissue oxygen delivery, and these data suggest that even severe anemia by itself would not be sufficient to impair wound healing. Thus, transfusion of autologous packed red blood cells solely to improve healing in surgical patients with no other indication for transfusion is not supported by these results.

Microdialysis assessment of local adipose tissue lipolysis during beta-adrenergic stimulation in upper-body-obese subjects with type II diabetes.

The present study was designed to investigate indicators of abdominal adipose tissue lipolysis (microdialysis), and subcutaneous adipose tissue blood flow and whole-body lipolysis, in obesity-associated type II diabetes during overnight-fasted conditions (baseline) and during intravenous infusion of the non-selective beta-agonist isoprenaline. Basal subcutaneous adipose tissue blood flow and isoprenaline-induced increases in adipose tissue blood flow were not significantly different between subjects with type II diabetes and non-obese, non-diabetic controls. Adipose tissue interstitial glycerol concentrations were significantly higher in subjects with type II diabetes compared with controls (P<0. 01), and during isoprenaline infusion there was a decrease in interstitial glycerol in both groups (P<0.001). Arterial glycerol concentrations were higher in subjects with type II diabetes compared with controls (P<0.05), whereas the increases in arterial glycerol concentration in response to isoprenaline infusion were of a similar magnitude in the two groups. Estimated subcutaneous adipose tissue glycerol release was not significantly different between the groups (controls and subjects with type II diabetes: baseline, -129+/-32 and -97+/-72 micromol.min(-1).100 g(-1) adipose tissue respectively; isoprenaline, -231+/-76 and -286+/-98 micromol. min(-1).100 g(-1) respectively). Values for fat oxidation were not significantly different between groups, whereas the isoprenaline-induced increase in fat oxidation tended to be less pronounced in subjects with type II diabetes compared with controls (0.022+/-0.008 and 0.038+/-0.003 g/min respectively; P=0.058). Thus estimated basal subcutaneous adipose tissue glycerol release, expressed per unit of fat mass, is not different in controls and in subjects with type II diabetes. Additionally, the isoprenaline-induced increases in indicators of local abdominal subcutaneous adipose tissue, systemic lipolysis and abdominal adipose tissue blood flow responses were comparable in obese subjects with type II diabetes and in controls. The last two findings contrast with previous data from obese subjects, indicating that the regulation of lipolysis may differ in obesity and obesity-associated type II diabetes.

Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon?

To elucidate potential mechanisms for insulin resistance occurring early in the development of type 2 diabetes, we studied 10 young healthy individuals, each with two first-degree relatives with type 2 diabetes, and 10 control subjects without known type 2 diabetic relatives. They were pairwise matched for age (35 +/- 1 vs. 35 +/- 1 years), BMI (23.6 +/- 0.6 vs. 23.1 +/- 0.4 kg/m2), and sex (four men, six women). Glucose turnover was assessed during a euglycemic clamp at two insulin levels (low approximately 20 mU/l; high approximately 90 mU/l), and abdominal subcutaneous adipose tissue (SAT) lipolysis and blood flow were concomitantly studied with microdialysis and 133Xe clearance. HbA1c was higher in patients with type 2 diabetic relatives than in control subjects (4.8 +/- 0.1 vs. 4.5 +/- 0.1%, P < 0.02), but fasting glucose, insulin, and C-peptide levels were similar. During the clamp, the insulin sensitivity index for glucose disposal was lower (P < 0.03) in relatives than in control subjects (low 12.0 +/- 1.6 vs. 18.1 +/- 1.4; high 9.4 +/- 0.8 vs. 12.9 +/- 0.6 [100 x mg x l x kg(-1) x mU(-1) x min(-1)]). This difference was partially attributed to slightly higher clamp insulin levels in the relatives (P < 0.03), suggesting an impaired rate for insulin clearance. SAT lipolysis measured as in situ glycerol release did not differ under basal conditions (2.0 +/- 0.2 vs. 2.1 +/- 0.2 micromol x kg(-1) x min(-1)), but the suppression during the insulin infusion was less marked in relatives than in control subjects (glycerol release: low 0.92 +/- 0.09 vs. 0.68 +/- 0.16; high 0.71 +/- 0.10 vs. 0.34 +/- 0.10 micromol x kg(-1) x min(-1); P < 0.03). Plasma nonesterified fatty acids also tended to be higher in relatives than in control subjects during the insulin infusion (NS). In contrast, in vitro experiments with isolated subcutaneous adipocytes displayed similar effects of insulin in relatives and control subjects with respect to both glucose uptake and antilipolysis. In conclusion, insulin action in vivo on both lipolysis and glucose uptake is impaired early in the development of type 2 diabetes. Since this impairment was not found in isolated adipocytes, it may be suggested that neural or hormonal perturbations precede cellular insulin resistance in type 2 diabetes.

Regional blood flow in the calf and plasma endothelin during prolonged orthostasis in humans

This study tested the hypothesis that circulating plasma levels of the vasoconstrictor endothelin increase during prolonged orthostasis in association with changes in both calf regional blood flow, systemic arterial blood pressure and heart rate, and that the 133Xenon wash-out method can be used for prolonged registration of skeletal muscle blood flow. The simultaneous effects of prolonged orthostasis on plasma endothelin, calf skeletal muscle and subcutaneous blood flow, heart rate and arterial blood pressure were investigated in 13 healthy subjects before, during and after 30 min of 50° head-up tilt. Blood flow rate was measured by the local 133Xenon wash-out method in the supine position and during 50° head-up tilt. The method was evaluated for skeletal muscle for prolonged observation in the supine position in five subjects and compared with blood flow rates measured with plethysmography. Plasma endothelin was unchanged during head-up tilt, despite a maximal reduction in skeletal muscle blood flow rate of 47% (p<0.001) and subcutaneous blood flow rate of 80% (p<0.01) and a maximal increase in heart rate of 15% (p<0.001) and diastolic (12%, p<0.01) blood pressure. The skeletal muscle wash-out curves for 133Xenon were monoexponential from 30 min after injection and at least during the next hour and correlated with total limb blood flow rate assessed simultaneously with plethysmography (r=0.76, p<0.0001). Circulating endothelin does not appear to be in the first line of regulation of calf microcirculation, systemic arterial blood pressure or heart rate during prolonged orthostasis. The 133Xenon wash-out method can be used for prolonged measurement of skeletal muscle blood flow.

Effects of dynamic leg exercise on subcutaneous blood flow rate in the lower limb of man.

Subcutaneous blood flow (SBF) was studied simultaneously in the upper arm at heart level and in the lower limb during positional changes and during leg exercise in seven healthy males. SBF was estimated by local clearance of 133Xenon registered by portable cadmium telluride detectors. Venous pressure was recorded directly on dorsum on the foot. Changing the position from supine to head-up tilt, SBF decreased by 43% (P less than 0.01) at the arm level, 40% at the thigh (P less than 0.01), 47% at the calf (P less than 0.01) and decreased by 51% at the ankle level (P less than 0.01). Performing 20 heel-raisings per min in nearly erect posture, SBF increased by 96% at the thigh (P less than 0.01), 25% at the calf (P greater than 0.1) and increased by 18% at the ankle level (P greater than 0.01). At 40 heel-raisings per min SBF increased by 99% at the thigh (P less than 0.01), 121% at the calf (P less than 0.01), but only 44% at the ankle level (P greater than 0.1). During leg exercise subcutaneous vascular resistance was significantly increased at arm and ankle levels. In contrast, a vasodilatory response was noticed at the thigh and calf levels and seemed associated with a decrease in local venous pressure to below the trigger level of the sympathetic veno-arteriolar reflex mechanism. In conclusion, SBF in the lower limb of man was increased during exercise. The increase in SBF could only partly be ascribed to the concomitant increase in perfusion pressure. The local blood flow response seemed modified by changes in sympathetic nervous activity and metabolic rate.

Glucose metabolism in chronic diabetic foot ulcers measured in vivo using microdialysis.

Ten subjects with diabetes mellitus and unilateral chronic foot ulcer were investigated. Local tissue concentrations of glucose and lactate were measured using the microdialysis method at a distance of 0.5-1 cm from the edge of the ulcer and in normal skin in the contralateral foot. Subcutaneous blood flow in the area investigated was measured using the 133Xewashout technique. The interstitial glucose concentration in the ulcer was found to be lower than in intact skin (8.0 +/- 1.0 mmol l-1 vs. 8.5 +/- 1.1 mmol l-1) (P < 0.02), and the interstitial lactate concentration was higher in the ulcer than in intact skin (3.2 +/- 0.2 mmol l-1 vs. 2.1 +/- 0.3 mmol l-1) (P < 0.01). The subcutaneous blood flow was on average 40% higher in the ulcer than in the intact skin. The calculated local glucose uptake and lactate outputs were twofold higher in the ulcer than in the intact skin. However, the molar ratio between lactate output and glucose uptake was approximately two, both in the ulcer and in the intact skin, indicating that the glucose metabolism was qualitatively the same in the two regions.

An exploratory investigation of the morphology and biochemistry of cellulite.

Dimpling of the skin of the thighs and buttocks is commonly referred to as cellulite, and it afflicts women much more frequently than men. Whereas many therapies that presume cellulite is caused by an abnormality of adipose tissue have gained recent popularity, the basic pathophysiology of cellulite has not been clearly identified. Theoretically, cellulite could reflect differences in adipose tissue biochemistry or connective tissue structure of affected versus unaffected individuals and/or of affected versus unaffected regions within an individual. We report here on direct experimental examination of these possibilities. Seven healthy adult subjects (five women, two men; four affected, three unaffected) underwent sonography of the thigh, measurement of regional in vivo subcutaneous adipose tissue metabolism (catecholaminergic responsiveness and blood flow) by microdialysis probe studies of the abdomen and the thigh, and full-thickness wedge biopsy of the thigh under local anesthesia. The presence of cellulite was defined as evidence of dimpling of the skin of the posterolateral thigh when the subject stood with the affected leg flexed to 90 degrees at the hip and knee. Any continuous area of skin at least 3 cm in diameter in which no dimpling was evident was designated as "unaffected." In all affected individuals, studies were performed to include both affected and unaffected areas of the thigh. In vitro pathologic examination of wedge biopsies and in vivo sonographic examination of the thigh both showed a diffuse pattern of extrusion of underlying adipose tissue into the reticular dermis in affected, but not unaffected, individuals. In vitro and in vivo studies also demonstrated that women had a diffuse pattern of irregular and discontinuous connective tissue immediately below the dermis, but this same layer of connective tissue was smooth and continuous in men. This connective tissue layer was more irregular and discontinuous in affected versus unaffected individuals. No significant differences were noted in subcutaneous adipose tissue morphology, lipolytic responsiveness, or regional blood flow between affected and unaffected sites within individuals. There is a sexual dimorphism in the structural characteristics of subdermal connective tissue that predisposes women to develop the irregular extrusion of adipose tissue into the dermis, which characterizes cellulite. These gender-related differences are diffuse and not localized only to affected areas. There is no evidence of any primary role for adipose tissue physiology, blood flow, or biochemistry in the etiology of cellulite, although the connective tissue of the female thigh is structured to accentuate differences in small subdermal adipose tissue depots.