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Adipose tissue microvascular blood flow (MBF) is stimulated postprandially to augment delivery of nutrients and hormones to adipocytes. Adipose tissue MBF is impaired in type 2 diabetes (T2D). Whether healthy individuals at-risk of T2D show similar impairments is unknown. We aimed to determine whether adipose tissue MBF is impaired in apparently healthy individuals with a family history of T2D. Overnight-fasted individuals with no family history of T2D for two generations (FH-, n = 13), with at least one parent with T2D (FH+, n = 14) and clinically diagnosed T2D (n = 11) underwent a mixed meal challenge (MMC). Metabolic responses [blood glucose, plasma insulin, plasma nonesterified fatty acids (NEFAs), and fat oxidation] were measured before and during the MMC. MBF in truncal subcutaneous adipose tissue was assessed by contrast ultrasound while fasting and 60 min post-MMC. FHþ had normal blood glucoses, increased adiposity, and impaired post-MMC adipose tissue MBF (Δ0.70 ± 0.22 vs. 2.45 ± 0.60 acoustic intensity/s, P = 0.007) and post-MMC adipose tissue insulin resistance (Adipo-IR index; Δ45.5 ± 13.9 vs. 7.8 ± 5.1 mmol/L × pmol/L, P = 0.007) compared with FH-. FH+ and T2D had an impaired ability to suppress fat oxidation post-MMC. Fat oxidation incremental area under the curve (iAUC) (35-55 min post-MMC, iAUC) was higher in FH+ and T2D than in FH- (P = 0.005 and 0.009, respectively). Postprandial MBF was negatively associated with postprandial fat oxidation iAUC (P = 0.01). We conclude that apparently healthy FH+ individuals display blunted postprandial adipose tissue MBF that occurs in parallel with adipose tissue insulin resistance and impaired suppression of fat oxidation, which may help explain their heightened risk for developing T2D. [ABSTRACT FROM AUTHOR]

Insulin infusion increases skeletal muscle microvascular blood flow (MBF) in healthy people but is impaired during insulin resistance. However, we have shown that eliciting insulin secretion via oral glucose loading in healthy people impairs muscle MBF, whilst others have demonstrated intravenous glucose infusion stimulates MBF. We aimed to show that the route of glucose administration (oral versus intravenous) influences muscle MBF, and explore potential gut‐derived hormones that may explain these divergent responses. Ten healthy individuals underwent a 120 min oral glucose tolerance test (OGTT; 75 g glucose) and on a subsequent occasion an intravenous glucose tolerance test (IVGTT, bypassing the gut) matched for similar blood glucose excursions. Femoral artery and thigh muscle microvascular (contrast‐enhanced ultrasound) haemodynamics were measured at baseline and during the OGTT/IVGTT. Plasma insulin, C‐peptide, glucagon, non‐esterified fatty acids and a range of gut‐derived hormones and incretins (gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1(GLP‐1)) were measured at baseline and throughout the OGTT/IVGTT. The IVGTT increased whereas the OGTT impaired MBF (1.3‐fold versus 0.5‐fold from baseline, respectively, P = 0.0006). The impairment in MBF during the OGTT occurred despite producing 2.8‐fold higher plasma insulin concentrations (P = 0.0001). The change in MBF from baseline (ΔMBF) negatively correlated with ΔGIP concentrations (r = −0.665, P < 0.0001). The natural log ratio of incretins GLP‐1:GIP was positively associated with ΔMBF (r = 0.658, P < 0.0001), suggesting they have opposing actions on the microvasculature. Postprandial hyperglycaemia per se does not acutely determine opposing microvascular responses between OGTT and IVGTT. Incretins may play a role in modulating skeletal muscle MBF in humans. Key points: Insulin or mixed nutrient meals stimulate skeletal muscle microvascular blood flow (MBF) to aid in the delivery of nutrients; however, this vascular effect is lost during insulin resistance.Food/drinks containing large glucose loads impair MBF in healthy people; however, this impairment is not observed when glucose is infused intravenously (bypassing the gut).We investigated skeletal muscle MBF responses to a 75 g oral glucose tolerance test and intravenous glucose infusion and aimed to identify potential gut hormones responsible for glucose‐mediated changes in MBF.Despite similar blood glucose concentrations, orally ingested glucose impaired, whereas intravenously infused glucose augmented, skeletal muscle MBF. The incretin gastric inhibitory polypeptide was negatively associated with MBF, suggestive of an incretin‐mediated MBF response to oral glucose ingestion.This work provides new insight into why diets high in glucose may be detrimental to vascular health and provides new avenues for novel treatment strategies targeting microvascular dysfunction. [ABSTRACT FROM AUTHOR]

Key points: Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high‐glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism.We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high‐glucose mixed‐nutrient meal ingested 3 and 24 h post‐exercise.Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high‐glucose mixed meal ingested 3 h post‐exercise, and to a lesser extent 24 h post‐exercise.High‐glucose ingestion 3 h post‐exercise leads to greater postprandial blood glucose, non‐esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control.Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion lead to increased muscle microvascular blood flow (MBF), whereas high‐glucose ingestion impairs MBF. We investigated whether prior cycling exercise could enhance postprandial muscle MBF and prevent MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion. In a randomized cross‐over design, eight healthy young men ingested a high‐glucose mixed‐nutrient meal (1.1 g glucose/kg body weight; 45% carbohydrate, 20% protein and 35% fat) after an overnight fast (no‐exercise control) and 3 h and 24 h after moderate‐intensity cycling exercise (1 h at 70–75% V̇O2peak). Skeletal muscle MBF, measured directly by contrast‐enhanced ultrasound, was lower at 60 min and 120 min postprandially compared to baseline in all conditions (P < 0.05), with a greater decrease occurring from 60 min to 120 min in the control (no‐exercise) condition only (P < 0.001). Despite this meal‐induced decrease, MBF was still markedly higher compared to control in the 3 h post‐exercise condition at 0 min (pre‐meal; 74%, P = 0.004), 60 min (112%, P = 0.002) and 120 min (223%, P < 0.001), and in the 24 h post‐exercise condition at 120 min postprandially (132%, P < 0.001). We also report that in the 3 h post‐exercise condition postprandial blood glucose, non‐esterified fatty acids (NEFAs), and fat oxidation were substantially elevated, and the insulin response to the meal delayed compared to control. This probably reflects a combination of increased post‐exercise exogenous glucose appearance, substrate competition, and NEFA‐induced insulin resistance. We conclude that prior cycling exercise elicits long‐lasting effects on muscle MBF and partially mitigates MBF impairments induced by high‐glucose mixed‐nutrient meal ingestion. Key points: Exercise, insulin‐infusion and low‐glucose mixed‐nutrient meal ingestion increases muscle microvascular blood flow which in part facilitates glucose delivery and disposal. In contrast, high‐glucose ingestion impairs muscle microvascular blood flow which may contribute to impaired postprandial metabolism.We investigated the effects of prior cycling exercise on postprandial muscle microvascular blood flow responses to a high‐glucose mixed‐nutrient meal ingested 3 and 24 h post‐exercise.Prior exercise enhanced muscle microvascular blood flow and mitigated microvascular impairments induced by a high‐glucose mixed meal ingested 3 h post‐exercise, and to a lesser extent 24 h post‐exercise.High‐glucose ingestion 3 h post‐exercise leads to greater postprandial blood glucose, non‐esterified fatty acids, and fat oxidation, and a delay in the insulin response to the meal compared to control.Effects of acute exercise on muscle microvascular blood flow persist well after the cessation of exercise which may be beneficial for conditions characterized by microvascular and glycaemic dysfunction. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is an important vasodilator and regulator in the cardiovascular system, and this link was the subject of a Nobel prize in 1998. However, NO also plays many other regulatory roles, including thrombosis, immune function, neural activity, and gastrointestinal function. Low concentrations of NO are thought to have important signaling effects. In contrast, high concentrations of NO can interact with reactive oxygen species, causing damage to cells and cellular components. A less-recognized site of NO production is within skeletal muscle, where small increases are thought to have beneficial effects such as regulating glucose uptake and possibly blood flow, but higher levels of production are thought to lead to deleterious effects such as an association with insulin resistance. This review will discuss the role of NO in skeletal muscle during and following exercise, including in mitochondrial biogenesis, muscle efficiency, and blood flow with a particular focus on its potential role in regulating skeletal muscle glucose uptake during exercise. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We have previously shown in humans that local infusion of a nitric oxide synthase (NOS) inhibitor into the femoral artery attenuates the increase in leg glucose uptake during exercise without influencing total leg blood flow. However, rodent studies examining the effect of NOS inhibition on contraction-stimulated skeletal muscle glucose uptake have yielded contradictory results. This study examined the effect of local infusion of an NOS inhibitor on skeletal muscle glucose uptake (2-deoxyglucose) and capillary blood flow (contrast-enhanced ultrasound) during in situ contractions in rats. RESEARCH DESIGN AND METHODS--Male hooded Wistar rats were anesthetized and one hindleg electrically stimulated to contract (2 Hz, 0.1 ms) for 30 min while the other leg rested. After 10 min, the NOS inhibitor N[sup G]-nitro-L-arginine methyl ester (LNAME) (arterial concentration of 5 µmol/l) or saline was infused into the epigastric artery of the contracting leg. RESULTS--Local NOS inhibition had no effect on blood pressure, heart rate, or muscle contraction force. Contractions increased (P < 0.05) skeletal muscle NOS activity, and this was prevented by L-NAME infusion. NOS inhibition caused a modest significant (P < 0.05) attenuation of the increase in femoral blood flow during contractions, but importantly there was no effect on capillary recruitment. NOS inhibition attenuated (P < 0.05) the increase in contraction-stimulated skeletal muscle glucose uptake by ∼35%, without affecting AMP-activated protein kinase (AMPK) activation. CONCLUSIONS--NOS inhibition attenuated increases in skeletal muscle glucose uptake during contraction without influencing capillary recruitment, suggesting that NO is critical for part of the normal increase in skeletal muscle fiber glucose uptake during contraction. Diabetes 56:2885-2892, 2007 [ABSTRACT FROM AUTHOR]