Obesity Blunts Microvascular Recruitment in Human Forearm Muscle After a Mixed Meal

OBJECTIVE

Ingestion of a mixed meal recruits flow to muscle capillaries and increases total forearm blood flow in healthy young lean people. We examined whether these vascular responses are blunted by obesity.

RESEARCH DESIGN AND METHODS

We fed eight middle-aged lean and eight obese overnight-fasted volunteers a liquid mixed meal (480 kcal). Plasma glucose and insulin were measured every 30 min, and brachial artery flow and muscle microvascular recruitment (contrast ultrasound) were assessed every 60 min over 2 h after the meal.

RESULTS

By 30 min, plasma glucose rose in both the lean (5.1 ± 0.1 vs. 6.7 ± 0.4 mmol/l, P < 0.05) and the obese groups (5.4 ± 0.2 vs. 6.7 ± 0.4 mmol/l, P < 0.05). Plasma insulin rose (28 ± 4 vs. 241 ± 30 pmol/l, P < 0.05) by 30 min in the lean group and remained elevated for 2 h. The obese group had higher fasting plasma insulin levels (65 ± 8 pmol/l, P < 0.001) and a greater postmeal area under the insulin-time curve (P < 0.05). Brachial artery flow was increased at 120 min after the meal in the lean group (38 ± 6 vs. 83 ± 16 ml/min, P < 0.05) but not in the obese group. Muscle microvascular blood volume rose by 120 min in the lean group (14.4 ± 2.2 vs. 24.4 ± 4.2 units, P < 0.05) but not in the obese group.

CONCLUSIONS

A mixed meal recruits muscle microvasculature in lean subjects, and this effect is blunted by obesity. This impaired vascular recruitment lessens the endothelial surface available and may thereby impair postprandial glucose disposal.Skeletal muscle is a major site for insulin-mediated glucose storage and thereby influences postprandial plasma glucose levels (1). Over the past 15 years it has become increasingly evident that insulin exerts important actions on muscle vasculature as an integral part of its action to increase glucose disposal (2–5). Within muscle the vascular endothelium is the first tissue that insulin encounters. A primary function of the endothelium is to serve as a permeability barrier that restricts transport of macromolecules such as insulin into the interstitial space. In addition to modulating delivery of insulin to muscle cells, the endothelium also directly responds to insulin by increasing production of nitric oxide, a potent vasodilator, and endothelin-1, a potent vasoconstrictor, to regulate muscle blood flow (6,7).Baron and colleagues (2,8,9) hypothesized that insulin increases leg blood flow to facilitate access of glucose and insulin to muscle, thereby increasing glucose disposal. Blocking insulin-induced increases in blood flow reduced insulin-stimulated glucose disposal by ∼30%. Furthermore, this vascular action of insulin was significantly blunted in insulin-resistant obese humans (8).These investigators used a thermodilution method that measured only total limb blood flow and not microvascular responses. Others have measured the effect of insulin on limb blood flow using a variety of methods with divergent findings (10,11). Our laboratories have developed new methods that assess the microvascular action of insulin in muscle (3,5,12,13). We reasoned that microvascular perfusion directly mediates nutrient exchange in muscle (14). We have previously shown that insulin acts on preterminal arterioles (which control microvascular blood flow) more rapidly and at more physiologically relevant insulin concentrations than is the case for resistance arteries (which control total muscle blood flow) (3,5,12).Using contrast-enhanced ultrasound (CEU) and the euglycemic insulin clamp method, we observed that physiological hyperinsulinemia expands the volume of microvasculature perfused in forearm muscle of healthy lean people (4,15) and that this action of insulin is markedly impaired in obese subjects (4). Indeed, we observed a negative correlation between insulin-mediated microvascular recruitment in muscle and BMI (4). Although the clamp technique provides an excellent assessment of the physiological actions of insulin, it does not mimic the changes that typically occur after the ingestion of a mixed meal. With the meal there are changes in blood glucose, amino acids, gut hormones, and parasympathetic/sympathetic tone. Few studies have reported on the effect of a meal on total limb blood flow, and these have yielded conflicting results. Although some investigators reported that the ingestion of a mixed meal (16) or an oral glucose load (17) increased total limb blood flow, others reported no effect (18). These differences may relate to techniques used to measure flow, the types of meals ingested, and differences in the population studied. However, in each of these clinical studies, investigators have measured only total limb blood flow and not microvascular responses.We have recently reported that ingestion of a mixed meal by lean young adults increases total forearm blood flow and increases microvascular flow (19). These vascular responses occurred at a time when plasma insulin was significantly elevated. Whether total muscle blood flow along with muscle microvascular recruitment after the ingestion of a mixed meal is normal or blunted in insulin-resistant obese subjects is unknown, and addressing this issue was the goal of the current study. We used Doppler ultrasound to study total forearm blood flow and CEU to quantify muscle microvascular responses of forearm muscle in healthy lean and otherwise healthy obese age-matched adults in response to a mixed meal. We hypothesized that both total limb blood flow and the microvascular response would be blunted by obesity.     

Effect of Agouti-related protein on development of conditioned taste aversion and oxytocin neuronal activation

Agouti-related protein (Agrp) is an orexigenic peptide that acts as an antagonist of the melanocortin-3 and -4 receptors. Initial studies suggest similarities between the effects of Agrp and opioid peptides on ingestive behavior. Given these observations, we examined whether Agrp, similarly to opioids, alleviates conditioned taste aversion (CTA) generated by peripheral injection of LiCl. Agrp (1 nmol) delivered to the lateral cerebral ventricle, a dose known to cause orexigenic effects, was shown to partially block acquisition of LiCl-induced CTA. Agrp also decreased the percentage of c-Fos-positive oxytocin neurons induced by LiCl in the hypothalamic paraventricular and supraoptic nuclei. Inhibitory effects of Agrp on acquisition of CTA and aversion-associated activation of oxytocin neurons parallel what has previously been shown with opioid receptor agonists.     

Single night video-game use leads to sleep loss and attention deficits in older adolescents

The present study investigated adolescent video-game use prior to bedtime and subsequent sleep, working memory and sustained attention performance. Participants were 21 healthy, good-sleeping adolescents (16 male) aged between 15 and 20 years (M = 17.6 years, SD = 1.8). Time spent video-gaming and subsequent sleep was measured across one night in the sleep laboratory. There were significant correlations between time spent video-gaming and sleep and between video-gaming and sustained attention, but not working memory. Sleep duration, in turn, had a significant negative association with sustained attention performance. Mediation analyses revealed that the relationship between video-gaming and sustained attention was fully mediated by sleep duration. These results indicate that video-gaming affected the ability to sustain attention only in as much as it affected sleep. In order to minimise negative consequences of video-game playing, video-games should be used in moderation, avoiding use close to the sleep period, to obviate detriments to sleep and performance.     

Functional reorganization and recovery after constraint-induced movement therapy in subacute stroke: case reports

Preliminary assessments of the feasibility, safety, and effects on neuronal reorganization measured with transcranial magnetic stimulation (TMS) from Constraint-Induced Movement Therapy (CIMT) of the upper extremity were made in eight cases of subacute stroke. Within fourteen days of their stroke, patients were randomly assigned to two weeks of CIMT or traditional therapy. Baseline motor performance and cortical/subcortical representation for movement with TMS were assessed before treatment. Post-treatment assessments were made at the end of treatment and at three months after the stroke. The TMS mapping showed a larger motor representation in the lesioned hemisphere of the CIMT patients as compared to the controls at the three-month follow-up assessment. The enlarged motor representation in the lesioned hemisphere for hand movement correlated with improved motor function of the affected hand, suggesting a link between movement representation size as measured with TMS and functionality. These results suggest that TMS can be safely and effectively used to assess brain function in subacute stroke and further suggest that CIMT may enhance cortical/subcortical motor reorganization and accelerate motor recovery when started within the first two weeks after stroke.