Regulation of microvascular flow and metabolism: An overview

Skeletal muscle is an important site for insulin to regulate blood glucose levels. It is estimated that skeletal muscle is responsible for ~80% of insulin-mediated glucose disposal in the post-prandial period. The classical action of insulin to increase muscle glucose uptake involves insulin binding to insulin receptors on myocytes to stimulate glucose transporter 4 (GLUT 4) translocation to the cell surface membrane, enhancing glucose uptake. However, an additional role of insulin that is often under-appreciated is its action to increase muscle perfusion thereby improving insulin and glucose delivery to myocytes. Either of these responses (myocyte and/or vascular) may be impaired in insulin resistance, and both impairments are apparent in type 2 diabetes, resulting in diminished glucose disposal by muscle. The aim of this review is to report on the growing body of literature suggesting that insulin-mediated control of skeletal muscle perfusion is an important regulator of muscle glucose uptake and that impairment of microvascular insulin action has important physiological consequences early in the pathogenesis of insulin resistance. This work was discussed at the 2015 Australian Physiological Society Symposium “Physiological mechanisms controlling microvascular flow and muscle metabolism”

The Reproducibility of 31-Phosphorus MRS Measures of Muscle Energetics at 3 Tesla in Trained Men

Magnetic resonance spectroscopy (MRS) provides an exceptional opportunity for the study of in vivo metabolism. MRS is widely used to measure phosphorus metabolites in trained muscle, although there are no published data regarding its reproducibility in this specialized cohort. Thus, the aim of this study was to assess the reproducibility of (31)P-MRS in trained skeletal muscle

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Skeletal Muscle Microvascular-Linked Improvements in Glycemic Control From Resistance Training in Individuals With Type 2 Diabetes

OBJECTIVE Insulin increases glucose disposal in part by enhancing microvascular blood flow (MBF) and substrate delivery to myocytes. Insulin’s microvascular action is impaired with insulin resistance and type 2 diabetes. Resistance training (RT) improves glycemic control and insulin sensitivity, but whether this improvement is linked to augmented skeletal muscle microvascular responses in type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS Seventeen (11 male and 6 female; 52 ± 2 years old) sedentary patients with type 2 diabetes underwent 6 weeks of whole-body RT. Before and after RT, participants who fasted overnight had clinical chemistries measured (lipids, glucose, HbA1c, insulin, and advanced glycation end products) and underwent an oral glucose challenge (OGC) (50 g × 2 h). Forearm muscle MBF was assessed by contrast-enhanced ultrasound, skin MBF by laser Doppler flowmetry, and brachial artery flow by Doppler ultrasound at baseline and 60 min post-OGC. A whole-body DEXA scan before and after RT assessed body composition. RESULTS After RT, muscle MBF response to the OGC increased, while skin microvascular responses were unchanged. These microvascular adaptations were accompanied by improved glycemic control (fasting blood glucose, HbA1c, and glucose area under the curve [AUC] during OGC) and increased lean body mass and reductions in fasting plasma triglyceride, total cholesterol, advanced glycation end products, and total body fat. Changes in muscle MBF response after RT significantly correlated with reductions in fasting blood glucose, HbA1c, and OGC AUC with adjustment for age, sex, % body fat, and % lean mass. CONCLUSIONS RT improves OGC-stimulated muscle MBF and glycemic control concomitantly, suggesting that MBF plays a role in improved glycemic control from RT

Subjects’ characteristics (<i>n</i> = 15).

<p>Subjects’ characteristics (<i>n</i> = 15).</p

Summary of published data regarding the reproducibility of ³¹P-magnetic resonance spectroscopy in skeletal muscle (in chronological order).

<p>Summary of published data regarding the reproducibility of ³¹P-magnetic resonance spectroscopy in skeletal muscle (in chronological order).</p

Typical experimental data (phosphocreatine concentration, normalised to resting values, in recovery from dynamic exercise) and a monoexponential function (solid line), fitted as described in Methods.

<p>Typical experimental data (phosphocreatine concentration, normalised to resting values, in recovery from dynamic exercise) and a monoexponential function (solid line), fitted as described in Methods.</p

Stacked plot showing 31-phosphorus magnetic resonance spectra acquired at 5-second intervals from the calf muscle of a single trained subject in recovery from dynamic exercise.

<p>Stacked plot showing 31-phosphorus magnetic resonance spectra acquired at 5-second intervals from the calf muscle of a single trained subject in recovery from dynamic exercise.</p

Reproducibility of ³¹P-MRS in trained skeletal muscle (<i>n</i> = 15).

*<p>Significant correlation between means and absolute differences at p<0.05. ¹n = 14.</p