Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity.

We tested the hypothesis that endothelium-dependent vasodilatation is a determinant of insulin resistance of skeletal muscle glucose uptake in human obesity. Eight obese (age 26+/-1 yr, body mass index 37+/-1 kg/m2) and seven nonobese males (25+/-2 yr, 23+/-1 kg/m2) received an infusion of bradykinin into the femoral artery of one leg under intravenously maintained normoglycemic hyperinsulinemic conditions. Blood flow was measured simultaneously in the bradykinin and insulin- and the insulin-infused leg before and during hyperinsulinemia using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET). Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose ([18F]FDG) and PET. Whole body insulin-stimulated glucose uptake was lower in the obese (507+/-47 mumol/m2 . min) than the nonobese (1205+/-97 micromol/m2 . min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 micromol/kg muscle . min) than in the nonobese (56+/-9 micromol/kg muscle . min, P < 0.005) subjects. Bradykinin increased blood flow during hyperinsulinemia in the obese subjects by 75% from 16+/-1 to 28+/-4 ml/kg muscle . min (P < 0.05), and in the normal subjects by 65% from 23+/-3 to 38+/-9 ml/kg muscle . min (P < 0.05). However, this flow increase required twice as much bradykinin in the obese (51+/-3 microg over 100 min) than in the normal (25+/-1 mug, P < 0.001) subjects. In the obese subjects, blood flow in the bradykinin and insulin-infused leg (28+/-4 ml/kg muscle . min) was comparable to that in the insulin-infused leg in the normal subjects during hyperinsulinemia (24+/-5 ml/kg muscle . min). Despite this, insulin-stimulated glucose uptake remained unchanged in the bradykinin and insulin-infused leg (18+/-4 mumol/kg . min) compared with the insulin-infused leg (19+/-4 micromol/kg muscle . min) in the obese subjects. Insulin-stimulated glucose uptake also was unaffected by bradykinin in the normal subjects (58+/-10 vs. 56+/-9 micromol/kg . min, bradykinin and insulin versus insulin leg). These data demonstrate that obesity is characterized by two distinct defects in skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation. Since a 75% increase in blood flow does not alter glucose uptake, insulin resistance in obesity cannot be overcome by normalizing muscle blood flow.     

Decreased blood flow but unaltered insulin sensitivity of glucose uptake in skeletal muscle of chronic smokers

Chronic cigarette smoking is associated with dysfunction of the vascular endothelium. Smokers have also been shown to be insulin-resistant, at least in some studies. Since insulin-induced vasodilation is dependent on endothelial cell nitric oxide (NO) synthesis, we tested the hypothesis that decreased skeletal muscle blood flow causes insulin resistance in smokers. We studied 37 young normotensive normolipidemic nondiabetic men, of which 14 were smokers and 23 lifelong nonsmokers. The groups were similar with respect to age, body mass index (BMI), and maximal oxygen uptake (VO2max). Basal and insulin-stimulated femoral muscle blood flow was measured using [(15)O]H2O and insulin-stimulated muscle glucose uptake using [18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET). Whole-body glucose uptake was measured using the hyperinsulinemic (insulin infusion 5 mU/kg x min)-euglycemic clamp technique. In the basal state, muscle blood flow was 51% lower in smokers (17 +/- 3 mL/kg muscle x min) versus nonsmokers (35 +/- 17 mL/kg x min, P < .0001). Insulin increased muscle blood flow comparably in both groups; the mean rate of insulin-stimulated blood flow was 30 +/- 10 and 55 +/- 38 mL/kg x min (P = .049), respectively. Whole-body and skeletal muscle glucose uptake were similar in both groups during insulin infusion. We conclude that muscle blood flow is lower in chronic smokers compared with nonsmokers under both fasting and hyperinsulinemic conditions. The insulin-induced increase in muscle blood flow and insulin-stimulated glucose uptake appear normal, suggesting that the vasodilatory and metabolic effects of insulin are intact in smokers and the reduced muscle blood flow per se does not cause insulin resistance in these subjects.     

Society position statement

Purpose

There are more than 200,000 Canadians living with permanent pacemakers or implantable defibrillators, many of whom will require surgery or invasive procedures each year. They face potential hazards when undergoing surgery; however, with appropriate planning and education of operating room personnel, adverse device-related outcomes should be rare. This joint position statement from the Canadian Cardiovascular Society (CCS) and the Canadian Anesthesiologists?? Society (CAS) has been developed as an accessible reference for physicians and surgeons, providing an overview of the key issues for the preoperative, intraoperative, and postoperative care of these patients.

Principal findings

The document summarizes the limited published literature in this field, but for most issues, relies heavily on the experience of the cardiologists and anesthesiologists who contributed to this work. This position statement outlines how to obtain information about an individual??s type of pacemaker or implantable defibrillator and its programming. It also stresses the importance of determining if a patient is highly pacemaker-dependent and proposes a simple approach for nonelective evaluation of dependency. Although the document provides a comprehensive list of the intraoperative issues facing these patients, there is a focus on electromagnetic interference resulting from electrocautery and practical guidance is given regarding the characteristics of surgery, electrocautery, pacemakers, and defibrillators which are most likely to lead to interference.

Conclusions

The document stresses the importance of preoperative consultation and planning to minimize complications. It reviews the relative merits of intraoperative magnet use vs reprogramming of devices and gives examples of situations where one or the other approach is preferable.     

Bacterial infection (BI)-INDEX: an improved and simplified rapid flow cytometric bacterial infection marker

The aim of this study was to develop a rapid and simple flow cytometric bacterial infection marker. In this prospective comparative study, quantitative flow cytometric analysis of CD10, CD35, CD66b, CD282, and MHC Class I molecules on human neutrophils, monocytes, and B-lymphocytes from 141 hospitalized febrile patients with suspected infection and from 50 healthy controls was performed. We developed a flow cytometric marker of local and systemic bacterial infections, designated “bacterial infection (BI)-INDEX”, incorporating the quantitative analysis of CD10, CD35, MHCI, CD66b, and CD282 on neutrophils, monocytes, and B-lymphocytes, which displayed 90% sensitivity and 96% specificity in distinguishing between microbiologically confirmed bacterial (n = 31) and viral infections (n = 27) within a 1-h time-frame. We propose that our novel rapid BI-INDEX test will be useful in assisting physicians to ascertain whether antibiotic treatment is required, thus limiting unnecessary antimicrobial usage.     

Brown adipose tissue thermogenesis in humans

The prevalence of obesity and type 2 diabetes is at epidemic proportions. Classical interventions aimed at targeting obesity, such as reducing energy intake or increasing exercise, are often not effective over the long term. In contrast to white adipocytes, which store energy, brown adipocytes generate heat via mitochondrial uncoupling protein 1, thereby acting as a defence against hypothermia and, potentially, obesity. In this issue of Diabetologia, Admiraal et al compare brown adipose tissue activation during cold exposure between two different ethnic groups: South Asians and Europids. The prevalence of abdominal obesity and type 2 diabetes differs among various ethnic groups and decreased BAT metabolic activity could be one causal factor. As yet, the clinical impact of this ‘rediscovered’ organ is largely unknown, but has potential as a drug target for obesity.     

Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids

Aims/hypothesis

We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data.

Methods

We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy (¹H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n?=?287) and validation (n?=?392) groups to build and validate the diagnostic models, respectively.

Results

Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids (‘lipid triplet’) was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study.

Conclusions/interpretation

The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.