Objective-Traditional risk factors for coronary artery disease (CAD) fail to adequately distinguish patients who have atherosclerotic plaques susceptible to instability from those who have more benign forms. Using plasma lipid profiling, this study aimed to provide insight into disease pathogenesis and evaluate the potential of lipid profiles to assess risk of future plaque instability. Methods and Results-Plasma lipid profiles containing 305 lipids were measured on 220 individuals (matched healthy controls, nϭ80; stable angina, nϭ60; unstable coronary syndrome, nϭ80) using electrospray-ionisation tandem mass spectrometry. ReliefF feature selection coupled with an L2-regularized logistic regression based classifier was used to create multivariate classification models which were verified via 3-fold cross-validation (1000 repeats). Models incorporating both lipids and traditional risk factors provided improved classification of unstable CAD from stable CAD (C-statisticϭ0.875, 95% CI 0.874 -0.877) compared with models containing only traditional risk factors (Cstatisticϭ0.796, 95% CI 0.795-0.798). Many of the lipids identified as discriminatory for unstable CAD displayed an association with disease acuity (severity), suggesting that they are antecedents to the onset of acute coronary syndrome. Key Words: acute coronary syndromes Ⅲ atherosclerosis Ⅲ lipids Ⅲ risk factors Ⅲ biomarker A cute coronary syndromes (unstable angina, myocardial infarction, and many cases of sudden cardiac death) are almost invariably the result of atherosclerotic plaque disruption and subsequent thrombosis (atherothrombosis). Although plaque accumulation and development is progressive throughout life, plaques may cycle between being stable and unstable throughout the disease process. Accurate identification of those at risk for unstable coronary syndromes is an important prerequisite to targeted treatment and prevention. However, current screening is limited by the predictive power of available tests, the high cost of these tests, or a combination of both. Furthermore, the ability of these tests to subclassify patients with CAD as having stable or unstable disease has been limited. Conclusion-PlasmaRisk assessment for coronary artery disease (CAD) is currently performed by the evaluation of traditional risk factors (eg, smoking status, body mass index, cholesterol level, blood pressure); by direct measures of arterial structural changes associated with atherosclerosis, such as carotid intima-medial thickness and the coronary artery calcification score; or by testing for myocardial ischemia using stress testing. For the most part, the addition of circulating biomarkers has added little to risk assessment by conventional methods, although the recent reports by Blankenberg et al 1 indicate that risk scores incorporating multiple biomarkers can improve on conventional risk models, and the report of Schnabel et al 2 suggests that this strategy may also be useful in the setting of stable CAD. The development of noninvasive screening tests that c...

Objective: Alterations in lipids in muscle and plasma have been documented in insulin-resistant people with obesity. Whether these lipid alterations are a reflection of insulin resistance or obesity remains unclear. Methods: Nondiabetic sedentary individuals not treated with lipid-lowering medications were studied (n 5 51). Subjects with body mass index (BMI) > 25 kg/m 2 (n 5 28) were stratified based on median glucose infusion rate during a hyperinsulinemic-euglycemic clamp into insulin-sensitive and insulin-resistant groups (above and below median, obesity/insulin-sensitive and obesity/insulin-resistant, respectively). Lean individuals (n 5 23) served as a reference group. Lipidomics was performed in muscle and plasma by liquid chromatography electrospray ionization-tandem mass spectrometry. Pathway analysis of gene array in muscle was performed in a subset (n 5 35).Results: In muscle, insulin resistance was characterized by higher levels of C18:0 sphingolipids, while in plasma, higher levels of diacylglycerol and cholesterol ester, and lower levels of lysophosphatidylcholine and lysoalkylphosphatidylcholine, indicated insulin resistance, irrespective of overweight/obesity. The sphingolipid metabolism gene pathway was upregulated in muscle in insulin resistance independent of obesity. An overweight/obesity lipidomic signature was only apparent in plasma, predominated by higher triacylglycerol and lower plasmalogen species. Conclusions: Muscle C18:0 sphingolipids may play a role in insulin resistance independent of excess adiposity.Obesity (2016) 24, 908-916.

Fourteen GH-deficient (GHD) adults were compared with 12 age-, sex-, and body mass index-matched control subjects using a baseline tritiated glucose equilibration period and euglycemic-hyperinsulinemic (approximately 55 mU/L) clamp in conjunction with paired muscle biopsies for measurement of glycogen synthase fractional velocity (FV0.1). Despite similar basal rates of total glucose disposal (Rd), there was a 64% reduction in the insulin-stimulated rise (delta) in Rd in the GHD adults compared to that in controls [16.6 +/- 2.8 vs. 44.7 +/- 6.0 mumol/kg fat free mass (FFM)/min; P < 0.001], which was mainly due to a decreased glucose storage (GS) rate (delta GS, 12.6 +/- 2.9 vs. 39.5 +/- 7.5 mumol/kg FFM/min; P < 0.01). Furthermore, the insulin sensitivity indexes of Rd (0.39 +/- 0.07 vs. 0.85 +/- 0.11; P < 0.05) and GS (0.25 +/- 0.07 vs. 0.72 +/- 0.13 mumol/kg FFM/min per mU/L; P < 0.02) were reduced in GHD adults compared to the control values. The insulin sensitivity of the glycolytic pathway was also reduced by approximately 50% in GHD adults (P = 0.07 vs. controls). Insulin-stimulated FV0.1 was decreased in GHD adults (0.31 +/- 0.02 vs. 0.47 +/- 0.03; P < 0.005) despite similar basal FV0.1. Using multiple and stepwise regression analysis, duration of GH deficiency, fasting triglycerides and fasting insulin accounted for 67% of the variance in the insulin sensitivity index of Rd. In conclusion, the severe insulin resistance in GHD adults is mainly due to the inhibition of the GS pathway and glycogen synthase activity in peripheral tissues, which is related to the duration of GH deficiency, fasting triglycerides, and fasting insulin.

The global view of lipid metabolism offered by lipidomics is accelerating our understanding of disease processes and identifying new avenues of research into metabolic syndrome and its sequelae. The ongoing identification and validation of lipid biomarkers will likely see their introduction into clinical practice for improved quantification of disease risk, earlier identification of disease and improved patient management in the near future.

To determine the impact of variable plasma insulin concentrations and glycemia on the partitioning of whole body glucose metabolism between glycolysis and glucose storage, we estimated endogenous hepatic glucose production and rates of in vivo glycolytic flux (GF) and glucose storage (GS) in six normal dogs from the generation of plasma tritiated water (3H2O) and [3-3H]glucose specific activity during 150 min of somatostatin euglycemic (E) and hyperglycemic (H) clamps at hypoinsulinemic, basal, intermediate, and high insulin levels. During both E and H clamps, overall rates of GF and GS increased with the rising insulin levels, but the relative contributions to in vivo glucose disposal of GF decreased, whereas GS rose progressively with increasing insulin levels. The relative contribution of GS during H to overall glucose disposal was greater at the lower insulin level. In addition, in absolute terms, GF and GS were significantly higher (P < 0.05) during H than during E at all insulin levels. Moreover, the incremental rise in GF induced by H was equal for the low to intermediate insulin levels tested, independent of the prevailing free fatty acid (FFA) levels. However, when whole body glucose disposal rates were matched, GF and GS rates were independent of the coexisting glycemia, insulin, and/or FFA levels. We conclude that 1) insulin has a major impact on the intracellular fate of infused glucose, with a lesser but significant effect of hyperglycemia per se on these processes; 2) the magnitude of the hyperglycemia-induced increase in GF is independent of the prevailing insulin level from low to intermediate levels; and 3) in vivo GF and GS are dependent on the net rate of glucose uptake into cells but independent of absolute FFA levels or whether glucose uptake is stimulated by raised insulin or glucose levels.

Objectives: While chronic obesity is associated with alterations in circulating glycerolipids, sphingolipids and plasmalogens, the effects of short-term overfeeding in humans are unclear. Design and Methods: Healthy individuals (n 5 40) were overfed by 1,250 kcal day 21 for 28 days. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), abdominal fat distribution and serum lipidomics (mass spectrometry) were assessed. Results: Overfeeding increased liver fat, insulin resistance, serum C-reactive protein and urinary F2-isoprostanes. HDL increased (11% 6 2%, P < 0.001) while LDL, triglycerides and nonesterified fatty acids were unchanged. Three hundred and thirty three serum lipids were detected, of which 13% increased and 20% decreased with overfeeding. Total diacylglycerol and lysoalkylphosphatidylcholine (LPC(O)) concentrations decreased (P < 0.01), while total ceramide, Cer22:0 and Cer24:0 increased (P 0.01). The most notable increases were observed in the HDL-associated phosphatidylethanolamine-based plasmalogens and their precursors alkylhosphatidylethanolamine (18 6 5% and 38 6 8% respectively, P 0.01). Conclusions: Overfeeding led to weight gain and changes in the serum lipid profile. Increases in ceramides were noted, which left unchecked may promote systemic insulin resistance. Uniform increases were observed in plasmalogens and their precursors. Because plasmalogens are powerful antioxidants, this may be an appropriate response against increased oxidative stress generated by over-nutrition. The metabolic consequences of changes in concentrations of many circulating lipid species with overfeeding require further study.

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. Prevailing hyperglycemia is critical in the regulation of glucose metabolism during exercise in poorly controlled alloxan-diabetic dogs. J Appl Physiol 98: 930 -939, 2005; doi:10.1152/japplphysiol.00687.2004.-The separate impacts of the chronic diabetic state and the prevailing hyperglycemia on plasma substrates and hormones, in vivo glucose turnover, and ex vivo skeletal muscle (SkM) during exercise were examined in the same six dogs before alloxan-induced diabetes (prealloxan) and after 4 -5 wk of poorly controlled hyperglycemic diabetes (HGD) in the absence and presence of ϳ300-min phlorizin-induced (glycosuria mediated) normoglycemia (NGD). For each treatment state, the ϳ15-h-fasted dog underwent a primed continuous 150-min infusion of [3-3 H]glucose, followed by a 30-min treadmill exercise test (ϳ65% maximal oxygen capacity), with SkM biopsies taken from the thigh (vastus lateralis) before and after exercise. In the HGD and NGD states, preexercise hepatic glucose production rose by 130 and 160%, and the metabolic clearance rate of glucose (MCRg) fell by 70 and 37%, respectively, compared with the corresponding prealloxan state, but the rates of glucose uptake into peripheral tissues (Rdtissue) and total glycolysis (GF) were unchanged, despite an increased availability of plasma free fatty acid in the NGD state. Exercise-induced increments in hepatic glucose production, Rdtissue, and plasma-derived GF were severely blunted by ϳ30 -50% in the NGD state, but increments in MCRg remained markedly reduced by ϳ70 -75% in both diabetic states. SkM intracellular glucose concentrations were significantly elevated only in the HGD state. Although Rdtissue during exercise in the diabetic states correlated positively with preexercise plasma glucose and insulin and GF and negatively with preexercise plasma free fatty acid, stepwise regression analysis revealed that an individual's preexercise glucose and GF accounted for 88% of Rdtissue during exercise. In conclusion, the prevailing hyperglycemia in poorly controlled diabetes is critical in maintaining a sufficient supply of plasma glucose for SkM glucose uptake during exercise. During phlorizin-induced NGD, increments in both Rdtissue and GF are impaired due to a diminished fuel supply from plasma glucose and a sustained reduction in increments of MCRg. glucose uptake; plasma-derived glycolysis; skeletal muscle; free fatty acids; metabolic clearance rate of glucose; phlorizin-induced normoglycemia THE REGULATION OF GLUCOSE METABOLISM in skeletal muscle (SkM) during exercise occurs predominantly via an insulinindependent pathway (13,16,22) and involves the recruitment of SkM GLUT4 transporters from a distinct insulin-independent GLUT-4 pool (13). It is known that the prior insulin sensitivity of an individual is important in determining the rate of glucose uptake into SkM (Rd tissue ) in response to acute exercise (28). Furthermore, the intensity and duration of the exercise are also critical in determining the relative importance of carbohydrate and fat substrates as ...