Karen Terembula

OBJECTIVE: Evidence favors apolipoprotein B (apoB) over LDL cholesterol as a predictor of cardiovascular events, but data are lacking on coronary artery calcification (CAC), especially in type 2 diabetes, where LDL cholesterol may underestimate atherosclerotic burden. We investigated the hypothesis that apoB is a superior marker of CAC relative to LDL cholesterol. RESEARCH DESIGN AND METHODS: We performed cross-sectional analyses of white subjects in two community-based studies: the Penn Diabetes Heart Study (N = 611 type 2 diabetic subjects, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (N = 803 nondiabetic subjects, 52.8% men) using multivariate analysis of apoB and LDL cholesterol stratified by diabetes status. RESULTS: In type 2 diabetes, apoB was associated with CAC after adjusting for age, sex, and medications [Tobit regression ratio of increased CAC for 1-SD increase in apoB; 1.36 (95% CI 1.06-1.75), P = 0.016] whereas LDL cholesterol was not [1.09 (0.85-1.41)]. In nondiabetic subjects, both were associated with CAC [apoB 1.65 (1.38-1.96), P < 0.001; LDL cholesterol 1.56 (1.30-1.86), P < 0.001]. In combined analysis of diabetic and nondiabetic subjects, apoB provided value in predicting CAC scores beyond LDL cholesterol, total cholesterol, the total cholesterol/HDL cholesterol and triglyceride/HDL cholesterol ratios, and marginally beyond non-HDL cholesterol. CONCLUSIONS: Plasma apoB, but not LDL cholesterol, levels were associated with CAC scores in type 2 diabetic whites. ApoB levels may be particularly useful in assessing atherosclerotic burden and cardiovascular risk in type 2 diabetes.

SCOPE: Fish oil-derived n-3 PUFA may improve cardiometabolic health through modulation of innate immunity. However, findings in clinical studies are conflicting. We hypothesized that n-3 PUFA supplementation would dose-dependently reduce the systemic inflammatory response to experimental endotoxemia in healthy humans. METHODS AND RESULTS: The Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) study was an 8-wk randomized double-blind trial of placebo or n-3 PUFA supplementation (Lovaza 465 mg eicosapentaenoic acid (EPA) + 375 mg docosahexaenoic acid (DHA)) at "low" (1/day, 900 mg) or "high" (4/day, 3600 mg) dose in healthy individuals (N = 60; age 18-45; BMI 18-30; 43% female; 65% European-, 20% African-, 15% Asian-ancestry) before a low-dose endotoxin challenge (LPS 0.6 ng/kg intravenous bolus). The endotoxemia-induced temperature increase was significantly reduced with high-dose (p = 0.03) but not low-dose EPA + DHA compared to placebo. Although there was no statistically significant impact of EPA + DHA on individual inflammatory responses (tumor necrosis factor-α (TNF-α), IL-6, monocyte chemotactic protein (MCP-1), IL-1 receptor agonist (IL-1RA), IL-10, C-reactive protein (CRP), serum amyloid A (SAA)), there was a pattern of lower responses across all biomarkers with high-dose (nine of nine observed), but not low-dose EPA + DHA. CONCLUSION: EPA + DHA at 3600 mg/day, but not 900 mg/day, reduced fever and had a pattern of attenuated LPS induction of plasma inflammatory markers during endotoxemia. Clinically and nutritionally relevant long-chain n-3 PUFA regimens may have specific, dose-dependent, anti-inflammatory actions.

BACKGROUND: Chronic inflammation may contribute to insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We hypothesized that very low-dose experimental endotoxemia would induce adipose tissue inflammation and systemic IR during a low-grade but asymptomatic inflammatory response and thus provide an experimental model for future tests of pharmacologic and genomic modulation of cardio-metabolic traits in humans. METHODS: Ten healthy, human volunteers (50% male, 90% Caucasian, mean age 22.7 ± 3.8) were randomized in a double-masked, placebo-controlled, crossover study to separate 36-hour inpatient visits (placebo versus intravenous-LPS 0.6 ng/kg). We measured clinical symptoms via the McGill pain questionnaire and serial vital signs. Plasma and serum were collected for measurement of cytokines, C-reactive protein, insulin and glucose, serial whole blood & subcutaneous adipose tissue mRNA expression were measured by real-time PCR. HOMA-IR, a well-validated measure of IR was calculated to estimate insulin resistance, and frequently sampled intravenous glucose tolerance testing (FSIGTT) was performed to confirm an insulin resistant state. We performed ANOVA and within subject ANOVA to understand the differences in cytokines, adipose tissue inflammation and IR before and after LPS or placebo. RESULTS: There was no significant difference between placebo and LPS in clinical responses of symptom scores, body temperature or heart rate. However, low-dose endotoxemia induced a rapid and transient 25-fold induction of plasma TNF-alpha and 100-fold increase in plasma IL-6 (Figure 1B) (p < 0.001 for both) both peaking at two hours, followed by modest inflammation in adipose tissue with increases in mRNA levels of several inflammatory genes known to modulate adipose and systemic insulin resistance. Adipose tissue mRNA levels of IL-6 (peak 6-fold, ANOVA F = 27.5, p < 0.001) and TNF-alpha (peak 1.8-fold, F = 2.9, p = 0.01) increased with MCP-1 (peak 10-fold, F = 5.6, p < 0.01) and fractalkine (CX3CL1) (peak 15-fold, F = 13.3, p < 0.001). Finally, HOMA-IR was 32% higher following LPS compared to placebo (p < 0.01) and insulin sensitivity declined by 21% following LPS compared to placebo (p < 0.05). CONCLUSIONS: We present a low dose human endotoxemia model of inflammation which induces adipose tissue inflammation and systemic insulin resistance in the absence of overt clinical response. Such a model has the potential for broad and safe application in the study of novel therapeutics and genomic influences in cardio-metabolic disease.

BACKGROUND: CKD, an independent risk factor for CV disease, increases mortality in T2DM. Treating modifiable CV risk factors decreases mortality in diabetics with microalbuminuria, but the role of early CV prevention in diabetics with mild CKD by GFR criteria alone remains unclear. The purpose of this study was to probe whether T2DM patients with mild GFR impairment have atherogenic lipid profiles compared to diabetic counterparts with normal renal function. METHODS: In the Penn Diabetes Heart Study (PDHS), a single-center observational cohort of T2DM patients without clinical CVD, cross-sectional analyses were performed for directly measured lipid fractions in 1852 subjects with eGFR>60 mL/min/1.73 m² determined by the CKD-EPI equation (n = 1852). Unadjusted and multivariable analyses of eGFR association with log-transformed lipid parameters in incremental linear and logistic regression models (with eGFR 90 mL/min/1.73 m² as a cut-point) were performed. RESULTS: Mild GFR impairment (eGFR 60-90 mL/min/1.73 m², median urinary ACR 5.25 mg/g) was associated with higher log-transformed Lp(a) values (OR 1.17, p = 0.005) and with clinically atherogenic Lp(a) levels above 30 mg/dL (OR 1.35, p = 0.013) even after full adjustment for demographics, medications, metabolic parameters, and albuminuria. Logistic regression demonstrated a trend towards significance between worse kidney function and apoB (p = 0.17) as well as apoC-III (p = 0.067) in the fully adjusted model. CONCLUSIONS: Elevated Lp(a) levels have a robust association with mild GFR impairment in type 2 diabetics independent of race, insulin resistance, and albuminuria.