Julie M. Martin

A Phase II Randomized Placebo-Controlled Trial of Omega-3 Fatty Acids for the Treatment of Acute Lung Injury

Objectives:Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury. Design:Phase II randomized controlled trial. Setting:Five North American medical centers. Patients:Mechanically ventilated patients with acute lung injury ≥18 yrs of age. Interventions:Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days. Measurements and Main Results:Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups. Conclusions:Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.

Treatment with the Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves Fasting Islet-Cell Function in Subjects with Type 2 Diabetes

CONTEXT Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state. OBJECTIVE The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function. DESIGN We conducted a randomized, double-blind, placebo-controlled trial. SETTING The study was performed in General Clinical Research Centers at two University Hospitals. SUBJECTS Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2-7.5%. INTERVENTION Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout. Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout. RESULTS There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P < 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023). CONCLUSION Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.

Plasma Amyloid-β Peptide Levels Correlate with Adipocyte Amyloid Precursor Protein Gene Expression in Obese Individuals

Background/Aims: Several studies have demonstrated that midlife obesity increases the risk for dementia and Alzheimer’s disease. Moreover, plasma 42-amino-acid amyloid-β (Aβ42) levels appear to correlate with BMI. We recently demonstrated that adipocyte amyloid precursor protein (APP) expression is upregulated in obesity and correlates with insulin resistance and adipose tissue inflammation. In this study, we aimed to investigate the relation between adipocyte APP expression and plasma Aβ peptide levels. Methods: We conducted a pilot study in which we measured adipocyte APP gene expression and the circulating plasma levels of Aβ40 in 10 obese individuals before and after a 6-month behaviorally based weight loss intervention. Subjects had an oral glucose tolerance test with measurement of insulin levels, Aβ40 levels measured by ELISA and transcript levels of APP in subcutaneous abdominal adipocytes measured by quantitative real-time PCR. Results: At baseline, adipocyte APP expression correlated significantly with plasma Aβ40 levels and with 2-hour insulin concentrations. Following the 6-month weight loss intervention, body weight and BMI decreased significantly. Fasting plasma concentrations of glucose and insulin were improved. Adipocyte APP expression was significantly decreased (p < 0.001) after weight loss. Changes in adipocyte APP expression correlated with changes in plasma Aβ40 levels (R = 0.74, p = 0.01) and changes in 2-hour insulin (R = 0.75, p = 0.01). Conclusion: The results of this pilot study suggest that increased circulating plasma levels of Aβ peptides in obesity may be due to increased adipocyte APP gene expression. While these results suggest a possible mechanism linking midlife obesity with the later development of Alzheimer’s disease, further research is necessary to elucidate the regulation and functional significance of APP in adipocytes.

Omega-3 fatty acids in critical illness

Supplementation of enteral nutritional formulas and parenteral nutrition lipid emulsions with omega-3 fatty acids is a recent area of research in patients with critical illness. It is hypothesized that omega-3 fatty acids may help reduce inflammation in critically ill patients, particularly those with sepsis and acute lung injury. The objective of this article is to review the data on supplementing omega-3 fatty acids during critical illness; enteral and parenteral supplemental nutrition are reviewed separately. The results of the research available to date are contradictory for both enteral and parenteral omega-3 fatty acid administration. Supplementation with omega-3 fatty acids may influence the acute inflammatory response in critically ill patients, but more research is needed before definitive recommendations about the routine use of omega-3 fatty acids in caring for critically ill patients can be made.

Fish Oil in Critical Illness: Mechanisms and Clinical Applications

Fish oil is rich in omega-3 fatty acids, which have been shown to be beneficial in multiple disease states that involve an inflammatory process. It is now hypothesized that omega-3 fatty acids may decrease the inflammatory response and be beneficial in critical illness. After a review of the mechanisms of omega-3 fatty acids in inflammation, research using enteral nutrition formulas and parenteral nutrition lipid emulsions fortified with fish oil were examined. The results of this research to date are inconclusive for both enteral and parenteral omega-3 fatty acid administration. More research is required before definitive recommendations can be made on fish oil supplementation in critical illness.

Acute and Chronic Impact of Bariatric Surgery on Plasma LDL Cholesterol and PCSK9 Levels in Patients With Severe Obesity

Context: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low‐density lipoprotein cholesterol (LDL‐C) concentrations. In patients with severe obesity, biliopancreatic diversion with duodenal switch (BPD‐DS) surgery induces substantial weight loss and influences lipoprotein metabolism. The effect of BPD‐DS on PCSK9 levels is unknown. Objectives: To determine the acute and chronic impact of BPD‐DS on PCSK9 levels and whether the acute impact of BPD‐DS could be explained by BPD‐DS‐associated caloric restriction (CR). Design, Settings, and Participants: PCSK9 levels were measured in 20 men and 49 women (age, 41.5 ± 11.1 years) with severe obesity before, 24 hours, 5 days, and 6 and 12 months after BPD‐DS and in a comparable control group (n = 31) at baseline and at 6 and 12 months. PCSK9 levels were also measured during 3‐day CR in patients (n = 7) with severe obesity and type 2 diabetes. Results: PCSK9 levels increased 13.4% after 24 hours (248.7 ± 64.8 to 269.7 ± 63.8 ng/mL; P = 0,02) and decreased 9.5% at 12 months compared with baseline (217.6 ± 43.0 ng/mL; P < 0,0001). LDL‐C levels decreased 36.2% after 24 hours (2.6 ± 0.7 to 1.7 ± 0.6 mmol/L; P < 0.0001) and 30% at 12 months compared with baseline (1.7 ± 0.5 mmol/L; P < 0.0001). Compared with baseline levels, PCSK9 levels were lower at day 2 but not at day 1 or 3 after CR. Conclusion: BPD‐DS is associated with acute increases in PCSK9 levels that do not appear to be explained by CR but may be due to an acute response following surgery. BPD‐DS induces chronic reductions in both PCSK9 and LDL‐C levels.

Contents Vol. 90, 2009

93 Abstracts of the 6th Annual ENETS Conference Granada, Spain, March 5–7, 2009 147 ENETS Newsletter