Docosahexaenoic Acid Supplementation Improved Lipocentric but Not Glucocentric Markers of Insulin Sensitivity in Hypertriglyceridemic Men Darshan S. Kelley, Ph.D., 1 Yuriko Adkins, Ph.D., 1 Leslie R. Woodhouse, Ph.D., 1 Arthur Swislocki, M.D., 2,3 Bruce E. Mackey, Ph.D., 4 and David Siegel, M.D., M.P.H. 3,5 Abstract Background: Increase in obesity and metabolic syndrome are associated with increases in insulin resistance (IR) and type 2 diabetes mellitus. Results from animal intervention studies and human epidemiological studies suggest that n-3 polyunsaturated fatty acids can prevent and reverse IR, but results from human intervention studies have varied. Results from some human and animal studies suggest that docosahexaenoic acid (22:6n-3; DHA) may be more effective than eicosapentaenoic acid (20:5n-3; EPA) in the prevention of IR. Methods: By using a placebo-controlled, parallel study design, we examined the effects of DHA supplementation (3 grams/day, 90 days) in the absence of EPA on glucocentric and lipocentric markers of IR in hyper- triglyceridemic men (n = 14–17/group). Results: DHA supplementation increased fasting plasma glucose concentration by 4.7% (P < 0.05), but did not alter other indices of IR based on fasting (insulin and homeostasis model assessment of insulin resistance [HOMA-IR]) or postprandial insulin and glucose concentrations (areas under curves for insulin and glucose, Matsuda index). Glucose increased by 2.7% in the placebo group and was not significant; increases in glucose in the two groups did not differ from each other. DHA decreased circulating concentrations of several lipocentric markers of IR, including plasma concentrations of nonesterified fatty acids (13.0%), small, dense low-density lipoprotein (LDL) particles (21.7%), and ratio of tryglycerides to high-density lipoprotein cholesterol (TG/HDL- C) (34.0%) (P < 0.05). None of the variables changed in the placebo group. Conclusions: Our results suggest that lipocentric markers of IR are more responsive to DHA supplementation than the glucocentric markers. Future studies with DHA in prediabetic subjects and direct measures of insulin sensitivity are needed. Introduction I nsulin resistance (IR) is a condition in which normal amounts of insulin fail to maintain normal blood glucose levels because of decreased responsiveness of muscle (glu- cose uptake), adipose tissue (glucose uptake and inhibition of lipolysis), and liver (inhibition of gluconeogenesis). 1,2 Thus, it is a reduced ability of insulin to exert its biological effects on its target tissues. IR is usually assessed by deter- mining fasting or postprandial plasma concentrations of in- sulin and glucose (glucocentric markers). A number of direct and surrogate methods are available to estimate glucocentric markers of IR. 3–7 The two direct methods used to evaluate insulin-mediated glucose uptake (IMGU) are insulin suppression test (IST) and the euglycemic clamp. These direct methods are often time and labor in- tensive and require experienced operators. Therefore, other surrogate methods such as fasting plasma glucose (FPG), 1 Western Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, and Department of Nutrition, University of California, Davis, California. 2 Veteran Affairs Northern California Health Care System, Martinez, California. 3 Department of Medicine, School of Medicine, University of California Davis, Sacramento, California. 4 Western Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, Albany, California. 5 Veteran Affairs Northern California Health Care System, Sacramento, California. METABOLIC SYNDROME AND RELATED DISORDERS Volume 10, Number 1, 2012 Ó Mary Ann Liebert, Inc. Pp. 32–38 DOI: 10.1089/met.2011.0081 32 32 32