Effects of Fish Oils on Inflammation and Insulin Resistance

The purpose of this study is to determine whether improvement in fat and muscle metabolism after the treatment with Omacor (fish oils) provides insight into the link between obesity, fat and muscle function leading to metabolic syndrome, which is a risk factor for heart disease and diabetes.

The development of type 2 diabetes (T2DM) represents a complex series of events, involving abnormalities in adipose tissue lipid distribution and insulin action. Along with an increase in adipose tissue mass is an increase in inflammation brought about by macrophages that infiltrate adipose tissue. These macrophages express inflammatory cytokines such as tumor necrosis factor (TNF) and Interleukin -6 (IL-6) which are correlated with insulin resistance and metabolic syndrome, and suggest that metabolic syndrome and diabetes are conditions characterized by a state of chronic, low-grade inflammation. Thiazolidinediones (TZDs) improve insulin sensitivity via activation of peroxisome proliferator-activated receptor (PPAR) , and there is much evidence that PPAR agonists also have anti-inflammatory properties. Fish oils are rich sources of Omega-3 fatty acids and there is a large literature on the potential benefits of fish oils on lowering serum triglycerides, cardiovascular protection, and immune modulation, and there is evidence that fish oils also activate PPAR . Hence, the focus of this study will be on subjects with insulin resistance and metabolic syndrome, but who do not yet have diabetes. We plan to treat insulin resistant subjects with fish oils and ask the following questions. Hypothesis 1. The treatment of insulin resistant subjects with fish oils will reduce adipose tissue inflammation. Aim 1. From blood samples drawn before and after treatment, we will measure levels of circulating inflammatory cytokines. Aim 2. Adipose tissue biopsies will be performed before and after fish oil treatment. From the adipose biopsies, we will quantitate cytokine expression, macrophage number, and we will look for evidence of macrophage apoptosis. Aim 3. We will determine whether fish oil treatment increases the adipose tissue secretion and serum level of the high molecular weight form of adiponectin. Hypothesis 2. The reduction in inflammatory markers occurs through an activation of PPAR by the fish oils. Aim 4. Adipose tissue and macrophages will be treated in vitro with fish oils in the presence and absence of a PPAR inhibitor. We will determine whether fish oils stimulate the secretion of the high molecular weight adiponectin isoform from adipose tissue and whether they induce apoptosis from macrophages, and whether this process is inhibited by the PPAR inhibitor. Hypothesis 3. Fish oils improve peripheral insulin sensitivity through a reduction in intramyocellular lipid, and an improvement in muscle insulin signal transduction. Aim 5. Before and after treatment with fish oils, insulin sensitivity will be measured, along with intramyocellular lipid and genes involved in insulin action and muscle lipid oxidation.

Prior to starting the fish oil regiment, participants will undergo an incisional abdominal biopsy to remove approximately 4g of adipose tissue to determine adipocyte size

After completing the fish oil regiment, participant will undergo an incisional abdominal biopsy to remove approximately 4g of adipose tissue to determine individual adipocyte size

Insulin sensitivity (Si) was measured with a frequently sampled intravenous glucose tolerance test. Participants received a bolus of glucose at Time Zero, then a bolus of insulin 20 minutes later. Blood was collected through an IV catheter at multiple time points over the course of 4 hours. Glucose levels were plotted on a time course curve and analyzed using the MIDMOD algorithm.

Insulin sensitivity (Si) was measured with a frequently sampled intravenous glucose tolerance test. Participants received a bolus of glucose at Time Zero, then a bolus of insulin 20 minutes later. Blood was collected through an IV catheter at multiple time points over the course of 4 hours. Glucose and Insulin levels will be plotted on a time course curve and analyzed using the MINMOD algorithm.

Inclusion Criteria: BMI 27-45 kg/m2 age 35-65 years abnormal carbohydrate metabolism Exclusion Criteria: triglycerides over 700 mg/dl renal disease liver disease congestive heart failure history of heart disease or stroke chronic aspirin or NSAID use (anti-coagulant) history of a bleeding disorder use of statins, fibrates, ACE inhibitors, angiotensin II receptor blockers and glucocorticoids diet heavy in omega-3 fatty acids (salmon, sardines, flaxseeds)

Spencer M, Finlin BS, Unal R, Zhu B, Morris AJ, Shipp LR, Lee J, Walton RG, Adu A, Erfani R, Campbell M, McGehee RE Jr, Peterson CA, Kern PA. Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes. 2013 May;62(5):1709-17. doi: 10.2337/db12-1042. Epub 2013 Jan 17.