The Protective Effects of Selective Omega-3 Ethyl Ester Prescription Drugs on Diet-Induced Glucose Intolerance and Insulin Resistance
Year: 2022
Type: dissertation
Abstract: Cardiometabolic diseases, including cardiovascular disease and diabetes mellitus, are the leading causes of death worldwide. Omega-3 ethyl ester prescription drugs, Vascepa (96% eicosapentaenoic acid (EPA) ethyl ester) and Lovaza (46.5% EPA and 37.5% docosahexaenoic acid (DHA) ethyl ester) are prescribed to patients with metabolic syndrome and cardiovascular disease to reduce hypertriglyceridemia and improve cardiovascular outcomes and are being tested to potentially treat non-alcoholic fatty liver disease (NAFLD). Since cardiovascular disease and NAFLD are closely linked to prediabetes and the development of type 2 diabetes (T2D), the effects of omega-3 ethyl esters on protecting from prediabetes and the progression to T2D need to be further studied. Thus, to examine more closely their potential effects in preventing prediabetes, mice were treated with Vascepa or Lovaza for one week prior to six weeks of high fat diet (HFD) feeding. Vascepa mice fed HFD had significantly reduced weight gain and diminished insulin resistance compared to control-HFD treatment, with no significant effects seen with Lovaza. Mice treated with Vascepa, and to a lesser extent Lovaza, had reduced fasting glucose and improved glucose excursions. Vascepa treated mice had reduced fasting insulin and reduced insulin secretion in vivo with no direct acute impact on beta cell function in vitro. Vascepa treatment reduced hepatic triglyceride and upregulated genes associated with PPAR-α signaling with increased expression of PPAR-α and Cyp4a31. As well, retinol and arachidonic acid (ARA) metabolism was upregulated with decreased circulating ARA, docosapentaenoic acid (DPA) and DHA and reduced ARA/EPA ratio indicating increased utilization of polyunsaturated fatty acids with Vascepa treatment. In comparison, we observed that EPA and DPA are elevated in subjects with T2D suggesting dysregulated metabolism of omega-3 fatty acids in T2D. Finally, we determined whether changes in insulin resistance and liver function are associated with altered gut microbiome composition. Vascepa treatment impacted the gut microbiome, decreasing Firmicutes, the phylum frequently associated with increased weight gain, and increasing Bacteroides, the phylum associated with reduced inflammation and insulin resistance. In conclusion, Vascepa alters the gut microbiome, reduces weight gain and hepatic triglycerides associated with overall improvements in insulin resistance, glucose homeostasis and insulin secretion.
Source: TSpace (University of Toronto)
Author: Al Rijjal, Dana
Institution: University of Toronto
Language: English
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7133077977