Long chain polyunsaturated fatty acids (LCPUFAs) and nordihydroguaiaretic acid (NDGA) modulate metabolic and inflammatory markers in a spontaneous type 2 diabetes mellitus model (Stillman Salgado rats)

Lipids in Health and Disease, Nov 2016

Background Diabetes mellitus (DM) is a complex disease with alterations in metabolic and inflammatory markers. Stillman Salgado rats (eSS) spontaneously develop type 2 DM by middle age showing progressive impairment of glucose tolerance with hyperglycemia, hypertriglyceridemia and hyperinsulinemia. We analyzed the effects of supplementation of ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) with or without nordihydroguaiaretic acid (NDGA) added, an antioxidant and lipoxygenase inhibitor, on metabolic and inflammatory parameters in eSS rats to evaluate whether they can delay development and/or prevent progression of DM. Methods After weaning, eSS rats received, intraperitoneally, once a month ω-3 (EPA 35% and DHA 40%–6.25 mg/Kg) or ω-6 (90% arachidonic acid- 6. 25 mg/Kg) for twelve months. Two additional groups of rats received 1.9 mg/kg NDGA added to ω-3 and ω-6 fatty acids. Blood samples were collected at day 40, and at the end of the 6th month and 12th month of age to determine plasma triglycerides (TGs), total plasma fatty acids (FA), A1C hemoglobin (HbA1C), C-reactive protein (CRP), gamma glutamyl transpeptidase (GGT), lipo and hydro peroxides, nitrites and IL-6 (in plasma and liver, kidney, and pancreas) and underwent oral glucose tolerance test (OGTT) as well. Wistar and eSS rats that received saline solution were used as controls. Results Plasma lipids profile, TG, fasting and post-prandial blood glucose levels, and glycosylated HbA1C showed significant improvements in ω-3 and ω-3 + NDGA treated animals compared to eSS control group. ω-3 and ω-3 + NDGA groups showed an inverse correlation with fasting blood glucose and showed lower plasma levels of GGT, TG, and CRP. eSS rats treated with ω-3 LCPUFAs showed reduced level of inflammatory and oxidative indices in plasma and liver, kidney and pancreas tissues in comparison with eSS control (non-treated) and ω-6 treated groups. Conclusions eSS rats are a useful model to study type 2 DM pathophysiology and related inflammatory indices. ω-3 + NDGA supplementation, at the doses tested, ameliorated inflammatory, metabolic and oxidative stress markers studied.

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Long chain polyunsaturated fatty acids (LCPUFAs) and nordihydroguaiaretic acid (NDGA) modulate metabolic and inflammatory markers in a spontaneous type 2 diabetes mellitus model (Stillman Salgado rats)

Dain et al. Lipids in Health and Disease Long chain polyunsaturated fatty acids (LCPUFAs) and nordihydroguaiaretic acid (NDGA) modulate metabolic and inflammatory markers in a spontaneous type 2 diabetes mellitus model (Stillman Salgado rats) Alejandro Dain 1 5 Gaston Repossi 1 3 4 5 Gustavo T. Diaz-Gerevini 1 5 Jairam Vanamala 7 Undurti N. Das 2 6 Aldo R. Eynard 1 3 5 0 K-202 , Federal Way, WA 98003 , USA 1 Biología Celular, Histología y Embriología, Facultad de Ciencias Medicas, INICSA (CONICET-Universidad Nacional de Córdoba) , Córdoba , Argentina 2 UND Life Sciences , 2020 S 360th St 3 CONICET , Córdoba , Argentina 4 Cátedra de Histología, Embriología y Genética, Universidad Nacional de La Rioja , La Rioja , Argentina 5 Biología Celular, Histología y Embriología, Facultad de Ciencias Medicas, INICSA (CONICET-Universidad Nacional de Córdoba) , Córdoba , Argentina 6 BioScience Research Centre and Department of Medicine, GVP Hospital, Gayatri Vidya Parishad College of Engineering Campus , Visakhapatnam 530 048 , India 7 Department of Food Science, Penn State University , 326 Food Science Building, University Park, PA 16802 , USA Background: Diabetes mellitus (DM) is a complex disease with alterations in metabolic and inflammatory markers. Stillman Salgado rats (eSS) spontaneously develop type 2 DM by middle age showing progressive impairment of glucose tolerance with hyperglycemia, hypertriglyceridemia and hyperinsulinemia. We analyzed the effects of supplementation of ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) with or without nordihydroguaiaretic acid (NDGA) added, an antioxidant and lipoxygenase inhibitor, on metabolic and inflammatory parameters in eSS rats to evaluate whether they can delay development and/or prevent progression of DM. Methods: After weaning, eSS rats received, intraperitoneally, once a month ω-3 (EPA 35% and DHA 40%-6.25 mg/Kg) or ω-6 (90% arachidonic acid- 6. 25 mg/Kg) for twelve months. Two additional groups of rats received 1.9 mg/kg NDGA added to ω-3 and ω-6 fatty acids. Blood samples were collected at day 40, and at the end of the 6th month and 12th month of age to determine plasma triglycerides (TGs), total plasma fatty acids (FA), A1C hemoglobin (HbA1C), C-reactive protein (CRP), gamma glutamyl transpeptidase (GGT), lipo and hydro peroxides, nitrites and IL-6 (in plasma and liver, kidney, and pancreas) and underwent oral glucose tolerance test (OGTT) as well. Wistar and eSS rats that received saline solution were used as controls. Results: Plasma lipids profile, TG, fasting and post-prandial blood glucose levels, and glycosylated HbA1C showed significant improvements in ω-3 and ω-3 + NDGA treated animals compared to eSS control group. ω-3 and ω-3 + NDGA groups showed an inverse correlation with fasting blood glucose and showed lower plasma levels of GGT, TG, and CRP. eSS rats treated with ω3 LCPUFAs showed reduced level of inflammatory and oxidative indices in plasma and liver, kidney and pancreas tissues in comparison with eSS control (non-treated) and ω-6 treated groups. Conclusions: eSS rats are a useful model to study type 2 DM pathophysiology and related inflammatory indices. ω-3 + NDGA supplementation, at the doses tested, ameliorated inflammatory, metabolic and oxidative stress markers studied. Type 2 diabetes; eSS rats (Stillman Salgado rats); PUFAs; Chronic inflammation; Oxidation process; Plasma triglycerides; Nordihydroguaiaretic acid - Background DM is a complex disease in which alterations in metabolic and inflammatory indices including perturbations in the metabolism of glucose, lipids and proteins occur. Perturbations in the oxidative cycle and cellular stress and alterations in glucose metabolism result in an elevation of inflammatory markers: interleukins-2 and 6 (IL-2 and IL6), leukotrienes (LTs such as LTB4), and C-reactive protein (CRP) [1]. The increasing incidence of DM not only impacts the health of the affected individual but also enhances the cost of health care and has implications for political, economic, and social issues of the society [2]. DM is estimated to affect about 366 million by 2030. DM and obesity have common pathophysiological pathways that may occur due to inadequate physical activity and consumption of high-calorie/high-fat food intake that results in insulin resistance and metabolic syndrome [3]. It has been reported that an imbalance in the metabolism of ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) occurs in obesity, insulin resistance, metabolic syndrome, and DM [4, 5]. eSS rats are a strain derived from inbred Wistar rats, which develop spontaneously type 2 DM without obesity that resembles closely type 2 DM seen in adult humans. Type 2 DM is more severe in male eSS rats and they survive an average of 18 months if insulin is not administered to control hyperglycemia. In early stages of the development of DM, eSS rats show glucose intolerance with hyperinsulinemia and dyslipidemia. These f (...truncated)


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Alejandro Dain, Gaston Repossi, Gustavo Diaz-Gerevini, Jairam Vanamala, Undurti Das, Aldo Eynard. Long chain polyunsaturated fatty acids (LCPUFAs) and nordihydroguaiaretic acid (NDGA) modulate metabolic and inflammatory markers in a spontaneous type 2 diabetes mellitus model (Stillman Salgado rats), Lipids in Health and Disease, 2016, pp. 205, 15, DOI: 10.1186/s12944-016-0363-8