Diabetes mellitus (DM) is chronic disease characterized by hyperglycemia and insulin resistance caused by dysfunction of pancreatic β cells. Over the past few decades, epidemiological studies have suggested that dietary long-chain polyunsaturated fatty acids such as docosahexaenoic acid and eicosapentaenoic acid decrease the risk of metabolic diseases including DM. The mechanisms underlying the therapeutic efficacy of dietary long-chain polyunsaturated fatty acids in treating DM have been partly revealed. In this review, the authors describe the antidiabetic effects of long-chain polyunsaturated fatty acids and also discuss their possibilities as therapeutics for DM in the light of recent findings.
World Health Organization (2015) Diabetes. Fact Sheet No. 312. http://www.who.int/mediacentre/factsheets/fs312/en/
American Diabetes Association (2012) Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 35, S64-S71.
de la Monte, S.M. and Wands, J.R. (2008) Alzheimer’s Disease is Type 3 Diabetes-Evidenced Review. Journal of Diabetes Science and Technology, 2, 1101-11138. http://dx.doi.org/10.1177/193229680800200619
Duarte, A.I., Candeias, E., Correia, S.C., et al. (2013) Crosstalk between Diabetes and Brain: Glucagon-Like Peptide-1 Mimetics as a Promising Therapy against Neurodegeneration. Biochimica et Biophysica Acta, 1832, 527-541.
Janson, J., Laedtk, T., Parisi J.E., et al. (2004) Increases Risk of Type 2 Diabetes in Alzheimer’s Disease. Diabetes, 53, 474-481. http://dx.doi.org/10.2337/diabetes.53.2.474
Takalo, M., Haapasalo, A., Martiskainen, H., et al. (2014) High-Fat Diet Increases Tau Expression in the Brain of T2DM and AD Mice Independently of Peripheral Metabolic Status. Journal of nutritional Biochemistry, 25, 634-641. http://dx.doi.org/10.1016/j.jnutbio.2014.02.003
Freund, L.Y., Vedin, I., Cederholm, T., et al. (2014) Transfer of Omega-3 Fatty Acids across the Blood-Brain Barrier after Dietary Supplementation with a Docosahexaenoic Acid-Rich Omega-3 Fatty Acid Preparation in Patients with Alzheimer’s Disease: The OmegAD Study. Journal of International Medicine, 275, 428-436. http://dx.doi.org/10.1111/joim.12166
Weir, G.C., Laybutt, D.R., Kaneto, H., et al. (2001) Beta-Cell Adaptation and Decompensation during the Progression of Diabetes. Diabetes, 50, S154-S159. http://dx.doi.org/10.2337/diabetes.50.2007.S154
Kanda, H., Tateya, S., Tamori, Y., et al. (2006) MCP-1 Contributes to Macrophage Infiltration into Adipose Tissue, Insulin Resistance, and Hepatic Steatosis in Obesity. Journal of Clinical Investigation, 116, 1494-1505. http://dx.doi.org/10.1172/JCI26498
Kamei, N., Tobe, K., Suzuki, R., et al. (2006) Overexpression of Macrophage Chemoattractant Protein-1 in Adipose Tissue Cause Macrophage Recruitment and Insulin Resistance. The Journal of Biological Chemistry, 281, 26602-26614. http://dx.doi.org/10.1074/jbc.M601284200
Flachs, P., Horakova, O., Brauner P., et al. (2005) Polyunsaturated Fatty Acids of Marine Origin up Regulate Mitochondrial Biogenesis and Induce β-Oxidation in White Fat. Diabetologia, 48, 2365-2375. http://dx.doi.org/10.1007/s00125-005-1944-7
Vaughan, R.A., Garcia-Smith, R., Bisoffiet M., et al. (2012) Conjugated Linoleic Acid or Omega 3 Fatty Acids Increase Mitochondrial Biosynthesis and Metabolism in Skeletal Muscle Cells. Lipid in Health and Disease, 11, 142-152. http://dx.doi.org/10.1186/1476-511X-11-142
Weisberg, S.P., McCann, D., Desai, M., et al. (2003) Obesity Is Associated with Macrophage Accumulation in Adipose Tissue. Journal of Clinical Investigation, 112, 1796-1808. http://dx.doi.org/10.1172/JCI200319246
Xu, H., Barnes, G.T., Yang, Q., et al. (2003) Chronic Inflammation in Fat Plays a Crucial Role in the Development of Obesity-Related Insulin Resistance. Journal of Clinical Investigation, 112, 1821-1830. http://dx.doi.org/10.1172/JCI200319451
Lazar, M.A. (2006) The Humoral Side of Insulin Resistance. Nature Medicine, 12, 43-44. http://dx.doi.org/10.1038/nm0106-43
Sell, H. and Eckel, J. (2007) Monocyte Chemotactic Protein-1 and Its Role in Insulin Resistance. Current Opinion in Lipidology, 18, 258-262. http://dx.doi.org/10.1097/MOL.0b013e3281338546
Sell, H. and Eckel, J. (2009) Chemotactic Cytokines, Obesity and Type 2 Diabetes: In Vivo and in Vitro Evidence for a Possible Causal Correlation? Proceedings of the Nutrition Society, 68, 378-384. http://dx.doi.org/10.1017/S0029665109990218
Pimentel, G.D., Lira, F.S., Rosa, J.C., et al. (2013) High-Fat Fish Oil Diet Prevents Hypothalamic Inflammatory Profile in Rats. ISRN Inflammation, 2013, Article ID: 419823.
Vandal, M., Alata, W., Tremblay, C., et al. (2014) Reduction in DHA Transport to the Brain of Mice Expressing Human APOE4 Compared to APOE2. Journal of Neurochemistry, 129, 516-526. http://dx.doi.org/10.1111/jnc.12640
Afshordel, S., Hagl, S., Werner, D., et al. (2015) Omega-3 Polyunsaturated Fatty Acids Improve Mitochondrial Dysfunction in Brain Aging—Impact of Bcl-2 and NPD-1 Like Metabolites. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 92, 23-31.
Eckert, G.P., Chang, S., Eckmann, J., et al. (2011) Liposome-Incorporated DHA Increases Neuronal Survival by Enhancing Non-Amyloidogenic APP Processing. Biochimica et Biophysica Acta, 1808, 234-243.
Wellhauser, L. and Belsham, D.D. (2014) Activation of the Omega-3 Fatty Acid Receptor GPR120 Mediates Anti-Inflammatory Actions in Immortalized Hypothalamic Neurons. Journal of Neuroinflammation, 27, 60. http://dx.doi.org/10.1186/1742-2094-11-60
Zhao, Y., Calon, F., Julien, C., et al. (2011) Docosahexaenoic Acid-Derived Neuroprotectin D1 Induces Neuronal Survival via Secretase- and PPARγ-Mediated Mechanisms in Alzheimer’s Disease Models. PLoS ONE, 6, e15816. http://dx.doi.org/10.1371/journal.pone.0015816
Wall, R., Ross, R.P., Fitzgerald, G.F. and Stanton, C. (2010) Fatty Acids from Fish: The Anti-Inflammatory Potential of Long-Chain Omega-3 Fatty Acids. Nutrition Reviews, 68, 280-289. http://dx.doi.org/10.1111/j.1753-4887.2010.00287.x
Bang, H.O. and Dyerberg, J. (1972) Plasma Lipids and Lipoproteins in Greenlandic West Coast Eskimos. Acta Medica Scandinavica, 192, 85-94. http://dx.doi.org/10.1111/j.0954-6820.1972.tb04782.x
Kromann, N. and Green, A. (1980) Epidemiological Studies in the Upernavik District, Greenland. Incidence of Some Chronic Diseases 1950-1974. Acta Medica Scandinavica, 208, 401-406. http://dx.doi.org/10.1111/j.0954-6820.1980.tb01221.x
Lim, G.E. and Brubaker, P.L. (2006) Glucagon-Like Peptide 1 Secretion by the L-Cell. The View from Within. Diabetes, 55, S70-S77. http://dx.doi.org/10.2337/db06-S020
Kieffer, T.J., McIntosh, C.H. and Pederson, R.A. (1995) Degradation of Glucose-Dependent Insulinotropic Polypeptide and Truncated Glucagon-Like Peptide 1 in Vitro and in Vivo by Dipeptidyl Peptidase IV. Endocrinology, 136, 3585-3596.
Holst, J.J. (2006) Glucagon-Like Peptide-1: From Extract to Agent: The Claude Bernard Lecture, 2005. Diabetologia, 49, 253-260. http://dx.doi.org/10.1007/s00125-005-0107-1
Drucker, D.J., Jin, T., Asa, S.L., et al. (2006) Activation of Proglucagon Gene Transcription by Protein Kinase-A in a Novel Mouse Enteroendocrine Cell Line. Molecular Endocrinology, 8, 1646-1655.
Abello, J., Ye, F., Bosshard, A., et al. (1994) Stimulation of Glucagon-Like Peptide-1 Secretion by Muscarinic Agonist in a Murine Intestinal Endocrine Cell Line. Endocrinology, 134, 2011-2017.
Reimer, R.A., Darimont, C., Gremlich, S., et al. (2001) A Human Cellular Model for Studying the Regulation of Glucagon-Like Peptide-1 Secretion. Endocrinology, 142, 4522-4528. http://dx.doi.org/10.1210/endo.142.10.8415
Drucker, D.J. (2006) The Biology of Incretin Hormones. Cell Metabolism, 3, 153-165. http://dx.doi.org/10.1016/j.cmet.2006.01.004
Rocca, A.S. and Brubaker, P.L. (1999) Role of the Vagus Nerve in Mediating Proximal Nutrient-Induced Glucagon-Like Peptide-1 Secretion. Endocrinology, 140, 1687-1694.
Roberge, J.N. and Brubaker, P.L. (1993) Regulation of Intestinal Proglucagon-Derived Peptide Secretion by Glucose-Dependent Insulinotropic Peptide in a Novel Enteroendocrine Loop. Endcrinology, 133, 233-240.
Elrick, H., Stimmler, L., Hlad Jr., C.J. and Rai, Y. (1964) Plasma Insulin Responses to Oral and Intravenous Glucose Administration. Journal of Clinical Endocrinology Metabolism, 24, 1076-1082. http://dx.doi.org/10.1210/jcem-24-10-1076
Toft-Nielsen, M.B., Damholt, M.B., Madsbad, S., et al. (2001) Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients. Journal of Clinical Endocrinology Metabolism, 86, 3717-3723. http://dx.doi.org/10.1210/jcem.86.8.7750
Vilsbøll, T., Krarup, T., Deacon, C.F., et al. (2001) Reduced Postprandial Concentrations of Intact Biologically Active Glucagon-Like Peptide 1 in Type 2 Diabetic Patients. Diabetes, 50, 609-613. http://dx.doi.org/10.2337/diabetes.50.3.609
Muscelli, E., Mari, A., Casolaro, A., et al. (2008) Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients. Diabetes, 57, 1340-1348. http://dx.doi.org/10.2337/db07-1315
Vilsbøll, T., Agersø, H., Krarup, T. and Holst, J.J. (2003) Similar Elimination Rates of Glucagon-Like Peptide-1 in Obese Type 2 Diabetic Patients and Healthy Subjects. Journal of Clinical Endocrinology and Metabolism, 88, 220-224. http://dx.doi.org/10.1210/jc.2002-021053
Green, C.J., Henriksen, T.I., Pedersen, B.K. and Solomon, T.P. (2012) Glucagon Like Peptide-1-Induced Glucose Metabolism in Differentiated Human Muscle Satellite Cells Is Attenuated by Hyperglycemia. PLoS ONE, 7, e44284. http://dx.doi.org/10.1371/journal.pone.0044284
Sonoki, K., Iwase, M. Takata, Y., et al. (2013) Effect of Thirty-Times Chewing per Bite on Secretion of Glucagon-Like Peptide-11 in Health Volunteers and Type 2 Diabetic Patients. Endocrine Journal, 60, 311-319. http://dx.doi.org/10.1507/endocrj.EJ12-0310
Tsuchiya, M., Niijima-Yaoita, F., Yoneda, H., et al. (2014) Long-Term Feeding on Powdered Food Causes Hyperglycemia and Signs of Systemic Illness in Mice. Life Science, 103, 8-14. http://dx.doi.org/10.1016/j.lfs.2014.03.022
Yamazaki, T., Yamori, M., Asai, K., et al. (2013) Mastication and Risk for Diabetes in Japanese Population: A Cross-Sectional Study. PLoS ONE, 8, e4113. http://dx.doi.org/10.1371/journal.pone.0064113
Rocca, A.S. and Brubaker, P.L. (1995) Stereospecific Effects of Fatty Acids on Proglucagon-Derived Peptide Secretion in Fetal Rat Intestinal Cultures. Endocrinology, 136, 5593-5599.
Brubaker, P.L., Schloos, J. and Drucker, D.J. (1998) Regulation of Glucagon-Like Peptide-1 Synthesis and Secretion in the GLUTag Enteroendocrine Cell Line. Endocrinology, 139, 4108-4114.
Oh, D.Y., Talukdar, S., Bae, E.J., et al. (2010) GPR120 Is an Omega-3 Fatty Acid Receptor Mediating Potent Anti-Inflammatory and Insulin-Sensitizing Effects. Cell, 142, 687-698. http://dx.doi.org/10.1016/j.cell.2010.07.041
Hirasawa, A., Tsumaya, K., Awaji, T., et al. (2005) Free Fatty Acids Regulate Gut Incretin Glucagon-Like Peptide-1 Secretion through GPR120. Nature Medicine, 11, 90-94. http://dx.doi.org/10.1038/nm1168
Katsuma, S., Hatae, N., Yano, T., et al. (2005) Free Fatty Acids Inhibit Serum Deprivation-Induced Apoptosis through GPR120 in a Murine Enteroendocrine Cell Line STC-1. Journal of Biological Chemistry, 280, 19507-19515. http://dx.doi.org/10.1074/jbc.M412385200
Adachi, T., Tanaka, T., Takemoto, K., et al. (2006) Free Fatty Acids Administrated into the Colon Promote the Secretion of Glucagon-Like Peptide-1 and Insulin. Biochemical and Biophysical Research Communications, 340, 332-357. http://dx.doi.org/10.1016/j.bbrc.2005.11.162
Morishita, M., Tanaka, T., Shida, T. and Takayama, K. (2008) Usefulness of Colon Targeted DHA and EPA as Novel Diabetes Medications That Promote Intrinsic GLP-1 Secretion. Journal of Controlled Release, 132, 99-104. http://dx.doi.org/10.1016/j.jconrel.2008.09.001
Shida, T., Kamei, N. and Takeda-Morishita, M. (2013) Colonic Delivery of Docosahexaenoic Acid Improves Impaired Glucose Tolerance via GLP-1 Secretion and Suppresses Pancreatic Islet Hyperplasia in Diabetic KK-Ay Mice. International Journal of Pharmacology, 450, 63-69. http://dx.doi.org/10.1016/j.ijpharm.2013.04.029
Morishita, M., Kajita, M., Suzuki, A., et al. (2000) The Dose-Related Hypoglycemic Effects of Insulin Emulsions Incorporating Highly Purified EPA and DHA. International Journal of Pharmacology, 201, 175-185. http://dx.doi.org/10.1016/S0378-5173(00)00411-7
Suzuki, A., Morishita, M., Kajita, M., et al. (1998) Enhanced Colonic and Rectal Absorption of Insulin Using a Multiple Emulsion Containing Eicosapentaenoic Acid and Docosahexaenoic Acid. Journal of Pharmaceutical Sciences, 87, 1196-1202. http://dx.doi.org/10.1021/js980125q
Andersen, G., Harnack, K., Erbersdobler, H.F. and Somoza, V. (2008) Dietary Eicosapentaenoic Acid and Docosahexaenoic Acid Are More Effective than Alpha-Linolenic Acid in Improving Insulin Sensitivity in Rats. Annals of Nutrition and Metabolism, 52, 250-256. http://dx.doi.org/10.1159/000140518
Ichimura, A., Hirasawa, A., Poulain-Godefroy, O., et al. (2012) Dysfunction of Lipid Sensor GPR120 Leads to Obesity in Both Mouse and Human. Nature, 483, 350-354. http://dx.doi.org/10.1038/nature10798
Oh, D.Y., Walenta, E., Akiyama, T.E., et al. (2014) A GPR120-Selective Agonist Improves Insulin Resistance and Chronic Inflammation in Obese Mice. Nature Medicine, 20, 942-947. http://dx.doi.org/10.1038/nm.3614
Luan, B., Zhao, J., Wu, H., et al. (2009) Deficiency of A Beta-Arrestin-2 Signal Complex Contributes to Insulin Resistance. Nature, 457, 1146-1149. http://dx.doi.org/10.1038/nature07617
Spencer, M., Finlin, B.S., Unal, R., et al. (2013) Omega-3 Fatty Acids Reduce Adipose Tissue Macrophages in Human Subjects with Insulin Resistance. Diabetes, 62, 1709-17171. http://dx.doi.org/10.2337/db12-1042
de Caterina, R., Madonna, R., Bertolotto, A. and Schmidt, E.B. (2007) N-3 Fatty Acids in the Treatment of Diabetic Patients. Diabetes Care, 30, 1012-1026. http://dx.doi.org/10.2337/dc06-1332
Labonté, M.è., Couture, P., Tremblay, A.J., Hogue, J.C., Lemelin, V. and Lamarche, B. (2013) Eicosapentaenoic and Docosahexaenoic Acid Supplementation and Inflammatory Gene Expression in the Duodenum of Obese Patients with Type 2 Diabetes. Nutrition Journal, 12, 98. http://dx.doi.org/10.1186/1475-2891-12-98
Brookheart, R.T., Michel, C.T. and Schaffer, J.F. (2009) As a Matter of Fat. Cell Metabolism, 10, 9-12. http://dx.doi.org/10.1016/j.cmet.2009.03.011
Xu, J., Teran-Garcia, M., Park, J.H., et al. (2001) Polyunsaturated Fatty Acids Suppress Hepatic Sterol Regulatory Element-Binding Protein-1 Expression by Accelerating Transcript Decay. Journal of Biological Chemistry, 276, 9800-9807. http://dx.doi.org/10.1074/jbc.M008973200
Xu, J., Nakamura, M.T., Cho, H.P. and Clarke, S.D. (2007) Sterol Regulatory Element Binding Protein-1 Expression Is Suppressed by Dietary Polyunsaturated Fatty Acids. Journal of Biological Chemistry, 274, 23577-23583. http://dx.doi.org/10.1074/jbc.274.33.23577
Liu, X., Xue, Y., Liu, C., et al. (2013) Eiocasapentaenoic Acid-Enriched Phospholipid Ameliorates Insulin Resistance and Lipid Metabolism in Diet-Induced-Obese Mice. Lipid in Health and Disease, 12, 109. http://dx.doi.org/10.1186/1476-511X-12-109
Neschen, S., Morino, K., Dong, J., et al. (2007) N-3 Fatty Acids Preserve Insulin Sensitivity in Vivo in a Peroxisome Proliferator-Activated Receptor-α-Dependent Manner. Diabetes, 56, 1034-1041. http://dx.doi.org/10.2337/db06-1206
Wu, J.H., Cahill, L.E. and Mozaffarian, D. (2013) Effects of Fish Oil on Circulating Adiponectin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Endocrinology and Metabolism, 98, 2451-2459. http://dx.doi.org/10.1210/jc.2012-3899
Flachs, P., Mohamed-Ali, V. and Horakova, O. (2006) Polyunsaturated Fatty Acids of Marine Origin Induce Adiponectin in Mice Fed a High-Fat Diet. Diabetologia, 49, 394-397. http://dx.doi.org/10.1007/s00125-005-0053-y
Banga, A., Unal, R., Tripathi, P., et al. (2009) Adiponectin Translation Is Increased by the PPARgamma Agonist Pioglitazone and Omega-3 Fatty Acids. American Journal of Physiology, Endocrinology and Metabolism, 296, E480-E489. http://dx.doi.org/10.1152/ajpendo.90892.2008
Tishinsky, J.M., Ma, D.W. and Robinson, L.F. (2011) Eicosapentaenoic Acid and Rosiglitazone Increase Adiponectin in an Additive and PPARγ-Dependent Manner in Human Adipocytes. Obesity, 19, 262-268. http://dx.doi.org/10.1038/oby.2010.186
World Health Organization. Diabetes Programme [Article Online]. http://www.who.int/diabetes/action_online/basics/en/index3.html
Sawada, N., Jiang, A., Takizawa, F., et al. (2014) Endothelial PGC-1α Mediates Vascular Dysfunction in Diabetes. Cell Metabolism, 19, 246-258. http://dx.doi.org/10.1016/j.cmet.2013.12.014
Cao, L., Aran, P.R., Kim, J., et al. (2010) Modulating Notch Signaling to Enhance Neovascularization and Reperfusion in Diabetic Mice. Biomaterials, 31, 9048-9056. http://dx.doi.org/10.1016/j.biomaterials.2010.08.002
Virtanen, J.K., Mursu, J., Voutilainen, S., Uusitupa, M. and Tuomainen, T.P. (2014) Serum Omega-3 Polyunsaturated Fatty Acids and Risk of Incident Type 2 Diabetes in Men: The Kuopio Ischemic Heart Disease Risk Factor Study. Diabetes Care, 37, 1189-1196. http://dx.doi.org/10.2337/dc13-1504
Iwasaki, M., Hoshian, F., Tsuji, T., et al. (2012) Predicting Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes: Association of Glycated Hemoglobin Reduction with Serum Eicosapentaenoic Acid and Docosahexaenoic Acid Levels. Journal of Diabetes Investigation, 3, 464-467. http://dx.doi.org/10.1111/j.2040-1124.2012.00214.x
Samimi, M., Jamilian, M., Asemi, Z. and Esmaillzadeh, A. (2014) Effects of Omega-3 Fatty Acid Supplementation on Insulin Metabolism and Lipid Profiles in Gestational Diabetes: Randomized, Double-Blind, Placebo-Controlled Trial. Clinical Nutrition, in press.
Serhiyenko, V., Serhiyenko, A. and Segin, V. (2014) The Effect of Omega-3 Polyunsaturated Fatty Acids on N-Terminal Pro-Brain Natriuretic Peptide and Lipid Concentration in Patients with Type 2 Diabetes Mellitus and Cardiovascular Autonomic Neuropathy. Romanian Journal of Diabetes Nutrition and Metabolic Diseases, 21, 97-101. http://dx.doi.org/10.2478/rjdnmd-2014-0014