Genetic variants of desaturase enzymes involved in fatty acid metabolism and risk of insulin resistance

Since 1996, the number of people in the UK diagnosed with diabetes has increased from 1.4 million to 2.6 million and it is estimated that these figures will rise to 4 million by 2025. This rise is specific to type II diabetes and is believed to be in part due to our ageing population and to the rapidly rising numbers of overweight and obese people. [i]

Increased consumption of energy-dense food induces insulin resistance, leads to the development of obesity and ultimately to metabolic syndrome, the precursor to type II diabetes.  Whilst it is well known that a consistently high intake of carbohydrate leads to elevations in blood glucose levels which can lead to insulin resistance, the importance of the role of dietary fat, in particular, specific fatty acids, needs to be recognised. The role of dietary fat intake, and its association with insulin resistance, is of particular interest, in addition to carbohydrate choices, when educating the public on dietary manipulations to reduce their risk of developing metabolic syndrome and type II diabetes.

Insulin needs to bind to its receptor on cell membranes to bring about its action.  Cell membrane structure and its functional integrity greatly influences the properties of the insulin receptor, including its affinity to insulin. Therefore, the properties of the cell membrane, especially its fluidity, depend on the lipid constitution of the membrane. A high saturated fatty acid content in the membrane will render it more rigid, causing a decrease in fluidity, leading to a corresponding decrease in the number of insulin receptors and therefore the affinity of insulin to its receptor which can lead to insulin resistance.  In contrast, an increase in the amount of polyunsaturated fatty acids in the cell membrane may produce a significant increase in the number of high-affinity sites with a concomitant decrease of low-affinity sites for insulin.  For example, feeding animals with diets high in saturated fat induces insulin resistance, and replacing saturated fat isocalorically with polyunsaturated fat, especially long-chain omega-3 fatty acids, has been show to prevent the development of insulin resistance.

As well as being a source of energy, fatty acids have a wide range of physiological functions required for normal homoeostasis.  The omega-3 and omega-6 families of polyunsaturated fatty acids are of particular significance as they cannot be synthesised endogenously, and therefore must be provided through the diet.  Linoleic acid (LA) and alpha-linolenic acid (ALA) are the essential fatty acids from which the long-chain fatty acids eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) are derived via elongase and desaturase enzyme activity.

Several factors can influence the efficiency of desaturase genes e.g. hyperglycaemia, hypertension and statins, as well as various dietary and lifestyle factors including: a high intake of saturated fat, trans-fat, alcohol and caffeine. Furthermore, zinc, magnesium, selenium, vitamin B complex and vitamin C are all necessary co-factors for elongase and desaturase enzymes, and deficiency in these can have significant effects on long-chain fatty acid synthesis.  In addition, inter-individual variability in human lipid metabolism can be attributed directly to genetic variation in desaturase genes, as reflected in long-chain fatty acid levels between different populations.[ii] Evidence certainly indicates that genetic variations (polymorphisms) in several genes involved in fatty acid metabolism of long-chain omega-3 and omega-6 fatty acids can influence fatty acid profiles in plasma, erythrocyte membranes and adipose tissue, which may ultimately influence insulin resistance.[iii] Certainly, the association between desaturase genotypes and fatty acid levels in human cells and tissues shows that genetic variations are, in addition to nutritional regulation of fatty acid synthesis, a very important regulator of long-chain fatty acid synthesis.

Ethnic-specific polymorphisms and the subsequential differences in lipid profiles observed within different populations calls for the development of improved therapies to prevent and manage diseases characterized by altered fatty acid profiles, such as type II diabetes.   Dietary strategies, including reduced intake of energy-dense, nutrient-free foods, reduced intake of saturated fat and an increase in long-chain polyunsaturated fat, are needed to improve health, reduce metabolic syndrome and lower the risk of developing type II diabetes.

Direct supplementation with omega-6 GLA and omega-3 EPA bypasses delta-6 desaturase (the first enzyme involved in fatty acid metabolism), and can increase red blood cell membrane and body tissue levels of long-chain polyunsaturated fats.  As such, the resulting positive changes in lipid profiles may help to prevent and manage not only type II diabetes, but also other diseases and conditions characterized by altered fatty acid profiles.

[i] González EL, Johansson S, Wallander MA, Rodríguez LA. 2009 Trends in the prevalence and incidence of diabetes in the UK: 1996-2005. J Epidemiol Community Health. 63:332-6

[ii] Merino DM, Johnston H, Clarke S, Roke K, Nielsen D, Badawi A, El-Sohemy A, Ma DW, Mutch DM. 2011 Polymorphisms in FADS1 and FADS2 alter desaturase activity in young Caucasian and Asian adults. Mol Genet Metab. 103

[iii] Das UN.  2010 A defect in Δ6 and Δ5 desaturases may be a factor in the initiation and progression of insulin resistance, the metabolic syndrome and ischaemic heart disease in South Asians.  Lipids Health Dis. 9:130.

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