Omega-3 Studien: Diabetes mellitus

Eicosanoid precursors: potential factors for atherogenesis in diabetic CAPD patients?
Holler C: Ludwig Boltzmann Institute for Nutrition, City Hospital Lainz, Vienna, Austria; Auinger M, Ulberth F, Irsigler K
Perit Dial Int 1996 16 Suppl 1:S250-3
Abstract
Prostaglandins, thromboxanes, and other eicosanoids represent a widespread lipid-mediator system for intercellular signalling, and, hence, have multiple cellular actions. Thus it is not surprising that numerous events in the pathogenesis of atherosclerosis are associated with an altered formation of eicosanoids. To reconsider the availability of eiconsanoid precursors as one possible cause of atherogenesis, the dietary intake and the serum concentrations of arachidonic acid (AA) and eicosapentaenoic acid (EPA) were determined in patients with high risk for atherosclerosis on continuous ambulatory peritoneal dialysis (CAPD) with and without diabetes in comparison to healthy controls and diabetic patients without late complications. The factor AA/EPA in serum was created as a marker for the atherosclerosis risk. The setting was in a CAPD unit in one city hospital. There were 26 CAPD patients [9 with insulin-dependent diabetes mellitus (IDDM), 9 with noninsulin-dependent diabetes mellitus (NIDDM), and 8 without diabetes], 27 IDDM without late complications, and 41 healthy control persons. The AA levels in serum were significantly higher in all of the CAPD groups. In contrast, the EPA concentrations in serum were significantly lower in the CAPD groups, with the lowest EPA levels found in the CAPD-IDDM group. Therefore, the factors AA/EPA in serum were significantly higher in all of the CAPD groups, and again significantly higher in the CAPD-IDDM group than in the other CAPD groups. No differences in the amount of dietary intake of AA existed between the groups. The daily intake of EPA was significantly highest in the control group. Higher concentrations of AA and a lack of n-3 fatty acids lead in the presence of a reduced prostaglandin I2 biosynthesis, to a higher formation rate of potentially proatherogenic metabolites such as thromboxane A2, a vasoconstricting and platelet aggregating agent. Thus, the quotient AA/EPA could possibly be used as a marker of atherogenicity in the future.

Supplementation with long-chain n-3 fatty acids in non-insulin-dependent diabetes mellitus (NIDDM) patients leads to the lowering of oleic acid content in serum phospholipids.
Haban P: Institute of Preventive and Clinical Medicine, Bratislava, Slovakia; Zidekova E, Klvanova J
Eur J Nutr 2000 Oct 39:201-6
Abstract
BACKGROUND: The dietary supplementation with EPA (eicosapentaenoic acid; 20:5n3) and DHA (docosahexaenoic acid; 22:6n3) has been recommended because of their favourable effects on the cardiovascular system (including complications of NIDDM). Oleic acid (18:1n9) from olive oil has some analogous and complementary effects. Potential competitive relations between long-chain n-3 fatty acids (FAs) and the oleic acid would therefore mean a problem. AIM OF THE STUDY: We focused primarily on the oleic acid changes in serum phospholipids (SPL) after a supplementation with EPA and DHA. METHODS: Thirty-five patients with type 2 diabetes mellitus (NIDDM) were supplemented for 28 days with 1.7 g of EPA plus 1.15 g of DHA/day (as Maxepa capsules, Seven Seas, U. K.). After that, a 3-month wash-out control period with 21 patients followed. A fatty acid composition of serum phospholipids (SPL) was determined by capillary gas-chromatography. Values were calculated as relative percentages of all FAs. RESULTS: After the supplementation with the Maxepa capsules, there was a very strong increase in EPA, docosapentaenoic acid (22:5n3) and DHA content in SPL. It was followed by a strong decrease after the wash-out (all p < 0.0001). The oleic acid SPL content after the intervention significantly decreased from 10. 105 +/- 0.307% (mean +/- S. E. M.) to 9.082 +/- 0.276 % (p < 0.0003). During the wash-out, the change was in the opposite direction (p < 0.0001). When the intervention and the wash-out periods were taken together, changes in the oleic acid were inversely correlated with changes in EPA, docosapentaenoic acid and DHA (r = -0.729; r = -0.552; r = -0.629, respectively; p < 0.0001; n = 56). On the background of the overall n-6 FA reduction, the decline in the arachidonic acid after the supplementation (p < 0.0001) and its rise after the wash-out (p < 0.0003) were similar. There were no significant changes in the saturated FA spectrum. CONCLUSIONS: Supplementation with long-chain n-3 FAs in NIDDM patients leads to the lowering of oleic acid SPL content. Whereas the reduction of the arachidonic acid may have some desirable aspects (e. g. suppression of thromboxane TxA2 or 4 series leukotriene production), the decline of the former is to be regarded as a potential problem. Therefore, the search for optimally balanced blends of n-3 polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs) seems to be more promising than a supplementation with only one type of FA.

Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension.
Woodman RJ: Department of Medicine, The University of Western Australia, Perth, Australia; Mori TA, Burke V, Puddey IB, Watts GF, Beilin LJ
Am J Clin Nutr 2002 Nov 76:1007-15
Abstract
BACKGROUND: n-3 Fatty acids lower blood pressure, improve lipids, and benefit other cardiovascular disease risk factors. Effects on glycemia in patients with type 2 diabetes are uncertain. OBJECTIVE: We determined whether purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have differential effects on glycemic control, including insulin sensitivity and stimulated insulin secretion; 24-h ambulatory blood pressure; and serum lipids in type 2 diabetic patients with treated hypertension. DESIGN: In a double-blind, placebo-controlled trial of parallel design, 59 subjects were randomly assigned to consume 4 g EPA, DHA, or olive oil/d for 6 wk while continuing to consume their usual diet. RESULTS: Thirty-nine men and 12 postmenopausal women with a mean (+/- SE) age of 61.2 +/- 1.2 y completed the study. In comparison with the change from baseline in fasting glucose in the olive oil group, fasting glucose in the EPA and DHA groups increased 1.40 +/- 0.29 mmol/L (P = 0.002) and 0.98 +/- 0.29 mmol/L (P = 0.002), respectively. Neither EPA nor DHA had significant effects on glycated hemoglobin, fasting insulin or C-peptide, insulin sensitivity or secretion, or blood pressure. Serum triacylglycerols in the EPA and DHA groups decreased 19% (P = 0.022) and 15% (P = 0.022), respectively. There were no significant changes in serum total, LDL, or HDL cholesterol, although HDL(2) cholesterol in the EPA and DHA groups increased 16% (P = 0.026) and 12% (P = 0.05), respectively. HDL(3) cholesterol decreased 11% (P = 0.026) with EPA supplementation. CONCLUSIONS: EPA and DHA had similar benefits on lipids but adverse effects on short-term glycemic control in hypertensive diabetic patients. The overall implications for cardiovascular disease require long-term evaluation.

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The effect of n-3 fatty acid administration on selected indicators of cardiovascular disease risk in patients with type 2 diabetes mellitus.
Habán P: Klinické oddelenie Výskumného ústavu výzivy v Bratislave; Simoncic R, Klvanová I, Ozdín L, Zideková E
Bratisl Lek Listy 1998 Jan 99:37-42
Abstract
BACKGROUND: Serum triacylglycerols (TG), VLDL, HDL, fatty acid and eicosanoid spectrum are among the factors determining the risk of cardiovascular complications in NIDDM. N-3 polyunsaturated fatty acids (PUFA) are expected to have beneficial effects on these factors. In NIDDM patients there have however been previously reported (late 1980s) some adverse effects. OBJECTIVES: Our aim was to verify the effects of n-3 PUFA in NIDDM patients using relatively low dosage. METHODS: The investigated group included 21 NIDDM patients with dyslipoproteinemia type IV. The patients were treated for 28 days with 1.7 g EPA (eicosapentaenoic acid) + 1.15 g DHA (docosahexaenoic acid)/day (10 capsules/day of MAXEPA, Seven Seas U.K.). The lipoproteins were measured using the BIO-LACHEMA kits, the fatty acid spectrum in phospholipids was determined by gas chromatography and prostanoids (after their separation) were measured by RIA methods. MAIN RESULTS AND CONCLUSIONS: After the MAXEPA treatment there has been a strong decrease in TG (p < 0.005) and VLDL (p < 0.002) serum levels, accompanied by a significant increase in HDL (p < 0.02). The final-to-baseline TG ratio in individual patients negatively correlated with the relative percentage of EPA in phospholipids after the treatment (p < 0.03; r = -0.474). There was no significant change in serum total cholesterol, fasting glycaemia and glycosylated hemoglobin. There was a slight, but statistically already significant (p < 0.05), rise in LDL. The relative percentage of EPA, docosapentaenoic acid and DHA in serum phospholipids increased sharply (p < 0.001, p < 0.001, p < 0.001). The increase of n-3 PUFA in individual patients was linked with the decrease in n-6 PUFA (p < 0.001; r = -0.686). The spectrum of the latter has changed also very markedly. The prostacyclin PGI2-to-thromboxane TxA2 ratio increased significantly (p < 0.001). Beneficial effects of n-3 fatty acids have prevailed and this kind of treatment seems very encouraging also in NIDDM patients. The results are logically compatible with other authors' results pattern formed in 1990s. A slight rise in serum LDL needs a more detailed discussion since only its phenotype B ("small dense LDL particles") has been recently found to be atherogenic.

Long-term administration of highly purified eicosapentaenoic acid ethyl ester prevents diabetes and abnormalities of blood coagulation in male WBN/Kob rats.
Nobukata H: Toxicology Laboratory, Research Center, Mochida Pharmaceutical, Shizuoka, Japan; Ishikawa T, Obata M, Shibutani Y
Metabolism 2000 Jul 49:912-9
Abstract
We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid, on the development of diabetes, insulin resistance, and abnormalities of blood coagulation in male WBN/Kob rats, a model of spontaneous diabetes mellitus. After 8-month oral EPA-E treatment, the incidence of diabetes at a dose of 0.1, 0.3, and 1.0 g/kg was 92%, 50%, and 17%, respectively. Its incidence was suppressed significantly and dose-dependently at a dose of 0.3 g/kg or higher compared with the rate (100%) for the vehicle control. Additionally, EPA-E significantly and dose-dependently decreased the elevation of plasma glucose after an oral glucose load and increased the glucose infusion rate (GIR) during the euglycemic insulin-glucose clamp test at a dose of 0.1 g/kg or higher compared with the vehicle control. Furthermore, EPA-E significantly and dose-dependently ameliorated coagulation-related parameters, including the prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen level, and factor II, V, VII, VIII, IX, X, XI, and XII and antithrombin III (AT III) activities, and fibrinolysis-related parameters, including plasminogen, tissue-type plasminogen activator (t-PA), alpha2-plasmin inhibitor (alpha2-PI), and plasminogen activator inhibitor (PAI), and also suppressed ADP- or collagen-induced platelet aggregation and the cholesterol to phospholipid (C/P) molar ratio in platelet membranes at a dose of 0.1 g/kg or higher. These data demonstrate multiple actions of the product in these laboratory animals. These include changes in platelet function, coagulation/fibrinolysis factors, plasma immunoreactive insulin secretion, and plasma glucose/insulin resistance.

Health benefits of docosahexaenoic acid (DHA)
Horrocks LA: Docosa Foods Ltd, 1275 Kinnear Road, Columbus OH, USA; Yeo YK
Pharmacol Res 1999 Sep 40:211-25
Abstract
Docosahexaenoic acid (DHA) is essential for the growth and functional development of the brain in infants. DHA is also required for maintenance of normal brain function in adults. The inclusion of plentiful DHA in the diet improves learning ability, whereas deficiencies of DHA are associated with deficits in learning. DHA is taken up by the brain in preference to other fatty acids. The turnover of DHA in the brain is very fast, more so than is generally realized. The visual acuity of healthy, full-term, formula-fed infants is increased when their formula includes DHA. During the last 50 years, many infants have been fed formula diets lacking DHA and other omega-3 fatty acids. DHA deficiencies are associated with foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and adrenoleukodystrophy. Decreases in DHA in the brain are associated with cognitive decline during aging and with onset of sporadic Alzheimer disease. The leading cause of death in western nations is cardiovascular disease. Epidemiological studies have shown a strong correlation between fish consumption and reduction in sudden death from myocardial infarction. The reduction is approximately 50% with 200 mg day(-1)of DHA from fish. DHA is the active component in fish. Not only does fish oil reduce triglycerides in the blood and decrease thrombosis, but it also prevents cardiac arrhythmias. The association of DHA deficiency with depression is the reason for the robust positive correlation between depression and myocardial infarction. Patients with cardiovascular disease or Type II diabetes are often advised to adopt a low-fat diet with a high proportion of carbohydrate. A study with women shows that this type of diet increases plasma triglycerides and the severity of Type II diabetes and coronary heart disease. DHA is present in fatty fish (salmon, tuna, mackerel) and mother's milk. DHA is present at low levels in meat and eggs, but is not usually present in infant formulas. EPA, another long-chain n-3 fatty acid, is also present in fatty fish. The shorter chain n-3 fatty acid, alpha-linolenic acid, is not converted very well to DHA in man. These longchain n-3 fatty acids (also known as omega-3 fatty acids) are now becoming available in some foods, especially infant formula and eggs in Europe and Japan. Fish oil decreases the proliferation of tumour cells, whereas arachidonic acid, a longchain n-6 fatty acid, increases their proliferation. These opposite effects are also seen with inflammation, particularly with rheumatoid arthritis, and with asthma. DHA has a positive effect on diseases such as hypertension, arthritis, atherosclerosis, depression, adult-onset diabetes mellitus, myocardial infarction, thrombosis, and some cancers.