Elaidic Acid and Oleic Acid Have Opposite Effects on Serum Glucose

Elaidic Acid and Oleic Acid Have Opposite Effects on Serum Glucose, Insulin and Immunoglobulin Levels and Eicosanoid Production in Streptozotocin-Induced Diabetic Rats

1＊ 2 2 3 Tamiho KOGA , Jong-Yan GU , Michiko NONAKA and Michihiro SUGANO 1 Nakamura Gakuen Junior College (5-7-1 Befu, Jhonanku, Fukuoka 814-0198, JAPAN) 2 Division of Applied Biological Chemistry, Faculty of Agriculture, Graduate School Kyushu University (6-10-1 Hakozaki, Higashiku, Fukuoka 812-8581, JAPAN) 3 Professor Emeritus, Kyushu University and Prefectural University of Kumamoto (5-38-23, Najima, Higashiku, Fukuoka 813-0043, JAPAN)

Edited by T. Itoh, Kitasato Univ., and accepted November 18, 2005 (received for review September 12, 2005)

Abstract: The present study was designed to evaluate the physiological effect of trans fatty acid in the diabetic condition. After feeding the mixture of oleic (cis) or elaidic (trans) acids with safflower oil (3 : 7, wt/wt) at the dietary level of 10% for 2 weeks, rats were treated with streptozotocin and reared on the same diets for an additional week. The dietary level of elaidic acid was 6.4 energy %, which corresponded to the level that causes an increase in plasma low-density lipoprotein cholesterol and a decrease in high-density lipoprotein cholesterol in humans. The following differences were observed in rats fed trans acid in comparison with those fed cis acid; (a) significant reduction of water consumption and serum glucose, and an elevation of serum insulin, (b) a reducing trend of serum and liver lipids, (c) a reducing trend of the proportion of stearic and arachidonic acids in liver phospholipids and (d) a significant reduction of the concentration of serum immunoglobulin G (IgG) and an increase in IgE. Thus, the results indicate that elaidic acid may not further aggravate metabolic disorders caused under the diabetic condition more than the cis counterpart even when consumed at a relatively high level, with the exception of the response of serum immunoglobulins. Key words: elaidic acid, oleic acid, streptozotocine-diabetes, immunoglobulin, prostaglandin E2, rat

exerts diverse metabolic influences more than choles- 1 Introduction terol issue (7,8). The observation that trans acids do not Recent studies on the physiological function of trans promote breast and colon carcinogenesis more than the fatty acid have exclusively been concentrated on its corresponding cis acid, oleic acid (9,10) is in part adverse effect on the serum cholesterol level and attributed to its interference with linoleic acid lipoprotein profile (1-3). The epidemiological studies metabolism, though current study suggested a possible also suggest the possible untoward effect of trans fatty detrimental effect of trans fatty acids in breast cancer acids on atherogenesis (4,5). In addition to this effect, incidence in womens (11). trans acid interferes with the metabolic pathway con- Diabetes mellitus is one of the most common dis- verting linoleic acid to arachidonic acid and hence, eases in the developed countries, and dietary manage- eicosanoids (6,7). Thus, it is expected that trans acid ment is a crucial approach to the treatment of this dis-

＊ Correspondence to: Tamiho KOGA, Nakamura Gakuen Junior College, 5-7-1 Befu, Jhonanku, Fukuoka 814-0198, JAPAN E-mail: [email protected]

Journal of Oleo Science ISSN 1345-8957 print / ISSN 1347-3352 online 127 http://jos.jstage.jst.go.jp/en/ T. Koga, J.-Y. Gu, M. Nonaka et al. ease. In addition to polyunsaturated fatty acids (PUFA) were given free access to respective experimental diets (12), monounsaturated fat shows clinical and metabolic for 2 weeks. The experimental diets were prepared benefits in Type 2 non-insulin-dependent diabetic melli- according to the recommendation by the American tus (NIDDM) patients (13,14). Monounsaturated fatty Institute of Nutrition (AIN, 1977) (28) and contained acid appears to have a favorable effect on serum choles- following ingredients, in g/100 g diet: casein, 20; saf- terol levels and lipoprotein profiles (15,16) and exerts a flower oil, 7; either oleic or elaidic acids (both purity > stability against oxidation (17). Since lipid peroxidation 99%, Wako Pure Chemicals, Osaka), 3; mineral mixture is one crucial factor for the pathogenesis of diabetes, it (AIN76TM) (28), 3.5; vitamin mixture (AIN76TM), 1; is interesting to know the influence of elaidic acid, the choline bitartrate, 0.2; cellulose, 5; corn starch, 15; and geometrical isomer of oleic acid, on diabetic symptoms. sucrose, 45.3. The fatty acid composition of dietary fats The trans configuration is more resistant against lipid is shown in Table 1 and the composition of monoene peroxidation than the cis counterpert (18). In this con- fatty acid was the sole variable in dietary fats. The ener- text, Christiansen et al. (19) showed that both trans gy value of elaidic acid corresponded to 6.4 energy % monounsaturated and saturated fatty acids when fed at a of the diet. Food intake, water consumption and body high level induce an increase in postprandial insuline- weight were recorded every day. After feeding for 2 mia in obese patients with NIDDM. One epidemiologi- weeks, rats were food deprived of for 16 h and received cal study demonstrated that the risk of diabetes is posi- intravenous streptozotocin (STZ, Sigma Chemical Co., tively associated with the intake of trans acid (20), St. Louis, MO) dissolved in 25 mM citrate buffer at a while it was not the case in other studies (21,22). How- dose of 50 mg/kg body weight (29). Rats were allowed ever, trans acid appears to increase insulin resistance to continue the respective diets. One week after STZ (23-25). More recently, Ibrahim et al. (26) showed that administration, foods were removed for 5 h (from 0600 dietary trans acid decreased adipocyte insulin sensitivi- to 1100 h) and blood was withdrawn from the abdomi- ty to a greater extent than did saturated acid. Thus, the nal aorta under diethyl ether anesthesia. Liver, kidney, relation between the intake of trans acid and the spleen and perirenal adipose tissue were excised imme- appearance of NIDDM has not yet been settled, diately. although there are some indications (27). Based on these considerations, in the present study 2･2Lipid Analyses rats previously fed the diets containing fats differing in Liver and serum lipids were extracted by the method the composition of octadecenoic acid, either elaidic of Folch et al. (30) and their lipid components were acid or oleic acid, were treated with streptozotocin and measured as reported elsewhere (31). Liver phospho- fed the same diet for an additional week. The effects of lipids were separated into their components by thin- dietary fat types on various parameters related to dia- layer chromatography (32), and their fatty acid compo- betes such as water consumption, serum glucose, sitions were analyzed by gas-liquid chromatography insulin levels, eicosanoid and immunoglobulin levels, (GC-14A, Shimadzu, Kyoto) using a CP-Sil 88 capil- and the fatty acid composition of liver phospholipids lary column (0.25 mm × 50 m, Chrompack, EA-Mid- were compared. dleburg, Netherlands) (33,34).

2 Experimental

2･1 Animals and Diets a The animal experiment adhered to the Nakamura Table 1 Fatty Acid Composition of Dietary Fat . Gakuen University guide for the care and use of labora- Fatty acid composition (g/100 g) tory animals. Male Sprague-Dawley rats, 4 weeks old, Fat16:0 18:0 t-18:1 c-18:1 18:2 were purchased from Seiwa Experimental Animals, Cis 7.1 1.7 - 42.5 48.4 Fukuoka. Rats were housed individually in a room with Trans 7.1 1.7 31.8 10.9 48.5 a controlled temperature and light (20-22℃, lights on a 0800 to 2000). After acclimation for 3 days, the animals Safflower oil was mixed with either oleic or elaidic acids at the ratio of 7 : 3, w/w. were divided into two groups of seven rats each and

128 J. Oleo Sci., Vol. 55, No. 3, 127-134 (2006) Trans Fatty Acid and Diabetes in Rats

2･3Measurement of Serum Glucose, Insulin, significantly more water, by 140% and gained less

Leukotriene B4, Prostaglandin E2 and weight than those in the trans acid group, although food Creatinine intake was increased by STZ treatment to a similar Serum glucose was measured by a kit (Glucose-Test extent in both groups. Among tissues weighed, relative Wako, Wako Pure Chemicals, Osaka) and insulin by a weight of kidney was significantly higher in rats fed cis radioimmunoassay kit (Insulin Riabead, Dainabot Co., acid than in those fed trans acid, but no difference was

Tokyo). Serum LTB4 and PGE2 were measured by observed in the weight of liver, spleen and adipose tis- radioimmunoassay using commercial kits (NEK-037 sue. and NEK-020, NEN Life Science Products, Boston, MA, respectively) (35,36). Serum creatinine was meas- 3･2 Serum Chemistries and Liver Lipids ured by a commercial kit (Creatinine-Test Wako). The concentration of serum insulin was significantly lower while that of serum glucose was significantly 2･4T-lymphocyte Population Analysis higher in rats fed cis acid than in those fed trans acid Spleen lymphocytes were isolated by Lympholyte- (Table 3). No difference was found in the serum creati- Rat (Cedarlane, Hornby, Canada) and the proportion of nine level between groups. The concentration of serum cells staining positive for CD4+ and CD8+ were ana- and liver lipids tended to be higher in the cis acid group lyzed by flowcytometry (Epics Plofile II, Coulter Elec- than in the trans acid group, and the difference in the tronics Ltd., Beds) (37). concentration of serum cholesterol and liver triglyceride was significant. 2･5 Measurement of Serum Immunoglobu- lins 3･3 Fatty Acid Composition of Liver Phos- Serum immunoglobulins were measured by the sand- pholipids wich ELISA method as reported previously (38,39). In all phospholipid classes except for cardiolipin, trans acid compared to cis acid significantly reduced 2･6Statistical Analysis the proportion of stearic acid and this was compensated Data were analyzed by Student’s t-test before and by the incorporation of the trans isomer (Table 4). after the STZ treatment and within the diet group. Val- Essentially no trans fatty acid was incorporated in car- ues in the text are means ± SE. diolipin and the proportion of stearic acid in this phospholipid was not different between the two groups. The stearic acid level in cardiolipin was negligibly low as 3 Results compared with other classes of phospholipids. There 3･1Growth Performance and Tissue was a difference in the extent of incorporation of elaidic Weight acid among phospholipids, and it was in the order of There were no differences in food intake, water con- phosphatidylethanolamine = phosphatidylcholine > sumption and weight gain between the two groups of phosphatidylinositol > phosphatidylserine. After feed- rats until they received STZ (Table 2). After treatment ing trans acid, a trend toward a reduction of arachidonic with STZ, however, rats in the cis acid group consumed acid and an increase in linoleic acid was observed. Con-

Table 2 Effects of Elaidic Acid on Body Weight Gain, Food Intake, Water Consumption and Tissue Weight a. Inital Body weight Food intake Water consumption Relative tissue weight Group body gain (g/day) (g/day) (ml/day) (g/100 g body weight) weight (g) STZ injection STZ injection STZ injection

Before After Before After Before After Liver Kidney Spleen Adipose

Cis 117 ± 1 6.5 ± 0.1 1.3 ± 0.3* 15.6 ± 0.3 21.4 ± 1.0 19.8 ± 1.8 139 ± 32* 5.16 ± 0.22 1.21 ± 0.04* 0.25 ± 0.01 0.70 ± 0.06 Trans 113 ± 3 6.9 ± 0.2 3.0 ± 0.7 15.2 ± 1.0 19.7 ± 1.0 18.2 ± 1.1 98.3 ± 21.2 5.68 ± 0.15 1.05 ± 0.06 0.27 ± 0.01 0.87 ± 0.06 a Values are means ± SE of 7 rats. *Significantly different from the trans group at p < 0.05.

129 J. Oleo Sci., Vol. 55, No. 3, 127-134 (2006) T. Koga, J.-Y. Gu, M. Nonaka et al.

Table 3 Effects of Dietary Fats on Serum Chemistries and two major phospholipids, phosphatidylcholine and Liver Lipids a. phosphatidylethanolamine. Group Chemistry 3･4 Serum Leukotriene B (LTB ) and Cis Trans 4 4 Prostaglandin E2 (PGE2) Serum The concentration of serum LTB4 was comparable Insulin (mU/ml) 16.8 ± 4.3* 33.8 ± 4.3 between the two groups (113 ± 4 and 123 ± 5 mg/L Glucose (mmol/L) 29.1 ± 0.8* 21.7 ± 3.2 for the cis and trans groups, respectively). There was no Creatinine (mmol/L) 63.0 ± 1.8 60.3 ± 2.4 significant difference in the serum PGE2 level due to a Cholesterol (mmol/L) 2.87 ± 0.18* 2.32 ± 0.06 large individual variation in the cis group, although it Triglyceride (mmol/L) 5.73 ± 1.09 3.48 ± 0.66 was approximately one-third in rats fed trans acid as Phospholipid (mmol/L) 3.31 ± 0.17 2.99 ± 0.10 compared with those fed cis acid (6.37 ± 2.22 and 2.16 Liver Cholesterol (mmol/g) 9.79 ± 0.48 7.94 ± 0.31 ± 0.37 mg/L for the cis and trans groups, respectively). Triglyceride (mmol/g) 47.0 ± 5.3* 34.3 ± 2.0 Phospholipid (mmol/g) 47.2 ± 1.6 42.1 ± 0.9 3･5 Serum Immunoglobulin Levels The concentration of serum IgG was significantly a Values are means ± SE of 7 rats. Significantly different from the higher and that of serum IgE was significantly lower in trans group at *p < 0.05. rats fed cis acid than in those fed trans acid (Table 5). No differences between groups were observed in serum IgA and IgM levels. sequently, the desaturation index for linoleic acid, (20:3n-6 + 20:4n-6)/18:2n-6, tended to be lower in rats 3･6 Splenic T-cell Population fed trans acid compared to those fed cis acid, the differ- T-cell population was dependent on the type of ence was significant in phosphatidylcholine and phos- dietary fats (Table 6). The proportion of cells staining phatidylinositol. In addition, the proportion of docosa- positive for CD4+ was significantly higher in rats fed hexaenoic acid decreased significantly by trans acid in trans acid compared to those fed cis acid. Since the pro-

Table 4 Effects of Elaidic Acid on Fatty Acid Composition of Liver Phospholipids a.

Phosphatidylcholine Phosphatidylethanolamine Phosphatidylinositol Phosphatidylserine Cardiolipin Fatty acid Cis Trans Cis Trans Cis Trans Cis Trans Cis Trans (mol/100 mol) 14:0 ------1.5 ± 0.1 1.6 ± 0.1 - - 16:0 17.1 ± 0.4 20.0 ± 1.3 13.8 ± 0.4 12.8 ± 0.9 3.6 ± 0.4 3.6 ± 0.3 4.8 ± 0.5* 6.6 ± 0.4 4.1 ± 0.3 4.1 ± 0.4 18:0 26.0 ± 0.7** 10.9 ± 0.6 29.1 ± 0.6** 16.5 ± 0.6 46.5 ± 0.6** 33.4 ± 1.1 46.3 ± 0.7** 36.4 ± 0.9 1.4 ± 0.2 1.5 ± 0.2 t-18:1 - 16.7 ± 1.1 - 17.3 ± 1.1 - 13.3 ± 0.8 - 8.1 ± 0.5 - - c-18:1 7.3 ± 0.3** 5.1 ± 0.5 6.8 ± 0.3** 3.6 ± 0.3 1.8 ± 0.1** 1.0 ± 0.1 2.7 ± 0.2 2.8 ± 0.2 20.0 ± 1.2* 16.0 ± 0.7 18:2n-6 11.4 ± 0.4** 14.1 ± 0.5 6.4 ± 0.3 6.8 ± 0.5 1.9 ± 0.1* 2.5 ± 0.2 2.7 ± 0.4 2.9 ± 0.2 68.7 ± 1.7 71.6 ± 1.6 20:3n-3 ------3.3 ± 0.3 2.4 ± 0.2 20:4n-6 29.8 ± 0.5** 26.4 ± 0.3 29.4 ± 0.4 29.4 ± 0.3 41.2 ± 0.5* 39.8 ± 0.2 30.8 ± 1.3 29.2 ± 0.8 - - 22:5n-6 0.6 ± 0.1 0.6 ± 0.1 1.5 ± 0.1 1.6 ± 0.1 0.9 ± 0.1 1.2 ± 0.1 1.5 ± 0.1 1.4 ± 0.5 - - 22:5n-3 2.1 ± 0.2 2.2 ± 0.2 4.3 ± 0.3 5.2 ± 0.7 1.2 ± 0.1 1.1 ± 0.1 3.4 ± 0.2 3.9 ± 0.2 1.7 ± 0.3 2.0 ± 0.5 22:6n-3 3.4 ± 0.2** 2.4 ± 0.2 8.2 ± 0.4** 6.2 ± 0.3 1.1 ± 0.1 1.0 ± 0.1 5.2 ± 0.4 4.9 ± 0.6 - - Desaturation index b 2.6 ± 0.1** 1.9 ± 0.1 4.7 ± 0.3 4.5 ± 0.4 22.3 ± 1.2* 16.8 ± 1.7 13.2 ± 2.1 10.4 ± 1.2 - - a Value are means ± SE of 7 rats. Significantly different from the corresponding elaidic acid group at *p < 0.05 and **p < 0.01. b (20:3n-6 + 20:4n-6)/18:2n-6.

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Table 5 Effects of Elaidic Acid on Concentrations of rats previously fed elaidic acid at least has tolerance Serum Immunoglobulins a. against the drug more than those fed oleic acid. IgG IgM IgA IgE Greater water consumption, higher serum glucose Group (mg/ml) (mg/ml) (mg/ml) (ng/ml) level, and lower serum insulin level in rats fed cis acid in relation to trans acid may indicate more severe dia- Cis 6.76 ± 1.61** 327 ± 46 26.0 ± 2.5 4.69 ± 0.84* betic state in the former group of rats. Additionally, Trans 1.98 ± 0.10 325 ± 27 25.6 ± 3.0 7.57 ± 0.72 there was a tendency of increased concentrations of a Values are means ± SE of 7 rats. Significantly different from the serum and liver lipids in the cis group, suggesting trans group at *p < 0.05 and **p < 0.01, respectively. greater disturbance of lipid metabolism in this group due to STZ. In NIDDM patients, it has been reported Table 6 Effects of Elaidic Acid on Splenic T-Lymphocyte that a high-monounsaturated-fat diet is more effective Subsets a. than a high-complex-carbohydrate diet in reducing blood glucose levels and improving the overall lipopro- Group CD4+ CD8+ CD4+/CD8+ tein profile (40). Christiansen et al. (19) showed in Cis 26.2 ± 1.9* 17.6 ± 0.5 1.48 ± 0.07** obese patients with NIDDM trans and cis acids are Trans 32.2 ± 1.4 16.4 ± 0.4 1.96 ± 0.07 equally glycemic but insulin and C-peptide responses a Values are means ± SE of 7 rats. Significantly different from the were significantly greater following the trans acid diet. trans group at *p < 0.05 and **p < 0.01, respectively. Thus, it is conceivable that trans monounsaturated fatty acid has a propensity that is different from the cis counterpart in its effect on diabetic situation, although the direct comparison may not be allowed between humans portion of CD8+ did not differ between groups, the and rats. In this context, it has been shown that trans trans acid group showed a significantly higher acid affects insulin receptors by decreasing the number CD4+/CD8+ ratio in relation to the cis acid group. and increasing the affinity, an effect similar to that observed with saturated acid (41), probably through a change in fatty acid composition in the cell membrane. 4Discussion Phosholipid model membranes containing trans acid In our preliminary experiments, STZ (Wako Pure had a higher membrane cholesterol affinity and lower Chemicals, Osaka) was administered at the level recom- receptor activation than their cis analogues (42). These mended by Junod et al.(29), 65 mg/kg body weight, to changes in membrane structure and function may con- rats which previously received either cis or trans acid tribute to metabolic change due to trans acid. diets under the same dietary condition with that of the The mechanism by which trans acid reduces the con- present study. Five out of 6 rats died 4 days after centration of serum glucose and increases that of administration and one 5 days after in the oleic acid insulin, in relation to the cis counterpart, is not apparent group, while in the elaidic acid group 2 out of 6 rats at present, but it seems unlikely that the increase in died 4 days after. When the dose level was reduced to serum insulin by trans acid is caused by increased 60 mg/kg under the same dietary manipulation, 4 and 2 insulin resistance in the peripheral tissues, since the out of 6 rats died 3 and 4 days after STZ, respectively, serum glucose was lowered. Therefore, there is a possi- in the oleic acid group, while each 2 rats in the elaidic bility that trans acid elevates or does not reduce a glu- acid group died in the same time interval. The dose was cose receptor (Glut 4) activity in relation to cis acid. It further reduced to 50 mg/kg and it was found that 8 and is known that the type of dietary fat differently influ- 6 out of 8 rats died 2 days after administration in the cis ences fasting blood insulin and glucose levels (43). The and trans acid groups, respectively. Then, the STZ difference in the fatty acid composition of membrane preparation from other supplier (Sigma Chemical Co., phospholipids between the cis and trans groups may St. Louis, MO) was given at a level of 50 mg/kg, and cause such a difference (44). In this context, the less one rat deceased 2 and 3 days after the STZ treatment oxidizable propensity of elaidic acid compared with in the cis and trans groups, respectively. Although the oleic acid may also be involved in the different response cause of this phenomenon is unclear, it is suggested that (18). The insulin secretion also is under regulation of

131 J. Oleo Sci., Vol. 55, No. 3, 127-134 (2006) T. Koga, J.-Y. Gu, M. Nonaka et al. dietary fat, and monoene fatty acid improves glycemic normal rats were received the diets same to those given control (14,40,45). Whatever the mechanism is con- currently, there was no difference in the concentration cerned, these results indicate that elaidic acid may miti- of individual serum immunoglobulins between the cis gate the diabetic state more than oleic acid in this ani- and trans groups, respectively (47). The concentrations mal model. Although the extent of decrease in the of serum IgG and IgE observed in the previous study antilipolytic effect of insulin and insulin-stimulated glu- were similar to those in the cis acid group in the present cose transport were greater in rats fed trans acid than in study. Thus, the under the diabetic condition, as com- those fed saturated acid, and the decrease was not prepared with the normal state, it is plausible that the dif- vented or reduced with linoleic acid (26). ference in the geometry of octadecenoic acid induces a Consistent with our previous observations with nor- different response to the serum immunoglobulins. mal rats (46,47), there was a difference in the extent of Although the mechanism is unknown, this observation incorporation of trans acid in individual phospholipids deserves further study. even in diabetic rats. Although an enough amount of linoleic acid was supplemented, trans acid interfered 5 Conclusion with the metabolism of linoleic acid to arachidonic acid, and this interference was more marked in the dia- In conclusion, elaidic acid, in comparison with oleic betic rats than in normal rats (46,47). This metabolic acid, even given at a relatively high level, approximate- pathway is known to be repressed under diabetic situa- ly 6 energy %, did not aggravate the pathogenesis of tion (7). Reflecting the reducing effect of trans acid on diabetic condition caused by STZ, in so far as the glu- the arachidonic acid level, the concentration of serum cose level is concerned. Since trans acid has been

PGE2 tended to be lower in rats fed elaidic acid, though shown to exert untoward effects on cholesterol distribu- not significant because of a large deviation of this tion in plasma lipoproteins at the dietary level above 4 parameter in rats fed oleic acid. Insulin stimulates D6 to 5 energy % (16,51,52), this observation seems to be desaturase activity (7), the key enzymatic step leading worth mentioning. However, the metabolic effects of linoleic acid to arachidonic acid, and trans acid elevated oleic acid and elaidic acid on diabetic parameters were the serum insulin level in relation to cis acid. However, complex and not necessarily unitary. In this context, it the desaturation index was rather lower in rats fed trans seems interesting to know how elaidic acid modifies the acid than in those fed cis acid, suggesting a consider- established STZ diabetes. able interfering effect of trans acid on PUFA metabolism. No influence was seen in the concentration References of serum LTB4, but it is frequently reported that the response of eicosanoid production is type-specific 1. P.L. ZOCK and M.B. KATAN, Butter, Margarine and Serum (29,47) and the magnitude of response to STZ treatment Lipoproteins, Atherosclerosis, Vol. 131, 1-16 (1997). also is different (48). 2. A.H. LICHTENSTEIN, Trans Fatty Acids and Cardiovascular Disease Risk, Curr. Opin. Lipidol., Vol. 11, 37-42 (2000). In rats oleic acid is shown to be immunosuppressive 3. M.B. KATAN, Trans Fatty Acids and Plasma Lipoproteins, Nutr. in relation to linoleic acid (49,50). The analysis of Rev., Vol. 58, 188-191 (2000). splenic T-lymphocyte population showed an increased 4. F.B. HU, M.J. STAMPFER, J.E. MANSON, E. RIMM, G.A. + proportion of CD4 positive cells and consequently the COLDITZ, B.A. ROSNER, C.H. HENNEKENS and W.C. WIL- CD4+/CD8+ ratio in rats fed elaidic acid, suggesting the LETT, Dietary Fat Intake and the Risk of Coronary Heart Dis- stimulation of immunoglobulin production (51). How- ease in Women, New England Journal of Medicine, Vol. 337, ever, the results of serum immunoglobulin levels were 1491-1499 (1997). not necessarily reflected the change in T-cell subsets, 5. C.M. OOMEN, M.C. OCKE, E.J.M. FESKENS, M.A.J. van ERP-BAART, F.J. KOK and D. KROMHOUT, Association and the level of IgG decreased significantly, and that of between trans Fatty Acid Intake and 10-year Risk of Coronary IgE increased significantly after feeding trans acid. Heart Disease in the Zutphen Elderly Study: a Prospective Popu- Although the spleen plays a crucial role in the produc- lation-Based Study, Lancet, Vol. 357, 746-751 (2001). tion of immunoglobulin on a whole body basis, it may 6. B. KOLETZKO and T. DESCI, Metabolic Aspects of trans Fatty be possible that the splenic production of immunoglob- Acids, Clin. Nutr., Vol. 16, 229-237 (1997). ulin is not totally reflected on the serum level. When 7. M. SUGANO, Isomeric Fatty Acids: Their Physiological Signif-

132 J. Oleo Sci., Vol. 55, No. 3, 127-134 (2006) Trans Fatty Acid and Diabetes in Rats

icance and Health Implications, World Rev. Nutr. Diet., Vol. 88, Nutr., Vol. 73, 1019-1026 (2001). 238-242 (2001). 21. R.M. van DAM, W.C. WILLETT, R.B. RIMM, M.J. 8. M. SUGANO and I. IKEDA, Metabolic Interactions between STAMPFER and F.B. HU, Dietary Fat and Meat Intake in Rela- Essential and trans-Fatty Acids, Curr.t Opin. Lipidol., Vol. 7, tion to Risk of Type 2 Diabetes in Men, Diabetes Care, Vol. 25, 38-42 (1996). 417-424 (2001). 9. M. SUGANO, M. WATANABE, K. YOSHIDA, M. MIYAMO- 22. K.A. MEYER, L.H. KUSHI, D.R. JACOBS and A.R. FOLSOM, TO and D. KRITCHEVSKY, Influence of Dietary cis- and Dietary Fat and Incidence of Type 2 Dabetes in Older Iowa trans-Fats on DMH-induced Colon Tumor, Steroid Excretion Women, Diabetes Care, Vol. 24, 1528-1535 (2001). and Eicosanoid Production in Rats Prone to Colon Cancer, Nutr. 23. G.A. BRY, J.C. LOVEJOY, S.R. SMITH, J.P. DeLANY, M. Cancer, Vol. 12, 177-187 (1989). LEFEVRE, D. HWANG, D.H. RYAN and D.A. YORK, the Iin- 10. M. WATANABE, M. SUGANO, H. MURAKAMI and H. fluence of Different Fats and Fatty Acids on Obesity, Insulin OMURA, 7, 12-Dimetylbenz- (a)anthracene- induced and Trans- Resistance and Inflammation, J. Nutr., Vol. 132, 2488-2491 plantable Mammary Tumors in Female Rats Fed Geometrically (2002). Different Fats, J. Clin. Biochem. Nutr., Vol. 2, 41-53 (1987). 24. E. CHRISTIANSEN, S. SCHNIDER, B. PLMVIG, E. 11. W. McKELOEY, S. GREENLAND and R.S. SANDLER, A Sec- TAUBER-LASSEN and O. PEDERSEN, Intake of a Diet High ond Look at the Relation between Colorectal Adenomas and in trans Monounsaturated Fatty Acids or Saturated Fatty Acids, Consumption of Foods Containing Partially Hydrogenated Oils, Effects on Postprandial Insulinemia and Glycemia in Obese Epidemiology, Vol. 11, 469-473 (2001). Patients with NIDDM, Diabetes Care, Vol. 20, 881-887 (1999). 12. A.K. SINHA, L.A. SCHARSCHMIDT, R. NEUWIRTH, H. 25. K.K. ALSTRUP, S. GREGERSEN, H.M. JENSEN, J.L. THOM- HOLTHOFER, N. GIBBONS, C.M. ARBEENY and D. SEN and K. HERMANSEN, Differential Effects of cis and trans SCHLONDORFF, Effects of Fish Oil on Glomerular Function in Fatty Acids on Insulin Release from Isolated Mouse Islets, Rats with Diabetes Mellitus, J. Lipid Res., Vol. 31, 1219-1228 Metabolism, Vol. 48, 22-29 (1999). (1990). 26. A. IBRAHIM, S. NATRAJAN and R. GHAFOORUNISSA, 13. M. PARILLO, A.A. RIVELLESE, A.V. CIARDULLO, B. Dietary trans-Fatty Acids Alter Adiposcyte Plasma Membrane CAPALDO, A. GIACCO, S. GENOVESE and G. RICCARDI, Fatty Acid Composition and Insulin Sensitivity in Rats, A High-Monounsaturated-Fat/Low-Carbohydrate Diet Improves Metabolism, Vol. 54, 240-246 (2005). Insulin Sensitivity in Non-Insulin-Dependent Diabetic Patients, 27. S. STENDER and J. DYERBERG, Influence of trans Fatty Metabolism, Vol. 41, 1373-1378 (1992). Acids on Health, Ann. Nutr. Metab., Vol. 48, 61-66 (2004). 14. A. GARG, High-Monounsaturated Fat Diet for Diabetic 28. American Institute of Nutrition Report of the American Institute Patients: Is It Time to Change the Current Dietary Recommen- of Nutrition ad hoc Committee on Standards for Nutritional dation?, Diabetes Care, Vol. 17, 242-246 (1994). Studies, J. Nutr., Vol. 107, 1340-1348 (1977). 15. S. HEYDEN, Polyunsaturated and Monounsaturated Fatty Acids 29. A. JUNOD, A.E. LAMBERT, W. STAUFFA and A.E. in the Diet to Prevent Coronary Heart Disease via Cholesterol RENOLD, Diabetogenic Action of Streptozotocin: Relationship Reduction, Ann. Nutr. Metab., Vol. 38, 117-122 (1994). of Dose to Metabolic Response, J. Clini. Invest., Vol. 48, 2129- 16. R.P. MENSINK and M.B. KATAN, Trans Monounsaturated 2139 (1969). Fatty Acids in Nutrition and Their Impact on Serum Lipoprotein 30. J. FOLCH, M. LEES and G.H. SLOANE-STANLEY, A Simple Levels in Man, Prog. Lipid Res., Vol. 32, 111-122 (1993). Method for the Isolation and Purification of Total Lipides from 17. H. BULUR, G. OZDEMIRLER, B. OZ, G. TOKER, M. Animal Tissues, J. Biol. Chem., Vol. 226, 497-509 (1957). OZTURK and M. UYSAL, High Colesterol Diet Supplemented 31. M. SUGANO, K. RYU and T. IDE, Cholesterol Dynamics in with Sunflower Seed Oil but not Olive Oil Stimulates Lipid Per- Rats Fed cis- and trans-Octadecenoate in the Form of Triglyc- oxidation in Plasma, Liver, and Aorta of Rats, J. Nutr. Biochem., eride, J. Lipid Res., Vol. 25, 474-485 (1984). Vol. 6, 547-550 (1995). 32. H. TAKAMURA, H. NARITA, H.J. PARK, K. TANAKA, T. 18. D.R. KODALI, Trans Fats-Chemistry, Occurrence, Functional MATUURA and M. KITO, Differential Hydrolysis of Phospho- Need in Foods and Potential Solutions, in Trans Fats Alternative lipid Molecular Species during Activation of Human Platelets (D.R. KODALI and G.R. LIST, eds.), AOCS Press, Champaign, with Thrombin and Collagen, J. Biol. Chem., Vol. 262, 2262- IL pp. 1-25 (2005). 2269 (1987). 19. E. CHRISTIANSEN, S. SCHNEIDER, B. PALMVIG, E. 33. R.L. WOLFF, Resolution of Linolenic Acid Geometrical Iso- TAUBER-LASSEN and O. PEDERSEN, Intake of a Diet High mers by Gas-Liquid Chromatography on a Capillary Column in trans Monounsaturated Fatty Acids or Saturated Fatty Acids. Coated with a 100% Cyanopropyl Polysiloxane Film (CPTMSil Effects on Postprandial Insulinemia and Glycemia in Obese 88), J. Chromatog. Sci., Vol. 30, 17-22 (1992). Patients with NIDDM, Diabetes Care, Vol. 20, 881-887 (1997). 34. I. IKEDA, Y. IMASATO, H. NAGAO, E. SASAKI, M. SUG- 20. J. SALMERON, F.B. HU, J.E. MANSON, M.J. STAMPFER, ANO, K. IMAIZUMI and K. YAZAWA, Lymphatic Transport of G.A. COLDITZ, E.B. RIMM and W.C. WILLETT, Dietary Fat Eicosapentaenoic and Docosahexaenoic Acids as Triglyceride, Intake and Risk of Type 2 Diabetes in Women, Am. J. Clin. Ethyl Ester and Free Acid, and Their Effect on Cholesterol

133 J. Oleo Sci., Vol. 55, No. 3, 127-134 (2006) T. Koga, J.-Y. Gu, M. Nonaka et al.

Transport in Rats, Life Sci., Vol. 52, 1371-1379 (1993). Lancet, Vol. 345, 357-358 (1995). 35. G.G. BRUCKNER, B. LOKESH, B. GERMAN and J.E. KIN- 44. O. RASMUSSEN, F.F. LAUSZUS, C. THOMSEN and K. HER- SELLA, Leukotriene Formation by Mouse Connective Tissue MANSEN, Different Effects of Saturated and Monounsaturated Mast Cells, Thromb. Res., Vol. 34, 479-497 (1984). Fat on Blood Glucose and Insulin Response in Subject with 36. J.-Y. GU, M. NONAKA, K. YAMADA, K. YOSHIMURA, M. Non-Insulin-Dependent Diabetes Meritus, Am. J. Clin. Nutr., TAKASUGI, Y. ITO and M. SUGANO, Effects of Sesamin and Vol. 63, 249-253 (1996). a-tocopherol on the Production of Chemical Mediators and 45. T. KOGA, T. YAMATO, J.-Y. GU, M. NONAKA, K. YAMADA Immunoglobulins in Brown-Norway Rats, Biosc. Biotech. and M. SUGANO, Diversity in the Incorporation into Tissue Biochem., Vol. 58, 1855-1858 (1994). Phospholipids and Effects on Eicosanoid Production of trans- 37. B.O. LIM, K. YAMADA, M. NONAKA, Y. KURAMOTO, P. monoene Fatty Acids in Rats Fed with different Dietary Pro- HUNG and M. SUGANO, Dietary Fibers Modulate Indices of teins, Biosci. Biotech. Biochem., Vol. 58, 384-387 (1994). Intestinal Immune Function in Rats, J. Nutr., Vol. 127, 663-667 46. T. KOGA, M. NONAKA, J.-Y. GU and M. SUGANO, Linoleic (1997). and a-linolenic Acids Differently Modify the Effects of Elaidic 38. N. MATSUO, K. OSADA, T. KODAMA, B.O. LIM, A. Acid on Polyunsaturated Fatty Acid Metabolism and Some NAKAO, K. YAMADA and M. SUGANO, Effects of g- Immune Indices in Rats, Br. J. Nutr., Vol. 77, 645-656 (1997). linolenic Acid and Its Positional Isomer Pinolenic Acid on 47. S.P. ROGERS and R.G. LARKINS, Production of 6-oxo- Immune Parameters of Brown-Norway Rats, Prostagl. Leukotr. prostaglandin F1 Alpha by Rat Aorta: Influence of Dieabetes, Essent. Fatty Acids, Vol. 55, 223-229 (1996). Insulin Treatment, and Caloric Deprivation, Diabetes, Vol. 30, 39. A. GARG, A. BONANOME, S.M. GRUNDY, Z.J. ZHANG and 935-939 (1981). R.H. UNGER, Comparison of a High-Carbohydrate Diet with a 48. N.M. JEFFERY, P. YAQOOB, E.A. NEWSHOLME and P.C. High-Monounsaturated-Fat Diet in Patients with Non-Insulin- CALDER, The Effects of Olive Oil upon Rat Serum Lipid Lev- Dependent Diabetes Mellitus, N. Engl. J. Med., Vol. 319, 829- els and Lymphocyte Functions Appear to be Due to Oleic Acid, 834 (1988). Ann. Nutr. Metab., Vol. 40, 71-80 (1996). 40. S.J. BHATHENA, Fatty Acids and Diabetes, in Fatty Acids in 49. N.M. JEFFERY, M. CORTINA, E.A. NEWSHOLME and P.C. Foods and Their Health Implications (C.K. CHOW, ed.), Marcel CALDER, Effects of Variations in the Proportions of Saturated, Dekker, Inc., New York, pp. 823-868 (1992). Monounsaturated and Polyunsaturated Fatty Acids in the Rat 41. S. IKEMOTO, M. TAKAHASHI, N. TSUNODA, K. MARU- Diet on Spleen Lymphocyte Functions, Br. J. Nutr., Vol. 77, 805- YAMA, H. ITAKURA and O. EZAKI, High-Fat Diet-Induced 823 (1997). Hyperglycemia and Obesity in Mice. Differential Effects of 50. M.L. KAPSENBERG, E.A. WIERANGA, J.D. BOS and H.M. Dietary Oils, Metabolism, Vol. 45, 1539-1546 (1996). JANSEN, Functional Subsets of Antigen-Reactive Human CD4- 42. S.-L. NIU, D.C. MITCHELL and B.J. LITMAN, Trans Fatty lymphocyte, Immunol. Today, Vol. 12, 392-395 (1991). Acid Deribed Phospholipids Show Increased Membrane Choles- 51. M.B. KATAN, Exit trans Fatty Acids, Lancet, Vol. 346, 1245- terol and Reduced Receptor Activation as Compared to Their cis 1246 (1995). Analogs, Biochemistry, Vol. 44, 4458-4465 (2005). 52. P. KHOSLA and K.C. HAYES, Dietary trans-Monounsaturated 43. P. TONG, T. THOMAS, T. BERRISH, B. HUMPHRISS, L. Fatty Acids Negatively Impact Plasma Lipids in Humans: Criti- BARRIOCANOL, M. STEWART, M. WALLZER, R. WILKIN- cal Review of the Evidence, J. Am. Coll. Nutr., Vol. 4, 325-339 SON and K.G.M.M. ALBERTI, Cell Membrane Dynamics and (1996). Insulin Resistance in Non-Insulin-Dependent Diabetes Mellitus,

134 J. Oleo Sci., Vol. 55, No. 3, 127-134 (2006)