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C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n
O R I G I N A L
Treatment With Dietary trans10cis12
Conjugated Linoleic Acid Causes Isomer-
Specific Insulin Resistance in Obese Men

With the Metabolic Syndrome
LF RIS´ERUS, MMED
KERSTIN BRISMAR, MD, PHD
ETER ARNER, MD, PHD
BENGT VESSBY, MD, PHD
ment decreased abdominal fat in obesemen but without improving metabolism(7). The latter was surprising, because ab-dominal fat and insulin sensitivity are OBJECTIVE — Conjugated linoleic acid (CLA) is a group of dietary fatty acids with antiobe-
strongly related (8). Similarly, studies on sity and antidiabetic effects in some animals. The trans10cis12 (t10c12) CLA isomer seems to cause these effects, including improved insulin sensitivity. Whether such isomer-specific effects mixture indicated decreased body fat after occur in humans is unknown. The aim of this study was to investigate whether t10c12 CLA or a commercial CLA mixture could improve insulin sensitivity, lipid metabolism, or body compo- in insulin levels (9). However, a strictly sition in obese men with signs of the metabolic syndrome.
RESEARCH DESIGN AND METHODS — In a randomized, double-blind controlled
any change in body fat or fasting glucose trial, abdominally obese men (n ϭ 60) were treated with 3.4 g/day CLA (isomer mixture), purified t10c12 CLA, or placebo. Euglycemic-hyperinsulinemic clamp, serum hormones, lipids, Thus, possible antiobesity actions of CLA and anthropometry were assessed before and after 12 weeks of treatment.
are still unclear. In spite of lacking clinicaland safety human data, dietary CLA sup- RESULTS — Baseline metabolic status was similar between groups. Unexpectedly, t10c12
CLA increased insulin resistance (19%; P Ͻ 0.01) and glycemia (4%; P Ͻ 0.001) and reduced HDL cholesterol (Ϫ4%; P Ͻ 0.01) compared with placebo, whereas body fat, sagittal abdominal group for type 2 diabetes. Therefore, clin- diameter, and weight decreased versus baseline, but the difference was not significantly different ical studies are critically needed on such from placebo. The CLA mixture did not change glucose metabolism, body composition, orweight compared with placebo but lowered HDL cholesterol (Ϫ2%; P Ͻ 0.05).
CONCLUSIONS — These results reveal important isomer-specific metabolic actions of CLA
in abdominally obese humans. A CLA-induced insulin resistance has previously been described only in lipodystrophic mice. Considering the use of CLA-supplements among obese individuals, it is important to clarify the clinical consequences of these results, but they also provide physi- trans10cis12 (t10c12) CLA and c9t11 ological insights into the role of specific dietary fatty acids as modulators of insulin resistance in CLA. Both isomers are present in the diet, with the c9t11 isomer being the mostprevalent (13). In rodents, different iso- Diabetes Care 25:1516 –1521, 2002
mers have distinct effects, and it has beensuggested that t10c12 CLA is responsiblefor the antiobesity (14) and insulin- Conjugated linoleic acid (CLA) is a bodyfat(2,3),andinmaleZDFrats,CLA sensitizing(5)propertiesofCLA.Toad-
improves insulin sensitivity (4,5). In con- tion for its metabolic and antiobesity ac- ated the effects of purified t10c12 CLA (6), indicating important species and sex isomers of linoleic acid, naturally found in domized controlled trial, we investigated dairy and beef fat. In mice, CLA decreases insulin action in abdominally obese men,a potential target group for the putative ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● antidiabetic and antiobesity effects of CLA From the 1Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Swe-den; the 2Department of Medicine, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden; and the 3Department of Molecular Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.
Address correspondence and reprint requests to Ulf Rise´rus, Clinical Nutrition Research Unit, Depart- RESEARCH DESIGN AND
ment of Public Health and Caring Sciences/Geriatrics, Box 609, 751 25 Uppsala, Sweden. E-mail: Received for publication 25 February 2002 and accepted in revised form 14 May 2002.
Abbreviations: BIA, bioelectrical impedance analysis; CLA, conjugated linoleic acid; FFA, free fatty acid;
M, glucose disposal; SAD, sagittal abdominal diameter; t10c12, trans10cis12; TG, triglycerides.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion with signs of the metabolic syndrome (ab- dominal obesity, insulin resistance, dys- DIABETES CARE, VOLUME 25, NUMBER 9, SEPTEMBER 2002 Rise´rus and Associates
Table 1—Baseline characteristics
Insulin sensitivity (M) (mg ⅐ kgϪ1 ⅐ min) Data are means Ϯ SD unless noted otherwise. There were no significant differences between the groups (ANOVA). *n ϭ 18 in the placebo group.
free fatty acids [FFAs]) was 35.9% t10c12 exercise habits during the study. To assess CLA, 35.4% c9t11 CLA, 13.1% 18:1c9, possible changes in dietary intake during insulin resistant (8,16), both of these dis- 2c9c12; that of the t10c12 CLA prepara- orders were included in the inclusion cri- tion (75% FFAs) was 76.5% t10c12 CLA, teria: waist girth Ͼ102 cm, waist-to-hip 11.4% 18:1c9, 3.4% 16:0, 2.9% c9t11 ratio Ͼ0.95, BMI 27–39 kg/m2, triglycer- CLA, 2.0% 18:2c9c12, and 0.8% 18:0. All disease or diabetes. Six subjects had fast- (possible isomerization products from the t10c12 CLA preparation were very low as mmol/l, indicating mild diabetes; all men Medical Faculty, Uppsala University.
broken after the study was completed.
free mass contains 73.2% water (18).
the morning, after instructions to fast (12 formula provided by the manufacturer.
h) and refrain from smoking, taking snuff sures included insulin sensitivity; fasting in physical activity in the morning and to levels of glucose, lipids, and leptin; and avoid alcohol and exercise the day before visits. Subjects completed a questionnaire ity, as described by Defronzo et al. (19) mer mixture), purified t10c12 CLA, or least one first-degree relative with type 2 scribed in detail (20). Insulin (Actrapid diabetes) and the use of medication or di- DIABETES CARE, VOLUME 25, NUMBER 9, SEPTEMBER 2002 CLA and insulin resistance
Table 2—Change in body composition from baseline to 12 weeks
Compliance (capsule count) did not sig-nificantly differ between groups (89.5%,n ϭ 57). No significant changes in dietary There were no significant differences be- fat, lean body mass, or waist girth at 12 Data are means Ϯ SD. There were no differences between the groups. All P values indicate within-group differences; *P Ͻ 0.05; †P Ͻ 0.01; ‡P Ͻ 0.001.
BMI, or waist girth compared with pla-cebo, although these variables signifi- was infused (336 pmol/l ⅐ mϪ2 ⅐ minϪ1) cantly decreased within the t10c12 CLA Values are expressed as means Ϯ SD.
level of 624 pmol/l, a level shown to al- creased within the CLA group (paired t logarithmically transformed before analy- production in insulin-resistant and type 2 sis. A nonparametric test was used if data diabetic subjects (21). Venous blood sam- were not normally distributed after loga- pling was obtained in the left hand, which rithmic transformation. Paired t test was Insulin sensitivity (M) decreased signifi- in the right antecubital vein. Plasma glu- cantly in the t10c12 CLA group compared test). In case of a significant overall test (Table 3). Also, when correcting M for the Instruments, Fullerton, CA), using an en- zymatic method. Glucose disposal (M) clamp (M/I ϭ M/pmol/l ϫ 100) (19), in- was calculated as the glucose infusion rate sulin sensitivity decreased (Ϫ19%; P Ͻ (mg ⅐ kgϪ1 ⅐ minϪ1) during the last 60 min tion coefficient was determined. It was es- 0.01) after t10c12 CLA treatment (data timated that n ϭ 20/group would be the t10c12 CLA group (P Ͻ 0.05) but not terol levels with a power of 0.80 at a sig- nificance level of 0.05. All tests were two- significant reduction in M after t10c12 CLA treatment was not affected by adjust- significant. JMP software (SAS Institute, ment for age or changes in glucose levels, –20°C. Lipoproteins were isolated from body fat, BMI, or abdominal fat. Baseline ative ultracentrifugation (22) and precip- betes heredity did not affect significance, and magnesium chloride solution (23).
plasma glucose Ն7.0 mmol/l. Of all vari- Baseline characteristics and diabetes he- redity were similar in all groups (Table 1).
change in M after t10c12 CLA treatment.
sons for withdrawal were gastrointestinal Fasting glucose increased after t10c12 samples were stored at –70°C. Serum free (t10c12 CLA group). One patient (place- after t10c12 CLA treatment versus base- line (P ϭ 0.01) but was not significantly ical, respectively) in the Monarch centri- completed the trial, but his data were ex- cluded from statistics; results were not in- The changes in serum lipids or leptin did follow-up data. For M, n ϭ 56 because in one subject only insulin values were avail- t10c12 CLA treatment (P ϭ 0.03 and P ϭ tolerated, with only minor transient gas- immunoassay kit (Linco Research, St.
t10c12 CLA versus placebo and CLA (P ϭ liver enzymes occurred (data not shown).
DIABETES CARE, VOLUME 25, NUMBER 9, SEPTEMBER 2002 Rise´rus and Associates
Table 3—Absolute and relative changes in glucose and lipid metabolism from baseline to 12 weeks
Insulin sensitivity (M) (mg ⅐ kgϪ1 ⅐ minϪ1) Data are means Ϯ SD (%). Values for M, n ϭ 18. *P Ͻ 0.01 vs. placebo; †P Ͻ 0.05 within the group; ‡P Ͻ 0.001 vs. placebo; §P Ͻ 0.01 within the group; ࿣P Ͻ 0.05vs. placebo.
primary goal, however, was to investigate The changes in M in the t10c12 CLA the clinical effects of CLA in an insulin- VLDL TG (r ϭ Ϫ0.74, P ϭ 0.0003) but not with other variables. The decrease in correlated only to a change in leptin (r ϭ that became severely insulin resistant and decrease after CLA treatment, but the dif- 31, P ϭ 0.02), which remained significant lipodystrophic after receiving a CLA mix- ture containing 36% t10c12 CLA (6).
cebo. The standard deviations for changes CONCLUSIONS — This randomized
of insulin resistance after CLA treatment placebo-controlled trial has revealed un- fatty acids in humans—actions that seem with the t10c12 CLA–induced insulin re- isomer-specific. The t10c12 CLA isomer, not affect the t10c12 CLA–induced insu- of current insulin resistance is unknown, lin resistance, with one exception. Adjust- creased insulin resistance, fasting glucose, ing. An intriguing speculation is that CLA tight relation between these two variables mice (6) and in vitro (6,25,26), and by the (31). It is likely that impaired insulin ac- target group for the putative beneficial ef- t10c12 isomer in particular (26). t10c12 tion after t10c12 CLA treatment preceded dyslipidemia (31), but this remains to be new, small, and insulin-sensitive fat cells t10c12 CLA might be diabetogenic in the effect was more pronounced with t10c12 t10c12 CLA–induced insulin resistance arate information regarding t10c12 CLA, function (28), possibly via increasing in- tramuscular fat content (29). Insulin re- peripheral tissues rather than in the liver, cular risk factor (33), the current reduc- 23% t10c12 CLA (12), indicating im- tion of 0.04 mmol/l (Ϫ4%) with t10c12 CLA is of clinical concern, as a change of other studies, diet and physical activity (30), did not change (unpublished data).
were controlled using metabolic suites in to coronary risk (33). Interestingly, the c11t13 CLA was higher and c9t11 CLA not related to insulin resistance, but were positively related to leptin levels.
DIABETES CARE, VOLUME 25, NUMBER 9, SEPTEMBER 2002 CLA and insulin resistance
Table 4—Changes in dietary intake during the study period
Moya-Camarena SY, Portocarrero CP,Peck LW, Nickel KP, Belury MA: Dietary conjugated linoleic acid normalizes im-paired glucose tolerance in the Zucker di- abetic fatty fa/fa rat. Biochem Biophys Res 5. Ryder JW, Portocarrero CP, Song XM, Cui antidiabetic properties of conjugated lino- skeletal muscle insulin action, and UCP-2gene expression. Diabetes 50:1149 –1157, develops lipodystrophy in mice. Diabetes 7. Riserus U, Berglund L, Vessby B: Conju- gated linoleic acid (CLA) reduced abdom-inal adipose tissue in obese middle-aged drome: a randomised controlled trial. Int J Data are means Ϯ SD. P values represent paired t tests. Data are based on subjects with two completed food Obes Relat Metab Disord 25:1129 –1135, records (n ϭ 42). There were no differences between groups (all P values for unpaired t tests Ͼ0.2; data not shown. *Amount of total polyunsaturated fats divided by saturated fats.
Further, the t10c12 CLA–induced in- metabolic complications of obesity. J Clin the concurrent increase in fasting glucose Endocrinol Metab 54:254 –260, 1982 was clinically irrelevant, the 19% reduc- enough to have clinical relevance (34), es- metabolic effects. Lipids 36:773–781,2001 pecially considering the prediabetic high- 10. Blankson H, Stakkestad JA, Fagertun H, Acknowledgments — This study was sup-
Conjugated linoleic acid reduces body fat control subjects, the relative decrease in mass in overweight and obese humans. J insulin sensitivity after t10c12 CLA treat- 04224), Swedish Society for Nutrition Re- search, Swedish National Fund for Industrial tional Association against Heart and Lung Dis- ease, and Swedish Diabetes Foundation. We rather powerful effect of this isomer. The thank Natural Lipids Ltd. AS, Norway, for amounts of t10c12 CLA in the diet (where and energy expenditure. Lipids 35:777– the major isomer is c9t11 CLA) are very 12. Medina EA, Horn WF, Keim NL, Havel PJ, contain ϳ20 – 45% t10c12 CLA, indicat- References
ing that a long-term use might be of con- Conjugated linoleic acid: implications for leptin concentrations and appetite. Lipids “weight loss agents” such as CLA are used human health. Pharmacol Res 42:503– 13. Chin S, Liu W, Storkson J, Ha Y, Pariza M: the present results should be of interest 2. Park Y, Albright KJ, Liu W, Storkson JM, Dietary sources of conjugated dienoic iso- mers of linoleic acid, a newly recognized class of anticarcinogens. J Food Comp Anal in mice. Lipids 32:853– 858, 1997 trials are needed to make firm conclusions 3. West DB, Delany JP, Camet PM, Blohm F, 14. Park Y, Storkson JM, Albright KJ, Liu W, regarding the clinical safety of CLA iso- mers and mixtures in obese patients.
gated linoleic acid on body fat and energy In summary, t10c12 CLA increased metabolism in the mouse. Am J Physiol in mice. Lipids 34:235–241, 1999 DIABETES CARE, VOLUME 25, NUMBER 9, SEPTEMBER 2002 Rise´rus and Associates
15. DeFronzo RA, Ferrannini E: Insulin resis- nation and chemical composition of ultra- acid composition, lipid oxidation, color, and water-holding capacity of pork loin. J human serum. J Clin Invest 34:1345– dyslipidemia, and atherosclerotic cardio- 30. Lee PDK, Jensen MD, Divertie GD, Hei- vascular disease. Diabetes Care 14:173– 16. Bonora E, Kiechl S, Willeit J, Oberhollen- determination: ultracentrifugation vs pre- response to insulin during suppression of endogenous insulin secretion. Metabolism and magnesium chloride. Clin Chem 27: insulin resistance in metabolic disorders: 31. Reaven GM: Banting Lecture 1988: Role the Bruneck Study. Diabetes 47:1643– 24. DeLany JP, Blohm F, Truett AA, Scimeca of insulin resistance in human disease. Di- 17. Berdeaux O, Voinot L, Angioni E, Juaneda 32. Benito P, Nelson GJ, Kelley DS, Bartolini without affecting energy intake. Am J poproteins and tissue fatty acid composi- methyl linoleate. J Am Oil Chem Soc 75: tion in humans. Lipids 36:229 –236, 2001 acid (CLA), body fat, and apoptosis. Obes 33. Gordon DJ, Rifkind BM: High-density li- 18. Pace N, Rathbun E: Studies on body com- poprotein: the clinical implications of re- 26. Evans M, Geigerman C, Cook J, Curtis L, cent studies. N Engl J Med 321:1311– relation to fat content. J Biol Chem 158: leic acid suppresses triglyceride accumu- 34. Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E, Knowler WC, Bennett 19. DeFronzo RA, Tobin JD, Andres R: Glu- preadipocytes. Lipids 35:899 –910, 2000 PH, Bogardus C: Insulin resistance and in- sulin secretory dysfunction as precursors of tifying insulin secretion and resistance.
Am J Physiol 237:E214 –E223, 1979 prospective studies of Pima Indians. N Engl 20. Pollare T, Lithell H, Selinus I, Berne C: Application of prazosin is associated with 35. Bonadonna RC, Groop L, Kraemer N, Fer- an increase of insulin sensitivity in obese patients with hypertension. Diabetologia sue mass in obese Zucker rats. J Clin Invest Obesity and insulin resistance in humans: adose-responsestudy.Metabolism39:452– 21. Pollare T, Vessby B, Lithell H: Lipoprotein 28. Vessby B: Dietary fat and insulin action in lipase activity in skeletal muscle is related humans. Br J Nutr 83 (Suppl. 1):S91–S96, 36. Blanck HM, Khan LK, Serdula MK: Use of to insulin sensitivity. Arterioscler Thromb nonprescription weight loss products: re- 29. Joo ST, Lee JI, Ha YL, Park GB: Effects of sults from a multistate survey. JAMA 286: 22. Havel R, Eder H, Bragdon J: The determi- dietary conjugated linoleic acid on fatty DIABETES CARE, VOLUME 25, NUMBER 9, SEPTEMBER 2002

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