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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1889
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 964-967
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Acetylsalicylic Acid Improves Lipid-Induced Insulin Resistance in Healthy Men

Matthias Möhlig, Madlen Freudenberg, Thomas Bobbert, Michael Ristow, Helmut Rochlitz, Martin O. Weickert, Andreas F. H. Pfeiffer and Joachim Spranger

Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Endocrinology, Diabetes, and Nutrition, Charité-University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany

Address all correspondence and requests for reprints to: Matthias Möhlig, M.D., German Institute of Human Nutrition Potsdam- Rehbruecke, Department of Clinical Nutrition, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. E-mail: mmoehlig{at}mail.dife.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context and Objective: Insulin resistance is a central feature of type 2 diabetes. Salicylates prevent lipid-induced insulin resistance in rodents by interrupting inflammatory pathways. We therefore investigated whether salicylates reduce lipid-induced insulin resistance in humans by affecting inflammatory pathways as reflected by serum adipocytokines.

Participants and Intervention: Ten healthy men were included in a crossover intervention study. Four euglycemic-hyperinsulinemic clamps were performed, one without pretreatment, one with prior 2-h lipid infusion, one after pretreatment with 4 g acetylsalicylic acid (ASA), and one with ASA pretreatment and prior lipid infusion.

Main Outcome Measure: Lipid-induced insulin resistance was quantified by the euglycemic-hyperinsulinemic clamp technique running at least 2 h. Repeated-measures ANOVA on two factors was used for comparison, and results were Bonferroni adjusted for multiple measurements. ASA effects on serum adipocytokines were addressed by comparing the areas under the curves.

Results: Glucose infusion rate (M value) of the control clamp without pretreatment was 6.3 (± 0.6) mg/kg·min. ASA pretreatment did not change glucose infusion rates (P = 0.6). Lipid infusion significantly decreased the M value to 4.1 (± 0.6) mg/kg·min (P = 0.008). After ASA pretreatment and lipid infusion, the M value was 4.8 (± 0.7) mg/kg·min and was significantly improved, compared with the lipid-only clamp (P = 0.036 after Bonferroni’s adjustment). General biomarkers of inflammatory processes (IL-6, C-reactive protein), the insulin-sensitizing mediator adiponectin, and circulating adiponectin oligomers were unchanged by ASA pretreatment.

Conclusions: ASA pretreatment attenuated lipid-induced insulin resistance in healthy humans. This acute insulin-sensitizing effect of ASA was unrelated to changes of circulating inflammatory markers.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PRECISE MOLECULAR mechanisms mediating insulin resistance in humans are not completely understood. Plasma nonesterified free fatty acids (NEFAs) are likely to contribute because acutely elevated NEFA levels impair insulin sensitivity (1). NEFAs have been described to activate the inflammatory nuclear factor {kappa}B (NF{kappa}B) pathway in human muscle biopsies (2), which might be one of the mechanisms leading to their deleterious effects. Supporting this hypothesis, mice with a partially suppressed NF{kappa}B pathway [heterozygous inhibitor of NF{kappa}B kinase-ß (IKKß) knockout mice] were protected from lipid-induced insulin resistance (3), although animal experimental data are conflicting (4). Furthermore, the antiinflammatory drug salicylic acid improved lipid-induced insulin resistance in rodents (3, 5), which may be the result of an inhibition of IKKß.

To date, we are not aware of studies investigating the effect of acetylsalicylic acid (ASA) treatment on lipid-induced insulin resistance and lipid-induced changes in serum adipocytokines in humans.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study was approved by the local ethical committee. Twelve healthy male volunteers were included after written informed consent was given. The volunteers did not take any medication and had normal oral glucose tolerance tests. One volunteer stopped the ASA medication due to abdominal discomfort (recovering after withdrawal), and another volunteer moved away and therefore could not complete the study within the given period. The remaining 10 volunteers were 42.5 (±4.7, 23–66) yr old (mean ± SEM, range). Their body mass index was 25.1 (±1.2, 21.2–31.9) kg/m2, and their waist circumference was 89.8 (±3.8, 76–112) cm. Fasting glucose was 4.7 (±0.1, 4.0–5.2) mmol/liter, fasting insulin was 10.8 (±2.2, 0.9–24.2) mU/liter, and homeostasis model assessment for insulin resistance was 2.3 (±0.5, 0.2–4.7). Total cholesterol was 5.0 (±0.3, 3.4–6.6) mmol/liter, high-density lipoprotein was 1.2 (±0.1, 0.8–1.9) mmol/liter, and triglycerides were 1.2 (±0.2, 0.4–2.2) mmol/liter. Aspartate-amino-transferase was 26.6 (±3.0, 18.4–49.7) U/liter, and creatinine was 91.2 (±1.8, 78.9–96.7) µmol/liter.

One volunteer missed one of the control clamps (ASA pretreatment without lipid infusion, which, however, had no impact on the result of the study (respective M value was replaced by the mean).

Euglycemic-hyperinsulinemic clamp test and intervention

In a crossover design, four clamps were performed after an overnight fast (one clamp without pretreatment, one with a lipid infusion started 2 h before the clamp, one with ASA pretreatment, and one with ASA pretreatment and lipid infusion). Subjects were instructed to maintain normal physical activity the day before the tests and to restrain from strenuous exercise. Euglycemic-hyperinsulinemic clamps were performed using 40 mU/m2·min human insulin (Actrapid, Novo Nordisk, Bagsværd, Denmark) and a variable infusion of 10% glucose (B. Braun, Melsungen, Germany) for at least 2 h. Capillary glucose was measured every 5 min using the glucose oxidase method (Dr. Muller, Super GL, Freital, Germany). Steady-state conditions were assumed as soon as capillary glucose was kept constant for at least 30 min within the range of 4.4 ± 0.4 mmol/liter. For lipid infusion 500 ml of a lipid emulsion (Abbolipid 20%, Abbott, Wiesbaden, Germany) were supplemented with heparin (Heparin Calcium 0.4 IU/kg body weight; Ratiopharm, Ulm, Germany). Infusion was started 2 h before the clamp at an infusion rate of 90 ml/h. For ASA pretreatment 1 g ASA (CT-Arzneimittel, Berlin, Germany) was dissolved in water and administered orally. The first dose was given 24 h before the test, and the next three doses were given every 8 h for a total ASA amount of 4 g.

All infusions were administered into an antecubital vein, whereas blood for analysis was drawn from a contralateral antecubital vein. Blood was collected before the start of the lipid infusion, immediately before the start of the clamp (120 min lipid infusion), and during the steady-state condition of the clamp. NEFAs were measured in samples taken every 30 min throughout the prior clamp lipid infusion. Blood was centrifuged and immediately frozen at –80 C.

Assays

Plasma NEFAs and serum C-reactive protein (CRP) were quantified using a colorimetric assay (NEFA; Wako, Neuss, Germany) or an immunoturbidimetric assay (CRP-Latex; ABX Diagnostics, Montpellier, France) on a Cobas Mira analyzer (Roche, Mannheim, Germany). Interassay coefficients of variation were 4.7 and 6.9%. Serum insulin, IL-6, and adiponectin were measured using ELISA (Mercodia, Uppsala, Sweden; R&D Systems, Minneapolis, MN; Biovendor, Nashville, TN, respectively). Intraassay coefficients of variation were 8, 10, and 14.7%. Adiponectin oligomers were separated by nonreducing, non-heat-denaturing SDS-PAGE as described (6).

Statistics

Mean ± SEM are presented. Homeostasis model assessment for insulin resistance was calculated as [fasting insulin (milliunits per liter) x fasting glucose (millimoles per liter)/22.5]. M values of the clamps were calculated as glucose infusion rates (milligrams per minute) during steady-state divided by body weight (kilograms). M values were compared by repeated-measures ANOVA on two factors (ASA pretreatment and lipid infusion), and post hoc contrasts were defined based on estimated marginal means adjusted for multiple comparison according to Bonferroni. Time courses for NEFAs were compared by repeated-measures ANOVA using Bonferroni’s adjustment. The impact of ASA on the time courses of NEFAs, IL-6, CRP, adiponectin, and adiponectin oligomers were addressed by comparing the areas under the curves (AUCs), calculated by the incremental trapezoidal method. SPSS software (version 8.0; Chicago, IL) was used.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
NEFAs increased without ASA pretreatment from 0.5 ± 0.1 to 1.5 ± 0.2 mmol/liter (P = 0.004) and with ASA pretreatment from 0.5 ± 0.1 at baseline to 1.4 ± 0.2 mmol/liter after 120 min lipid infusion (P < 0.001). NEFA time courses as calculated by AUC were not significantly affected by ASA (P = 0.98).

Lipid infusion induced substantial insulin resistance with the M value declining from 6.3 ± 0.6 mg/kg·min (clamp without pretreatment) to 4.1 ± 0.6 mg/kg·min during the clamp with lipid infusion (P = 0.008 after Bonferroni’s adjustment). Interestingly, compared with the clamp with lipid infusion, insulin sensitivity was improved after combined ASA pretreatment and lipid infusion (M value 4.8 ± 0.7 mg/kg·min, P = 0.036 after Bonferroni’s adjustment) (Fig. 1Go). In contrast, without lipid infusion ASA had no effect on insulin sensitivity, and the M value of the clamp with ASA pretreatment, but without lipid infusion (6.0 ± 0.8 mg/kg·min), did not significantly differ from the clamp without pretreatment (P = 0.6).


Figure 1
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  		FIG. 1. M values calculated from the steady-state glucose infusion rates of euglycemic-hyperinsulinemic clamps.

 
Steady-states insulin did not differ between the clamp with lipid infusion and the clamp with ASA pretreatment and lipid infusion (P = 0.14).

To address the overall antiinflammatory properties of an ASA pretreatment, we also investigated CRP and IL-6 levels, two central markers of inflammation. Furthermore, we investigated ASA effects on adiponectin and adiponectin oligomer distribution because adiponectin is supposed to have additional antiinflammatory properties (7, 8).

ASA pretreatment did not affect the time courses of IL-6, adiponectin, or the distribution of the adiponectin oligomers. The marked increase in IL-6 during the steady-state condition of both clamps about 4 h after start of the lipid infusion is most likely explained by the insertion of a venous catheter, as described earlier (9). CRP was the only marker that tended to differ (P = 0.074). However, somewhat surprisingly there was a trend to increased CRP levels after ASA pretreatment (Table 1Go).


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  		TABLE 1. Effect of ASA pretreatment on IL-6, CRP, adiponectin, and adiponectin oligomers

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Lipid infusion is known to impair insulin sensitivity, mimicking a probably general mechanism by which nutrient lipids impair human health (10). Insulin resistance is associated with an increase in inflammatory markers (11, 12) and a reduction of adiponectin (13). The mechanisms linking lipids, insulin resistance, and inflammation are not entirely understood. The finding that salicylates reduce lipid-induced insulin resistance in animals (3, 5) suggests common underlying mechanisms for both inflammatory and lipid-induced insulin resistance.

Within this study, a 4-h lipid infusion induced insulin resistance in the same range as described previously (1). Interestingly, ASA pretreatment resulted in a reduced effect of lipid infusion on insulin sensitivity, with an improvement of insulin sensitivity of about 30%, compared with that after isolated lipid infusion.

NEFA time courses were not affected by ASA. However, despite standardized analytical procedures, we cannot completely exclude that slight differences of ex vivo lipolysis might have resulted in an underestimation of putative differences of NEFA concentrations in vivo. Furthermore, the beneficial effect of ASA was not accompanied by changes in the inflammatory markers IL-6 or CRP investigated here or changes in adiponectin or the adiponectin oligomer distribution.

In vitro and rodent data indicate that IKKß and c-Jun NH2-terminal kinase might be molecular targets of ASA (3, 14, 15). In humans, a degradation of I{kappa}B (inhibitor of NF{kappa}B) in muscle biopsies was reported during lipid infusion (2), suggesting a role of the NF{kappa}B pathway in the development of lipid-induced insulin resistance. The inhibition of IKKß by ASA and thus the inhibition of the NEFA-activated NF{kappa}B pathway might therefore explain the beneficial effects of ASA on lipid-induced insulin resistance.

Previously effects of ASA on insulin resistance but not lipid-induced insulin resistance were addressed, and controversial results have been published (16, 17, 18, 19), probably due to different doses of ASA used. Furthermore, study designs, cohort characteristics, and methods to determine insulin resistance differed considerably. Insulin resistance (determined by euglycemic-hyperinsulinemic clamp) was found to be unchanged after 3 d treatment with ASA (3 g/d), which is pretty comparable with the 4 g pretreatment used within the study presented here (18). In agreement, we also found no effects of ASA on insulin resistance in the clamps without lipid infusion. Thus, specifically the lipid-induced insulin resistance appears to be attenuated by ASA.

In conclusion, pretreatment with ASA improved lipid-induced insulin resistance in healthy men. This beneficial effect of ASA was not accompanied by any changes in inflammatory markers or in adiponectin or adiponectin oligomer distribution. These data tentatively suggest that effects of ASA on lipid-induced insulin resistance are more likely to be mediated by downstream molecular targets such as IKKß or c-Jun NH2-terminal kinase.


   Acknowledgments
 
We thank Melanie Hannemann, Susann Richter, and Katrin Sprengel for technical assistance and Dr. Corinna Koebnick for statistical advice.


   Footnotes
 
First Published Online December 29, 2005

Abbreviations: ASA, Acetylsalicylic acid; AUC, area under the curve; CRP, C-reactive protein; IKKß, inhibitor of NF{kappa}B kinase-ß; NEFA, nonesterified free fatty acid; NF{kappa}B, nuclear factor-{kappa}B.

Received August 26, 2005.

Accepted December 16, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  4. Röhl M, Pasparakis M, Baudler S, Baumgartl J, Gautam D, Huth M, De Lorenzi R, Krone W, Rajewsky K, Brüning JC 2004 Conditional disruption of I{kappa}B kinase 2 fails to prevent obesity-induced insulin resistance. J Clin Invest 113:474–481[CrossRef][Medline]
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  8. Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y 2000 Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96:1723–1732[Abstract/Free Full Text]
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