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Meal modulation of circulating interleukin 18 and adiponectin concentrations in healthy subjects and in patients with type 2 diabetes mellitus^1,2,3

¹ From the Department of Geriatrics and Metabolic Diseases, Second University of Naples.

² Supported in part by a grant from the Second University of Naples.

³ Reprints not available. Address correspondence to K Esposito, Dipartimento di Geriatria e Malattie del Metabolismo, Policlinico Universitario, Piazza L Miraglia, 80138 Napoli, Italy. E-mail: katherine.esposito{at}unina2.it.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: A single high-fat meal induces endothelial activation, which is associated with increased serum concentrations of inflammatory cytokines.

Objective: We compared the effect of 3 different meals on circulating concentrations of interleukin 8 (IL-8), interleukin 18 (IL-18), and adiponectin in healthy subjects and in patients with type 2 diabetes mellitus.

Design: Thirty patients with newly diagnosed type 2 diabetes and 30 matched, nondiabetic subjects received the following 3 isoenergetic (780 kcal) meals separated by 1-wk intervals: a high-fat meal; a high-carbohydrate, low-fiber (4.5 g) meal; and a high-carbohydrate, high-fiber meal in which refined-wheat flour was replaced with whole-wheat flour (16.8 g). We analyzed serum glucose and lipid variables and serum IL-8, IL-18, and adiponectin concentrations at baseline and at 2 and 4 h after ingestion of the meals.

Results: Compared with nondiabetic subjects, diabetic patients had higher fasting IL-8 (P < 0.05) and IL-18 (P < 0.01) concentrations and lower adiponectin concentrations (P < 0.01) at baseline. In both nondiabetic and diabetic subjects, IL-18 concentrations increased and adiponectin concentrations decreased (P < 0.05) from baseline concentrations after consumption of the high-fat meal. After consumption of the high-carbohydrate, high-fiber meal, serum IL-18 concentrations decreased from baseline concentrations (P < 0.05) in both nondiabetic and diabetic subjects; adiponectin concentrations decreased after the high-carbohydrate, low-fiber meal in diabetic patients. IL-8 concentrations did not change significantly after consumption of any of the 3 meals.

Conclusions: This study provides evidence that circulating IL-18 and adiponectin concentrations are modulated by familiar foodstuffs in humans. Meal modulation of cytokines involved in atherogenesis may represent a safe strategy for ameliorating atherogenetic inflammatory activity in diabetic patients.

Key Words: Type 2 diabetes mellitus • interleukin 8 • interleukin 18 • adiponectin • high-fat meal • high-carbohydrate meal • dietary fiber

	INTRODUCTION

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It has been postulated that type 2 diabetes mellitus is a manifestation of the inflammatory host response (1). This host response is orchestrated by the production of pro- and antiinflammatory cytokines that are under genetic control. In support of this hypothesis, several studies showed elevated circulating concentrations of the proinflammatory cytokines interleukin 6 and tumor necrosis factor among subjects with clinically overt type 2 diabetes (2–4) or impaired glucose tolerance (5). Moreover, a low production capacity for interleukin 10, a centrally operating cytokine with strong antiinflammatory properties, is associated with the metabolic syndrome in obese women (6) and with type 2 diabetes in aged people (7).

The risk of coronary artery disease is increased by consumption of a diet rich in saturated fat (8). Both in healthy subjects and in patients with type 2 diabetes, a single high-fat meal induces endothelial activation, which is associated with increased inflammatory cytokine production (9). Increased inflammatory activity is believed to play a critical role in the development of atherogenesis and to predispose established atherosclerotic plaques to rupture (10). Type 2 diabetes mellitus is associated with an increased risk of premature atherosclerosis (11), which may be linked to stimulation of proatherogenetic inflammatory activity. Interleukin 8 (IL-8) is a potent chemoattractant and induces recruitment of neutrophils and T lymphocytes into the subendothelial space and adhesion of monocytes to endothelium (12). Interleukin 18 (IL-18) is a potent proinflammatory cytokine that is reported to play a role in plaque destabilization (13) and to be of value in predicting cardiovascular death in patients with coronary artery disease (14). Adiponectin is an adipocyte-derived plasma protein (adipokine) that accumulates in injured arteries and has potential antiatherogenic properties: the prevalence of coronary artery disease in male patients with hypoadiponectinemia is 2-fold that in male patients without hypoadiponectinemia (15).

The first aim of the present study was to compare circulating concentrations of IL-8, IL-18, and adiponectin in patients with type 2 diabetes mellitus with those in matched healthy subjects. The other aim of the study was to evaluate the effects of 3 different isoenergetic meals (a high-fat meal and 2 high-carbohydrate meals, which were either low or high in fiber) on circulating concentrations of IL-8, IL-18, and adiponectin. There is evidence that dietary fat may influence circulating cytokines (9) and that a diet high in fiber is beneficial for patients with type 2 diabetes (16), as well as for patients with coronary artery disease (17, 18).

	SUBJECTS AND METHODS

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Subjects
Thirty subjects (15 men and 15 women) with newly diagnosed type 2 diabetes mellitus were recruited from the Diabetes Clinic at the teaching hospital of the Second University of Naples. Exclusion criteria included the presence of hepatic or renal disease, microvascular or macrovascular diabetic complications, cigarette smoking, hypertension, and any acute illness. Particular care was taken to insure against the recent use of aspirin, dietary antioxidant supplements, and lipid-lowering drugs. All diabetic subjects were treated only by diet and were instructed not to change their dietary habits for the duration of the study. Thirty healthy subjects (15 men and 15 women), who were matched for age, sex, and body weight with the diabetic group, were recruited from the medical and paramedical staff of the Department of Geriatrics and Metabolic Diseases at the Second University of Naples. The healthy subjects had no evidence of any acute or chronic illness, were following ad libitum diets, had no recent change in body weight, and were not taking any drugs. All subjects (diabetic and nondiabetic) volunteered for the study and gave written informed consent. The protocol was approved by the institutional committee of ethical practice of the Second University of Naples.

Design of the study
Blood samples for measurement of glucose, lipid (total, HDL cholesterol, and triacylglycerol), IL-8, IL-18, and adiponectin concentrations were drawn at 0800 after the subjects had fasted overnight for 12 h. After collection of the blood samples, each subject (diabetic and nondiabetic) ate the following 3 isoenergetic meals in random order and separated by 1-wk intervals: 1) a high-fat meal; 2) a high-carbohydrate, low-fiber meal; and 3) a high-carbohydrate, high-fiber meal. The high-fat meal consisted of 2 sausages (80 g), 6 bread slices (90 g), a small egg (40 g), butter (15 g), and olive oil (5 g); the high-carbohydrate, low-fiber meal consisted of a pizza (300 g) made with refined-wheat flour and tomatoes (60 g); and the high-carbohydrate, high-fiber meal consisted of the same amount of pizza made with whole-wheat flour and tomatoes (60 g). The compositions of the 3 meals are shown in Table 1. A person who was not involved in trial management randomly assigned the subjects to the meals by using random numbers derived from published tables. The meals were prepared in one batch in the kitchen and were consumed under medical supervision. All variables evaluated during fasting were measured again 2 and 4 h after consumption of the meals.

Statistical analysis
Sample size was determined on the basis of 2 preliminary experiments with a high-fat meal, 2 preliminary experiments with a high-carbohydrate, low-fiber meal, and 2 preliminary experiments with a high-carbohydrate, high-fiber meal. These experiments allowed us to estimate the SD and the difference between the means. For a desired P value of 0.05 and 80% power to detect a difference of 15% in cytokine concentrations after consumption of the high-fat meal, a sample size of 12 per group was considered satisfactory (19). Analysis of variance was used to assess the significance of differences between groups, and Bonferroni-corrected t tests were then used for post hoc comparisons. Changes over time in response to each meal were analyzed with a 3-factor repeated-measures analysis of variance with interaction; post hoc analysis was performed with the use of Tukey’s test. The effect of order was tested with analysis of variance. The significance of the correlations was examined by using the nonparametric Spearman’s rank correlation test. A P value < 0.05 was chosen as the level of significance. Calculations were made on a personal computer by using SPSS (version 10.0; SPSS Inc, Chicago).

	RESULTS

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The nondiabetic subjects enrolled in the study were well matched with the diabetic subjects in age, sex, and body mass index (Table 2). Fasting concentrations of glucose, glycated hemoglobin, and triacylglycerol were significantly higher in the diabetic patients than in the nondiabetic control subjects, but serum HDL-cholesterol concentrations were significantly lower in the diabetic patients (Table 2). Serum IL-8 and IL-18 concentrations were significantly higher in the diabetic patients than in the nondiabetic subjects, whereas serum adiponectin concentrations were significantly lower in the diabetic patients (Table 2). In the diabetic patients, glucose concentrations were positively correlated with IL-8 (r = 0.27, P < 0.05) and IL-18 (r = 0.31, P < 0.05) concentrations, and triacylglycerol concentrations were negatively correlated with adiponectin concentrations (r = -0.41, P < 0.01). There was no significant correlation between glucose concentrations and IL-8 or IL-18 concentrations in the nondiabetic subjects.

Table 3

Table 4

In both groups, individual changes in triacylglycerol concentration after consumption of the high-fat meal correlated with changes in adiponectin concentration (r = -32, P < 0.02). Changes in insulin and changes in adiponectin concentrations after consumption of each of the 3 meals were not correlated (r = -0.05).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The results of the present study show that patients with newly diagnosed type 2 diabetes who were free of vascular complications had higher serum IL-8 and IL-18 concentrations and lower serum adiponectin concentrations than did age- and body weight–matched nondiabetic subjects. Moreover, a single high-fat meal acutely increased circulating IL-18 concentrations and decreased circulating adiponectin concentrations in both the diabetic and the nondiabetic subjects; on the other hand, the fiber content of the carbohydrate meals influenced the response of serum IL-18 and adiponectin concentrations to the same meals, because ingestion of the high-carbohydrate meal that was naturally enriched in fiber reduced IL-18 concentrations below the baseline concentration whereas adiponectin concentrations decreased transiently after consumption of the high-carbohydrate, low-fiber meal. Taken together, these results indicate that familiar foodstuffs may acutely affect serum concentrations of IL-18 and adiponectin.

Our results confirm previous findings (20, 21) that circulating IL-8 concentrations are higher and circulating adiponectin concentrations are lower in type 2 diabetic patients than in nondiabetic control subjects. IL-8 has recently been suggested to contribute to atherogenesis by acting as a local chemoattractant for neutrophils and T cells, by inducing adhesion of monocytes to the surface of the atherosclerotic lesion or plaque, and by stimulating smooth muscle cell migration and proliferation; all of these elements are reported to be part of the pathogenesis of atherosclerosis (12). Beside being involved in atherogenesis (15), low serum adiponectin concentrations are predictive of the future development of type 2 diabetes mellitus in the Pima Indian population (22). Acute hyperinsulinemia has been reported to decrease plasma adiponectin concentrations (23); however, we did not find any relation between the increase in insulin concentrations after consumption of the meals and adiponectin concentrations, which suggests that insulin does not play a major role in the control of adiponectin, at least in the postprandial state.

IL-18 is a pleiotropic cytokine that acts in both acquired and innate immunity and that may be involved in atherosclerosis (24). The first direct evidence indicating that IL-18 is atherogenetic was recently provided: administration of exogenous IL-18 enhances the development of atherosclerosis in apoe^-/- mice and increases lesion development through enhancement of an inflammatory response via an interferon –dependent mechanism (25). Moreover, in a prospective study of 1229 patients with documented coronary artery disease, serum IL-18 concentration was identified as a strong independent predictor of future cardiovascular events (14). IL-18 is produced mainly by monocytes and macrophages (13), although a contribution from adipose tissue was recently suggested (26).

The relation between diet and chronic disease is well established. In general, high intakes of dietary fat are associated with obesity and its comorbid conditions, including heart disease and type 2 diabetes (27). The paradigm that dietary fats act exclusively via effects on serum lipids and lipoproteins has been challenged: the Lyon Heart Study (28) and the Indian Heart Study (29) both showed in clinical trials that diet can prevent fatal and nonfatal cardiovascular events in persons with cardiovascular disease without significantly affecting plasma lipids. In support of this challenging view, a single high-fat meal induces endothelial dysfunction in healthy subjects (30). We found that a single high-fat meal can increase IL-18 concentrations and decrease adiponectin concentrations in both healthy and diabetic subjects, and this finding is consistent with previous findings of increased circulating concentrations of cytokines (interleukin 6 and tumor necrosis factor ) and adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) after ingestion of a high-fat meal (9).

An additional finding of our study is that the fiber content of complex carbohydrates seems to affect circulating IL-18 and adiponectin concentrations in response to the same carbohydrate load. Unlike the pizza that was made with refined flour and was low in fiber, the pizza that was prepared with whole flour and was rich in fiber was associated with reduced serum IL-18 concentrations and unchanged serum adiponectin concentrations, at serum glucose and triacylglycerol concentrations that were not significantly different from those obtained with the refined-flour, low-fiber pizza. On the basis of dietary guidelines, patients with diabetes mellitus are advised to replace saturated fat with carbohydrates, although an alternative approach of replacing saturated fat with cis monounsaturated fat is also included in the recommendations (16). Moreover, increasing the intakes of fruit, vegetables, and whole grains, which are rich sources of dietary fiber, is also recommended. Although patients with diabetes are advised to increase their intake of dietary fiber to 20–35 g/d, their average daily intake in the National Health and Nutrition Examination Survey was found to be 16–17 g (31).

The mechanism by which the fiber content of meals influences circulating IL-18 concentrations is not resolved by our study. Macronutrient intake produces oxidative stress that leads to a proinflammatory state (32); this intriguing evidence is also supported by the ability of antioxidant vitamins to normalize both impaired endothelium-dependent vasodilation in healthy subjects after consumption of a single high-fat meal (33) and endothelial activation (increased serum concentrations of cytokines and adhesion molecules) in diabetic patients after consumption of a high-fat meal (9). Following this line of thought, one might speculate that the fiber content of meals may affect in some way the transient oxidative stress that occurs after macronutrient ingestion. Although dietary fiber may have antiinflammatory roles, at least in intestinal functions (34), additional studies are needed to test the possibility that an antioxidant mechanism is implicated in the amelioration of cardiovascular health by dietary fiber. However, from a public health perspective, it may be unnecessary to elucidate every mechanism of every individual nutrient or food: current recommendations for disease prevention emphasize simultaneous changes in several dietary behaviors, such as decreasing fat consumption and increasing the consumption of whole grains and greens (35).

In conclusion, fasting concentrations of IL-8 and IL-18 are higher and those of adiponectin are lower in patients with type 2 diabetes mellitus than in matched nondiabetic subjects. Ingestion of a high-fat meal is associated with a cytokine milieu tending toward inflammation, whereas isoenergetic substitution of saturated fat in the meal with complex carbohydrates that are rich in fiber has the opposite effect. Because patients with type 2 diabetes are particularly prone to cardiovascular disease (11), and because both IL-18 and adiponectin may be implicated in atherogenesis (14, 15), our findings reinforce current dietary advice recommending a diet high in fiber, high in complex carbohydrates, and low in saturated fat to prevent chronic diseases, including diabetes mellitus (36) and coronary artery disease (17, 18).

	ACKNOWLEDGMENTS

 
We acknowledge the expert technical assistance of Gennaro D’Orta.

KE and FN performed the data analyses and wrote the first version of the manuscript. FG, CDP, MC and MB collected data. GP and DG supervised the data analyses. KE was the principal investigator of the study and was responsible for designing and conducting the study. All authors contributed to the interpretation of the data and the writing of the manuscript and approved the final version of the manuscript. None of the authors had any personal or financial affiliation with any organization involved in the study.

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