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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 3 1228-1233
Copyright © 2003 by The Endocrine Society

Induction of Postprandial Inflammatory Response in Adult Onset Growth Hormone Deficiency Is Related to Plasma Remnant-Like Particle-Cholesterol Concentration

T. B. Twickler, G. M. Dallinga-Thie, F. L. J. Visseren, W. R. de Vries, D. W. Erkelens and H. P. F. Koppeschaar

Departments of Vascular Medicine (T.B.T., G.M.D.-T., F.L.J.V., D.W.E.), Sport Physiology (W.R.d.V.), and Endocrinology (H.P.F.K.), University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Institut National de la Santé et de la Recherche Médicale Unit 551 (T.B.T.), Hopital Pitié-Salpetrière, 75651 Paris, France

Address all correspondence and requests for reprints to: T. B. Twickler, M.D., Institute National de la Santé et de la Recherche Médicale Unit 551, Hopital Pitié-Salpetrière, 83 Boulevard de l’Hopital, 75651 Paris, France. E-mail: Th.B.Twickler{at}azu.nl.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Increased cardiovascular mortality due to premature atherosclerosis is a clinical feature in the adult-onset GH deficiency (AGHD) syndrome. Inflammation is a key feature in atherogenesis and may be triggered by postprandial lipoprotein remnants. We hypothesized that increased postprandial lipoprotein remnant levels in AGHD may be associated with an inflammatory response. In this case-control study, 10 AGHD patients [6 males and 4 females; age, 48 ± 9 yr; body mass index (BMI), 26.9 ± 2.6 kg/m2] and 10 healthy control subjects (matched for age, BMI, gender, baseline lipid levels, and apolipoprotein E genotype) were included. They all ingested an oral fat load. Fasting and postprandial levels of plasma remnant-like particle-cholesterol (RLP-C; 0.31 ± 0.13 mmol/liter and 4.14 ± 1.37 mmol/liter·h in GHD; 0.18 ± 0.06 mmol/liter and 2.56 ± 1.02 mmol/liter·h in controls, respectively) were significantly increased in AGHD patients compared with control subjects. The median inflammatory cytokines, IL-6 and TNF-{alpha}, were higher in the fasting [3.9 (range, 3.1–11.9) pg/ml and 6.8 (range, 2.5–27.6) pg/ml, respectively] and postprandial [151.7 (range, 87.0–294.3) pg/ml·24 h and 289.9 (range, 87.5–617.6) pg/ml·24 h, respectively] states in AGHD than in controls [fasting, 0.9 (range, 0.2–5.2) pg/ml and 2.8 (range, 2.5–5.7) pg/ml; and postprandial, 54.5 (range, 11.50–126.5) pg/ml·24 h and 118.3 (range, 81.2–243.1) pg/ml·24 h, respectively]. In addition, postprandial profile of RLP-C and IL-6 in AGHD and in the total group were significantly associated (r2 = 0.44, P < 0.05; and r2 = 0.38, P < 0.01, respectively). In conclusion, the increased postprandial RLP-C level in GHD is associated with an inflammatory response that may result in increased susceptibility for premature atherosclerosis.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE SYNDROME OF GH deficiency (GHD) is characterized by increased cardiovascular morbidity and mortality due to premature and progressive atherosclerosis (1, 2, 3, 4, 5). Endothelial dysfunction in GHD, which occurs early in atherosclerotic disease, is probably a consequence of low circulating levels of GH and IGF (which are both known to produce endothelial nitric oxide) that cause vasodilation (6, 7). Besides those direct effects of GHD on the endothelial lining, disturbances in lipoprotein (9, 10) and lipoprotein remnant metabolism (11) are considered to be an indirect atherosclerotic process. Postprandially, lipoprotein remnants dominate (12), and they are high atherogenic lipoproteins (13) that give rise to foam cell formation and inflammation in vitro (14). Inflammation is an evident key factor in premature atherosclerosis (for review, see Refs.15, 16, 17), but despite its strong association, the definite interaction of an inflammatory state and premature atherosclerosis is still under debate (18, 19). The pathophysiological explanation may be an excessive lipoprotein retention in the extracellular matrix with increased uptake of lipoproteins by macrophages (20, 21, 22). Consequently, atherogenic processes are initiated (23, 24). Reports in animal models support this retention hypothesis for triglyceride (TG)-rich apolipoprotein (apo) B lipoproteins, such as lipoprotein remnants. The plasma levels of these diet-derived-lipoproteins were associated with inflammatory components with increased intracellular nuclear factor-{kappa}B (NF-{kappa}B) levels in stripped endothelium of rat aorta that subsequently activates proinflammatory genes and secretion of subsequent proinflammatory cytokines (25). Hitherto, only an increase in postprandial hydroperoxides (26) has been reported. In this study, we hypothesize that the presence of atherogenic lipoproteins in the postprandial period in GHD may be associated with an inflammatory response.


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

Adult-onset GHD (AGHD) patients were recruited from the outpatient clinic of the department of Internal Medicine and Endocrinology from the University Hospital Utrecht (Utrecht, The Netherlands). All AGHD patients had acquired AGHD in adult life due to recent (within 1 yr) neurosurgery (pituitary adenoma) and/or irradiation. Other deficient pituitary hormones were supplemented for at least 6 months and were at a stable level at the start of the study. GHD was defined as a peak plasma GH concentration less than 5 µg/liter after the combined GHRH/arginine infusion test. Exclusion criteria were the presence of lipoprotein disorders (as familial hypercholesterolemia and familial combined hyperlipidemia), body mass index (BMI) greater than 30 kg/m2, renal and/or liver disease, diabetes mellitus, apo E genotype E2/E2, and family history of premature atherosclerosis.

Normolipidemic controls

Healthy control subjects, matched for age, gender, BMI, and apo E genotype, were selected for this study by advertisement. They had no diabetes; no hepatic, renal, thyroid, or cardiac dysfunction; and a negative family history for cardiovascular disease. The protocol had been approved by the human investigation review committee of the University Hospital Utrecht, and written informed consent was obtained from all participants.

Oral fat loading test (OFLT)

Matched controls and AGHD patients underwent an OFLT. After a 12-h overnight fast, participants were admitted to the metabolic ward at 0730 h. They ingested a test meal [consisting of 40% fat (wt/vol) with a phospholipid to sphingomyelin ratio of 0.06, 0.001% cholesterol (wt/vol), and 2.8% carbohydrates (wt/vol)] of 50 g fat/m2 body surface area. Venous blood samples from the antecubital vein were obtained before the test meal and hourly after ingestion of the cream up to 24 h. All blood samples were immediately put on ice. Only water or tea without sugar was allowed for drinking during the OFLT. None of the subjects had gastrointestinal complaints after drinking the cream.

Baseline measurements

Before the test, meal blood samples were obtained for baseline values. Plasma was obtained by centrifugation at 3000 rpm for 15 min at 4 C. TG and cholesterol were measured with a colorimetric assay (Monotest cholesterol kit no. 237574 and GPO-PAP no. 701912, Roche Molecular Biochemicals, Mannheim, Germany). The coefficient of variance (CV) for TG and cholesterol was less than 5%. Cholesterol was determined in the high-density lipoprotein fraction isolated by the heparin-MnCl2 dextran-sulfate precipitation method. Low-density lipoprotein (LDL)-cholesterol was calculated with the Friedewald formula. Apolipoprotein B concentrations were analyzed automatically on a Cobas Mira autoanalyzer (Unimate 3 Apo B, Roche Diagnostic Systems, Inc., Montclair, NJ). The plasma insulin and IGF-I concentrations were determined with a RIA (27). Homeostasis model assessment-index (fasting glucose x fasting insulin/22.5) was calculated to estimate the insulin sensitivity. Body composition was assessed with bioimpedance analysis. Apolipoprotein E genotype was determined as described (28).

RLP-C analysis

The RLP fraction was prepared using an immunoseparation technique described by Nakajima et al. (29, 30). Briefly, 5 µl serum were added to 300 µl of mixed immunoaffinity gel suspension containing monoclonal antihuman apo A-I (H-12) and antihuman Apo-B-100 (JI-H) antibodies (Japan Immunoresearch Laboratories, Takasaki, Japan). The reaction mixture was gently shaken for 120 min at room temperature, followed by standing for 15 min. Then 200 µl of the supernatant were withdrawn for the assay of RLP-C. Cholesterol (CV < 3%) in the RLP fraction was measured by an enzymatic assay using a Cobas Mira S auto-analyzer (ABX Diagnostis, Montpellier, France).

IL analysis

IL-6, IL-10, and TNF-{alpha} (in picograms per milliliter) were analyzed in fasting and in postprandial plasma samples with a commercially available ELISA kit (CLB, Amsterdam, The Netherlands). Both the inter- and intra-assay CV were less than 10%.

Statistical analysis

Data are presented as means ± SD. In case of a skewed distribution, the median plus minimum and maximum values are presented. Total integrated area under the curve (AUC) was calculated for postprandial plasma RLP-C, postprandial IL-6, TNF, and IL-10 using GraphPad Prism software (version 3.1, GraphPad Software, Inc., San Diego, CA). In case of a significant difference in baseline levels, the incremental (with correction for baseline levels) AUC was calculated. Differences between AGHD patients and controls were analyzed by unpaired t test. Pearson’s correlation or Spearman’s rank correlation was calculated to assess the relationships between different variables. P value less than 0.05 (two-tailed) was considered to be significant. Statistical analysis was performed with GraphPad InStat version 3.00 for Windows 95 (GraphPad Software, Inc.).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Subjects

Table 1Go shows characteristics of the subjects. The AGHD patients were strictly matched with the control subjects for age, gender, BMI, and apo E genotype. Average duration of hypopituitarism was 28 ± 8 months. All 10 patients were substituted with T4, 8 patients with hydrocortisone, 2 patients with cortisone acetate, 9 patients with sex hormones (males, testosterone esters; females, cyclic estrogen and progesterone), and 8 patients with desmopressin. The distribution of the apo E genotype in AGHD was as follows: E3/E3 (n = 8), E2/E3 (n = 1), and E3/E4 (n = 1).


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  		Table 1. Baseline characteristics

 
Fasting plasma TG levels were significantly higher in AGHD patients (1.44 ± 0.68 mmol/liter) than in control subjects (0.88 ± 0.26 mmol/liter; P < 0.05). No differences were found in baseline plasma cholesterol, apo B, and LDL-cholesterol (Table 1Go). Baseline plasma IGF-I levels were lower in AGHD patients than in controls. No difference was found in free T3 levels.

Postprandial responses

Postprandial RLP-C response. After the oral fat load, the time course of postprandial plasma RLP-C concentrations is shown in Fig. 1Go. Fasting levels of RLP-C were significantly higher in AGHD patients (0.31 ± 0.13 mmol/liter) than in control subjects (0.18 ± 0.06 mmol/liter; P < 0.05). The postprandial peak time of RLP-C was between 2 and 4 h in control subjects and between 4 and 6 h in AGHD patients, with a maximum level of 0.43 ± 0.2 mmol/liter in controls and 0.70 ± 0.34 mmol/liter in AGHD patients (P < 0.05). The AUC RLP-C (Table 2Go) was enhanced in AGHD (4.14 ± 1.37 mmol·h/liter) compared with control subjects (2.56 ± 1.02 mmol·h/liter; P < 0.05).



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  		Figure 1. Postprandial plasma RLP-C response for the GH-deficient patients (•) and control subjects ({diamond}). Values are presented as mean (SD).

 

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  		Table 2. Postprandial data for RLP-C, IL-6, TNF, and IL-10

 
Postprandial cytokines. After the oral fat load, the time course of postprandial plasma IL-6 concentration is shown in Fig. 2Go. Median fasting levels of IL-6 were higher in AGHD patients [3.9 (range, 3.1–11.9) pg/ml] than in control subjects [0.9 (range, 0.2–0.5) pg/ml; P < 0.01]. In controls, the postprandial IL-6 response remained low, with maximum levels of 3.4 ± 2.3 pg/ml at 10 h. In GHD, a distinctive peak level of 13.1 ± 4.6 pg/ml (P < 0.01) was reached at 10 h. The AUC IL-6 (Table 2Go) was enhanced in AGHD [151.2 (range, 87.0–294.3) pg/ml·24 h] compared with control subjects [54.5 (range, 11.5–126.5) pg/ml·24 h; P < 0.05].



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  		Figure 2. Postprandial plasma cytokine response for the GH-deficient patients (•) and the control subjects ({diamond}). IL-6, TNF-{alpha}, and IL-10. Values are presented as mean (SD).

 
After the oral fat load, the time course of postprandial plasma TNF-{alpha} concentration is shown in Fig. 2Go. Fasting levels of TNF-{alpha} were not significantly higher in AGHD patients than in control subjects. The postprandial peak time of TNF-{alpha} was between 4 and 8 h in control subjects and at 10 h in AGHD patients with a maximum level of 4.7 ± 3.4 pg/ml and 20.4 ± 7.2 pg/ml, respectively; P < 0.01. The AUC TNF (Table 2Go) was enhanced in AGHD [289.9 (range, 87.5–617.6) pg/ml·24 h] compared with control subjects [118.3 (range, 81.2–243.1) pg/ml·24 h; P < 0.05].

After the oral fat load, a decrease in postprandial IL-10 was found in AGHD, whereas a significant increase in postprandial IL-10 was found in the control subjects (Fig. 2Go). Fasting levels of IL-10 were higher in AGHD patients [16.7 (range, 5.3–24.2) pg/ml] than in control subjects [6.1 (range, 5.0–15.1) pg/ml; P < 0.05]. The postprandial peak time of IL-10 was reached at 10 h in control subjects (14.6 ± 8.7 pg/ml), and the lowest level of postprandial IL-10 was reached at 12 h in AGHD patients (10.5 ± 4.8 pg/ml).

Correlations

The integrated AUC for IL-6 and RLP-C (AUC IL-6 vs. AUC RLP-C) were significantly associated in all the subjects together (r2 = 0.38; P < 0.01), and in only the AGHD patients (r2 = 0.44; P < 0.05; Fig. 3Go). Also, the incremental postprandial response of IL-6 (dAUC IL-6) and RLP-C (dAUC RLP-C) were positively associated in the GHD patients (r2 = 0.24; P < 0.05) and all the subjects together (r2 = 0.34; P < 0.01). No correlations between area under the incremental curve (AUIC)-Tg and AUIC-IL-6 or AUIC-TNF could be demonstrated (data not shown). The AUC-TNF was significantly associated with waist to hip ratio (r2 = 0.21; P < 0.05) and plasma IGF-I (r = -0.57; P < 0.05) in all subjects together and in AGHD patients (for both waist to hip ratio and plasma IGF-I, r2 = 0.30; P < 0.05). Baseline plasma IL-6 or IL-10 levels were not associated with baseline IGF-I levels, waist to hip ratio, or RLP-C levels.



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  		Figure 3. Scatterplot for the relationship between the postprandial plasma RLP-C response (AUC RLP-C) and postprandial IL-6 response (AUC IL-6). GH-deficient patients (•) and control subjects ({diamond}). Correlations were calculated with the use of GraphPad InStat as indicated in Patients and Methods.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this report, we found evidence that the presence of atherogenic lipoproteins in the postprandial period in GHD may be responsible for the induction of an inflammatory response. Recent observations stress the importance of a proinflammatory profile in the development of progressive atherosclerosis (31), but the origin of inflammation is still under debate. These observations suggest that the postprandial period in GHD may be an atherogenic interval that needs a supplemental approach in treatment. We realize that deficiencies in other pituitary hormones, such as TSH and ACTH, may have an effect on the postprandial inflammatory response. However, currently no support is available for such an influence in human, in contrast to reported effects in animal models and in vitro cell culture systems. Moreover, the patients were adequately substituted for all end-organ hormone deficiencies. Substitution with end-organ hormones, albeit adequate, does not mimic completely the diurnal variations of these hormones.

In previous studies, atherosclerotic disease in GHD presents as endothelial dysfunction (postischemic dilation of brachial artery) or increased intima media thickness (IMT) of femoral or carotid artery (32). During recombinant human GH treatment, initial increased IMT decreased with a marked progress. Parallel results in IMT decrease were estimated to be equal to 3- to 4-yr aggressive lipid-lowering treatment in dyslipidemic patients (33, 34, 35). Therefore, it is of general importance to get more insight into the pathways that give rise to this accelerated atherogenesis and that could be reversed so adequately by GH therapy.

Negative influence by the GHD state on metabolic pathways (such as the lipoprotein remnant) with a high atherogenetic potential is an example of an indirect implication in atherosclerosis. In line with earlier observations, elevated postprandial lipoprotein remnant levels are counteracted by recombinant human GH therapy with an additional improvement in flow mediated dilation of the brachial artery after 6 months of therapy. Furthermore, IMT of carotid arteries and the angiographically verified progression of focal coronary atherosclerosis were positively associated with the plasma RLP-C levels, even independently from plasma LDL-cholesterol and TG levels (36, 37). In a statin-fibrate crossover study in healthy subjects, fluctuations of postprandial levels of plasma lipoprotein remnants are closely related to postischemic changes in diameter of the brachial artery, a marker for early atherosclerosis (38). Additionally, in a model with rat aortic rings, incubation with RLP-C results in endothelial dysfunction that was mediated through the NF-{kappa}B up-regulation, resulting in an enhanced endothelial response (39, 40, 41). The intracellular NF-{kappa}B pathway is part of the inflammatory response. Moreover, incubation of ß-very-LDL with endothelial cells indeed increases the expression of endothelial TNF. This observation is in line with the presence of elevated fasting plasma RLP-C levels in AGHD and increased fasting plasma levels of TNF and IL-6. Moreover, in the present study, we show in humans, that plasma levels of proinflammatory cytokines (such as IL-6 and TNF-{alpha}) are increased during the postprandial period and are related to the presence of elevated levels of lipoprotein remnants. The plasma levels of these inflammatory cytokines are a result of spilling into circulation. Endothelial cells and monocyte/macrophages are secretors of cytokines, whereas TG-rich lipoproteins, of which lipoprotein remnants are a subset form, are able to induce an inflammatory response in endothelial cells and macrophages through specific receptors on their surface (42, 43). The postprandial response of RLP-C was closely associated with the postprandial IL-6 response, which suggests that lipoprotein remnants may induce an inflammatory response. Inflammation is a key feature in atherogenesis (44). In several clinical studies, strong correlations were found between mortality from coronary artery disease with other inflammatory markers, such as fibrinogene and C-reactive protein (45, 46). Moreover, TNF induces apoptosis of endothelial cells, blockade of TNF-{alpha} accelerates functional endothelial recovery after balloon angioplasty, and plasma TNF-{alpha} levels are associated with the carotid IMT in humans (47, 48, 49). As a consequence, three meals a day, as occurs in Western diet, result in several postprandial inflammatory responses during the day. The inflammatory response consists of a proinflammatory and an anti-inflammatory pathway that are both fine tuned (50). An exaggerated proinflammatory response is also found in animal models and in patients with a defect in the anti-inflammatory response, e.g. a deficiency in the IL-10 secretion. In rat models with IL-10 deficiency, the area of the atheromatous plaque is more extensive and more suspicious to rupture, and restoration of plasma IL-10 levels decreased the atherosclerosis (51, 52). In the present study, baseline plasma IL-10 levels were elevated in AGHD patients compared with controls, revealing an induction of anti-inflammatory factors during an ongoing inflammatory condition in AGHD. This explained the observation that the postprandial IL-10 response in the patients is absent. Currently, we are conducting in vitro experiments to elucidate further these observations.

In conclusion, we observed a pronounced postprandial inflammatory response in GHD in relation to the presence of elevated plasma levels of postprandial RLP-C. This observation offers an additional approach for studying the importance of increased susceptibility of premature atherosclerosis in AGHD patients.


   Acknowledgments
 
We especially thank Miss M. Verkerk for the technical assistance and the very pleasant collaboration in determining the cytokines. The microbiology department in the Diakonesse Hospital (Utrecht, The Netherlands; headed by Dr. Diepensloot) kindly offered the infrastructure for the cytokine analysis. We thank Dr. P. S. van Dam and Dr. M. C. Castro Cabezas for inclusion of some GHD patients.


   Footnotes
 
Financial support for this work was obtained by Novo Nordisk BV (Alphen A/d Rijn, The Netherlands). Grants were obtained from the foundation De Drie Lichten and the Netherlands Organization for Scientific Research (NWO). T.B.T. received the Poste Verte Fellowship of the Institute National de la Santé et de la Recherche Médicale, France, and a travel fellowship of the International Atherosclerosis Society.

Abbreviations: AGHD, Adult-onset GHD; apo, apolipoprotein; AUC, integrated area under the curve; AUIC, area under the incremental curve; BMI, body mass index; CV, coefficient of variance; GHD, GH deficiency; IMT, intima media thickness; LDL, low-density lipoprotein; NF-{kappa}B, nuclear factor-{kappa}B; OFLT, oral fat loading test; RLP-C, remnant-like particle-cholesterol; TG, triglyceride.

Received March 26, 2002.

Accepted December 9, 2002.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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