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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-2527
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3935-3940
Copyright © 2007 by The Endocrine Society

Relationships between Desacylated and Acylated Ghrelin and Insulin Sensitivity in the Metabolic Syndrome

Rocco Barazzoni, Michela Zanetti, Clara Ferreira, Pierandrea Vinci, Alessia Pirulli, MariaPia Mucci, Franca Dore, Maurizio Fonda, Beniamino Ciocchi, Luigi Cattin and Gianfranco Guarnieri

Clinica Medica (R.B., M.Z., C.F., P.V., A.P., M.F., B.C., L.C., G.G.), Department of Clinical, Morphological and Technological Sciences, University of Trieste, 34127 Trieste, Italy; and Department of Nuclear Medicine (M.M., F.D.), Azienda Ospedaliera Ospedali Riuniti, 34127 Trieste, Italy

Address all correspondence and requests for reprints to: Rocco Barazzoni, M.D., Ph.D., Clinica Medica, University of Trieste, Ospedale Cattinara, Strada di Fiume 447, 34127 Trieste, Italy. E-mail: barazzon{at}units.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Metabolic syndrome shows clustered metabolic abnormalities with major roles for insulin resistance and obesity. Ghrelin is a gastric hormone whose total plasma concentration (T-Ghr) is associated positively with insulin sensitivity and is reduced in obesity. Ghrelin circulates in acylated (A-Ghr) and desacylated (D-Ghr) forms, but their potential differential associations with insulin resistance and whether they are differentially altered in obesity remain undefined.

Objective: Our objective was to determine potential differential associations of ghrelin forms with insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] and the impact of obesity on their plasma concentrations in metabolic syndrome.

Design: This is a cross-sectional study.

Setting: The study was performed in a metabolic outpatient unit.

Patients: Patients with metabolic syndrome (National Cholesterol Education Program-Adult Treatment Panel III; n = 45, 23 males/22 females) were included in the study.

Main Outcomes: The main study outcomes were metabolic syndrome criteria, HOMA-IR, and ghrelin forms.

Results: Plasma insulin and HOMA-IR were associated negatively with T-Ghr and D-Ghr but positively with A-Ghr and acylated to desacylated ghrelin (A/D-Ghr) ratio (n = 45; P < 0.05). Compared with nonobese [body mass index (BMI) < 27.5 kg/m2; n = 12, six males/six females], obese metabolic syndrome patients (BMI > 27.5 kg/m2; n = 33) had lower T-Ghr and D-Ghr but comparable A-Ghr and higher A/D-Ghr ratio (P < 0.05). BMI and waist circumference (WC) were positively related with HOMA-IR (n = 45; P < 0.05). However, opposite associations between A/D-Ghr ratio and HOMA-IR remained significant after adjustment for sex and BMI (or WC). Additional obese individuals without metabolic syndrome (n = 10: age-, sex-, BMI-, and WC-matched to obese metabolic syndrome patients) had lower T-Ghr but higher A-Ghr (P < 0.05) compared with age-, sex-matched healthy nonobese counterparts (n = 15). T-Ghr and A-Ghr were comparable in obese with or without metabolic syndrome.

Conclusion: Obesity could alter circulating ghrelin profile, and relative A-Ghr excess could contribute to obesity-associated insulin resistance in metabolic syndrome.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
METABOLIC SYNDROME IS characterized by clustered metabolic abnormalities leading to enhanced cardiovascular morbidity and mortality (1, 2, 3, 4, 5, 6). In particular, obesity and insulin resistance are common and have a proposed central pathophysiological role in metabolic syndrome patients. Despite extensive research, the mediators of this association are, however, only partly understood. Ghrelin is a gastric hormone with central orexigenic effects (7), but total plasma ghrelin (T-Ghr) is reduced in obesity or after diet-induced weight gain (8, 9), and it is in turn increased in lean individuals or after caloric restriction and weight loss (10, 11). T-Ghr levels are positively associated with insulin sensitivity in both lean and obese humans (12, 13, 14, 15, 16), but ghrelin circulates in acylated (A-Ghr) and desacylated (D-Ghr) forms (12), and their potential differential roles in the modulation of glucose metabolism have recently emerged. In nonobese rodent models, A-Ghr administration enhanced muscle mitochondrial oxidative capacity while reducing tissue lipid content, and both effects are potential markers of enhanced insulin action (17). In agreement with the aforementioned report, A-Ghr increased insulin-mediated muscle glucose disposal during acute hyperinsulinemia-euglycemia in nonobese mice (18). However, A-Ghr also exerted negative effects on hepatic insulin action and lipid metabolism, and sustained ghrelin administration increased circulating glucose in the same rodent models (17, 18). In humans, A-Ghr acutely reduced oral glucose disposal (19) or enhanced plasma glucose concentration (20). In addition, insulin-induced suppression of A-Ghr was related to insulin sensitivity in obese postmenopausal women and in children with Prader-Willi syndrome (21, 22). D-Ghr has differential neuroendocrine effects compared with A-Ghr (23), and it has been recently suggested to counteract negative acute metabolic effects of A-Ghr (19, 20).

Potential differential associations of ghrelin forms with insulin action under different pathophysiological conditions in humans remain largely undefined. In particular, the relationships between circulating ghrelin forms and insulin resistance in metabolic syndrome are unknown. The potential differential impact of obesity on different ghrelin forms is also undetermined. In the current study, we measured T-Ghr, A-Ghr, and D-Ghr [as well as the acylated to desacylated ghrelin (A/D-Ghr) ratio], and their relationships with insulin sensitivity in metabolic syndrome patients. It was hypothesized that in metabolic syndrome patients: 1) insulin sensitivity is associated positively with T-Ghr and D-Ghr, but negatively with A-Ghr; 2) obesity is associated with lower T-Ghr and D-Ghr with A-Ghr hormone excess, that could therefore be involved in obesity-associated insulin resistance.


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

Metabolic syndrome patients were recruited for the study from the metabolic outpatient Unit in Trieste Hospital. The study protocol was approved by the local Ethics Committee. All patients were given detailed oral and written information on the study aims and risks, and they gave written consent before entering the study. Inclusion criteria were diagnosis of metabolic syndrome according to the National Cholesterol Education Program-Adult Treatment Panel III criteria (1). Exclusion criteria were previous diagnosis or clinical or laboratory evidence of liver failure or disease, renal failure (plasma creatinine above 1.5 mg/dl), cancer, chronic autoimmune and thyroid disease, history of alcohol abuse, or self-reported daily alcohol intake above 50 g. Females (Fs) taking hormonal estrogen therapy were also excluded from the study. No patient had undergone weight-reduction therapeutic programs in the previous 3 yr. Ten patients [five males (Ms)/five Fs] and three nonobese control subjects were current smokers or had quit smoking for less than 1 yr. Among patients, T-Ghr, A-Ghr, and D-Ghr were similar in this subgroup to those in nonsmokers (total, 931 ± 79 vs. 878 ± 40 pg/ml; A-Ghr, 79 ± 7 vs. 72 ± 5; D-Ghr, 445 ± 45 vs. 406 ± 35 pg/ml; all P > 0.4) so that all were considered together.

Upon a baseline screening visit, each participant was admitted to the outpatient ward in the morning under postabsorptive conditions after overnight fasting for 10 h. A blood sample was collected for measurement of routine variables for diagnosis of metabolic syndrome, a baseline examination was performed, and detailed medical history was collected. Blood pressure was measured on the right and left arms using a standard mercury sphygmomanometer. Weight and height were measured in duplicate, and recorded to the nearest 0.1 kg and 0.5 cm, respectively. Body mass index (BMI) was calculated as weight (in kilograms) divided by height (in meters) squared. Waist circumference (WC) was measured on bare skin during midrespiration at the natural indentation between the 10th rib and iliac crest to the nearest 0.5 cm. All variables were measured in duplicate, and the average of two measures was used for patient classification. Patients meeting the inclusion criteria were admitted for a second visit under the same conditions within 2 wk for collection of a blood sample for hormonal analyses. For analyses aimed at investigating the impact of obesity on different study variables in the context of the metabolic syndrome, patients were subdivided into two groups of nonobese or obese subjects based on BMI, with cutoff value set at 27.5 kg/m2 based on previous reports (6).

Plasma analyses

Plasma glucose, high-density lipoprotein (HDL) cholesterol, and plasma triglycerides were measured using standard methods. T-Ghr (intraassay coefficient of variation 4.4%; interassay coefficient of variation 9.2%) and A-Ghr (intraassay coefficient of variation 4.9%; interassay coefficient of variation 8.9%) were measured using RIA (Linco, St. Charles, MO). Plasma D-Ghr (intraassay coefficient of variation 6%; interassay coefficient of variation 9.6%) was measured using ELISA (DRG, New York, NY) following the manufacturer’s recommendations. Plasma insulin was measured by RIA (Linco). Insulin sensitivity was assessed by the validated homeostasis model assessment (HOMA) index (24) using the following formula: HOMA = (FPG * FPI)/22.5, where FPG and FPI are fasting plasma glucose (mmol) and fasting plasma insulin (µU/ml), respectively.

Statistical analysis

Univariate linear and multivariate regression analyses were used to assess associations between variables. Results in the two groups of obese and nonobese metabolic syndrome patients were compared using the unpaired Student’s t test. Multivariate regression analyses were performed to adjust the relationships between ghrelin forms and HOMA for sex and BMI. Due to unequal variances, log-transformed values for homeostasis model assessment of insulin resistance (HOMA-IR), D-Ghr, and A/D-Ghr ratio were used for correlations, and log-transformed HOMA-IR was used as a dependent variable in multivariate regression analyses. P values <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Anthropometric, biochemical, and hormonal profile (Tables 1Go and 2Go)

Anthropometric and metabolic characteristics of metabolic syndrome patients are reported in Table 1Go. Obese patients with metabolic syndrome had comparable age but higher BMI, WC, and plasma insulin compared with nonobese patients. Systolic blood pressure was also higher in obese patients, whereas HDL-cholesterol was lower. Both T-Ghr and D-Ghr were lower in obese compared with nonobese patients with metabolic syndrome (Table 2Go). In contrast A-Ghr was comparable in the two groups, and A/D-Ghr ratio was higher in obese than nonobese individuals. Plasma D-Ghr was also estimated as the difference between T-Ghr and A-Ghr hormone. Similar qualitative changes among groups were observed using calculated or measured values, although measured hormone concentrations were lower [in agreement with previous results (12)] (Table 2Go). A positive association (r = 0.85) was observed between calculated and measured D-Ghr. Measured hormone levels are shown in further analyses. In all patients, F subjects had higher plasma T-Ghr (1019 ± 75 vs. 793 ± 46 pg/ml; P < 0.05), and measured (499 ± 60 vs. 336 ± 29 pg/ml; P < 0.05) as well as calculated (941 ± 74 vs. 716 ± 49 pg/ml; P < 0.05) D-Ghr than Ms, whereas A-Ghr [78 ± 11 vs. 73 ± 8 pg/ml; P = nonsignificant (NS)] was comparable among genders. Gender-related differences were confirmed in the smaller nonobese group (T-Ghr and D-Ghr, F > M; P < 0.05; six Ms/six Fs), whereas they did not reach statistical significance in the larger obese one (data not shown).


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  		TABLE 1. Age, BMI, WC, plasma triglycerides (Tg), and HDL cholesterol (Chol), systolic (SBP) and diastolic (DBP) blood pressure, plasma glucose and insulin in all metabolic syndrome patients as well as in nonobese and obese patient subgroups

 

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  		TABLE 2. T-Ghr, D-Ghr, A-Ghr, and A/D-Ghr ratio in all as well as nonobese or obese subjects with metabolic syndrome

 
Ghrelin correlates (Tables 3Go and 4Go, and Fig. 1Go)

In all metabolic syndrome patients (n = 45), plasma insulin was related negatively with T-Ghr and D-Ghr but positively with A-Ghr and A/D-Ghr ratio (Table 3Go). HOMA-IR was also related negatively with T-Ghr (r = –0.41; P = 0.01) and D-Ghr but positively with A-Ghr and A/D-Ghr ratio in all subjects (Fig. 1Go). BMI and WC were correlated negatively or not correlated with T-Ghr and D-Ghr, whereas they were correlated positively with A-Ghr and A/D-Ghr ratio (Table 3Go). BMI (r = 0.49; P < 0.01) as well as WC (r = 0.47; P < 0.01) were positively associated with HOMA-IR in all patients (n = 45), as expected (data not shown). In all subjects, the association between D-Ghr and A/D-Ghr ratio and HOMA-IR, as well as plasma insulin remained significant also after adjusting for sex and BMI (or WC), and similar results were observed when using calculated D-Ghr (data not shown). On the other hand, the associations between A-Ghr and HOMA-IR or insulin were significant after adjusting for sex, but not for BMI (or waist).


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  		TABLE 3. Univariate analysis between anthropometric parameters, metabolic syndrome parameters, and T-Ghr, D-Ghr, A-Ghr, and A/D-Ghr ratio in all metabolic syndrome subjects

 

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  		TABLE 4. Multivariate regression analyses (F value) of plasma ghrelin forms (D-Ghr, A-Ghr, and A/D-Ghr ratio as independent variables) and plasma insulin, glucose and HOMA-IR (dependent variables) in metabolic syndrome patients

 

Figure 1
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  		FIG. 1. Correlations between D-Ghr (A), A-Ghr (B), or A/D-Ghr ratio (C) and HOMA-IR in metabolic syndrome patients (n = 45).

 
Impact of obesity on plasma ghrelin profile in people without metabolic syndrome

The aforementioned data suggest that altered balance of circulating ghrelin forms with relative increments of A-Ghr hormone occurs in obese metabolic syndrome patients. This alteration appears to be associated with higher BMI and WC, a surrogate marker of abdominal fat accumulation. As a secondary aim of the study, to dissect the potential independent impacts of metabolic syndrome and obesity per se on plasma ghrelin profile, additional groups of age-, sex-, and BMI-matched obese and nonobese people without the metabolic syndrome were studied. Obese individuals without the metabolic syndrome were further selected to be matched to their metabolic syndrome counterparts for WC. T-Ghr and A-Ghr hormone was measured using the same RIA kits used for metabolic syndrome subjects, whereas direct D-Ghr measurement was not available in all control subjects due to technical reasons, and we report calculated D-Ghr. Differences between the two control groups were studied using the unpaired Student’s t test. One-way ANOVA followed by the unpaired Student’s t test was used for comparisons across groups with or without metabolic syndrome.

Anthropometric and biochemical profile. Anthropometric and biochemical characteristics of both nonobese (n = 15, eight Ms/seven Fs) and obese (n = 10, five Ms/five Fs) individuals without the metabolic syndrome who gave informed consent to participate in the study are reported in Table 5Go. Obese subjects had higher BMI and WC by design, but blood pressure and lipid profile were comparable to the nonobese group. Plasma glucose was also comparable in the two groups, but plasma insulin was higher in obese subjects. Obese nonmetabolic syndrome subjects had BMI and WC similar to BMI-matched metabolic syndrome patients but lower plasma glucose, triglycerides, and diastolic blood pressure, with higher HDL-cholesterol (all P < 0.05). Compared with BMI-matched patients with metabolic syndrome, lean nonmetabolic syndrome subjects had lower WC and plasma triglycerides with higher HDL-cholesterol, whereas plasma glucose and insulin were not statistically different; all parameters were in turn lower compared with obese patients with metabolic syndrome (P > 0.01).


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  		TABLE 5. Anthropometric and biochemical profile of nonmetabolic syndrome subjects

 
Plasma ghrelin profile (Fig. 2Go). Obese nonmetabolic syndrome subjects had lower T-Ghr compared with the nonobese control group (Fig. 2AGo). Calculated D-Ghr was accordingly also lower in obese compared with nonobese subjects without metabolic syndrome (1167 ± 118 vs. 807 ± 79 pg/ml; P < 0.05). In contrast, obese nonmetabolic syndrome subjects had A-Ghr higher than nonobese counterparts and comparable to both metabolic syndrome groups (Fig. 2BGo). Similar to nonobese metabolic syndrome patients, nonobese F subjects without metabolic syndrome had higher T-Ghr than M counterparts (1530 ± 74 vs. 964 ± 87 pg/ml; P < 0.05) but comparable A-Ghr hormone (40 ± 3 vs. 48 ± 5 pg/ml; P = NS). On the other hand, these differences between sexes did not reach statistical significance in the smaller obese nonmetabolic syndrome group for T-Ghr (949 ± 109 vs. 791 ± 64 pg/ml; P = NS) or A-Ghr (68 ± 1 vs. 68 ± 5 pg/ml; P = NS). Inclusion of control subjects in linear or multiple regression analyses confirmed and considerably strengthened associations between ghrelin forms, insulin sensitivity, and BMI or WC. In particular, in all subjects (n = 70) a significant positive correlation was confirmed between A-Ghr and HOMA-IR (r = 0.425; P = 0.0002) that was significant also after adjusting for sex and BMI or WC (F = 5.529; P = 0.022). A positive correlation was further observed between A-Ghr and both BMI (r = 0.406; P = 0.0005) and WC (r = 0.367; P = 0.0018). Negative associations were in turn confirmed in all subjects between T-Ghr and HOMA-IR (r = –0.407; P = 0.0005), BMI (r = –0.231; P = 0.05), and WC (r = –0.355; P = 0.0005). Similar negative associations were finally observed between calculated D-Ghr and HOMA-IR, BMI, and WC in all subjects (all P < 0.001).


Figure 2
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  		FIG. 2. T-Ghr (A) and A-Ghr (B) in nonobese (black bars) or obese (white bars) individuals without or with metabolic syndrome. *, P < 0.05 vs. corresponding nonobese. $, P < 0.05 vs. all other groups. T-Ghr was comparable in groups with similar BMI, whereas A-Ghr was lowest in nonobese nonmetabolic syndrome subjects and comparable in all other groups.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The current study investigated the potential differential associations of different ghrelin forms with insulin resistance in the setting of the metabolic syndrome. In addition, we tested the hypothesis that obesity differentially affects different ghrelin forms and that these changes could be involved in obesity-associated insulin resistance. The data showed that both T-Ghr and D-Ghr are inversely related to insulin resistance, but in contrast, A-Ghr is associated with higher insulin resistance both in terms of absolute plasma concentration and as a fraction of total circulating hormone. Results further demonstrated that obese metabolic syndrome patients have marked alterations in plasma ghrelin profile compared with nonobese counterparts. In particular, T-Ghr as well as D-Ghr were lower in obese patients, but A-Ghr was comparable in the two groups, and the fraction of acylated relative to desacylated circulating hormone was more than doubled in obese individuals. The expected positive associations between BMI, WC, and insulin resistance were also confirmed in the current study population. However, the link between ghrelin balance and insulin resistance appeared to be independent of obesity.

It should be pointed out that associations can suggest but not prove causality. Nevertheless, the current results are supported by reports of differential acute impacts of A-Ghr and D-Ghr on oral glucose disposal and metabolism in postabsorptive humans (19, 20, 21, 22). Differential effects appear to extend also to hepatic insulin sensitivity, at least in experimental models (25). Thus, the current findings introduce the novel concept that A/D-Ghr balance could contribute to modulate insulin action in metabolic syndrome. The aforementioned observations further provide support to the hypothesis that unbalanced plasma concentrations of different ghrelin forms could contribute to the association between insulin resistance and increased body mass commonly observed in metabolic syndrome (1, 2, 3, 4, 5, 6), and they suggest that strategies aimed at lowering A/D-Ghr ratio could potentially result in improved insulin action in this setting.

Obesity-associated reduction of T-Ghr and D-Ghr is supported by previous reports of lower T-Ghr in obese people not characterized for metabolic syndrome (16), and higher plasma insulin as well as leptin concentrations have been previously suggested as potential contributors to these changes (11). However, factors regulating circulating A-Ghr levels are largely unknown, although increased availability of fatty acids was reported to enhance directly hormone acylation in experimental models (26). The current data suggest that increased BMI and WC may lead to relative excess of A-Ghr in the presence of metabolic syndrome. Moreover, comparable alterations of plasma ghrelin profile in obese subjects both with and without metabolic syndrome support an independent impact of obesity in increasing plasma acylated over total and calculated desacylated hormone. Obese subjects without metabolic syndrome had a normal lipid profile, plasma glucose, and blood pressure but notably higher plasma insulin compared with healthy nonobese individuals, and this finding suggests lower insulin action in keeping with the positive association between A-Ghr and insulin resistance. Therefore, the current results indicate that altered ghrelin balance and an absolute or relative increase of acylated hormone are potential novel obesity-related alterations with negative impact on insulin action. It should be pointed out that higher A-Ghr was also observed in nonobese metabolic syndrome patients compared with matched healthy individuals. However, nonobese patients had larger WC compared with control subjects, consistent with abdominal fat accumulation, despite similar BMI (4, 5). Abdominal fat distribution is indeed a pivotal alteration strongly associated with all other metabolic syndrome features (1, 2, 3, 4, 5, 6), and the data suggest that abdominal fat accumulation could be involved in increased ghrelin acylation, even in the presence of near-normal total body mass. Further epidemiological studies with direct assessment of abdominal fat content are needed to confirm this hypothesis.

Previous studies in experimental models interestingly indicated selected positive metabolic effects of A-Ghr in skeletal muscle (17, 18). Opposite effects or no effects on glucose-lipid metabolism were in turn observed in the liver in both studies (17, 18), and sustained administration of A-Ghr leads to increased body weight and plasma glucose (17). These studies were performed in lean young adult animals, and it is possible that the lack of overweight, different age, and mode of administration influenced A-Ghr effects in muscle or at the whole body level. In addition, it should also be noted that A-Ghr appears to induce desacylated hormone secretion because its administration acutely causes parallel and more pronounced increments of D-Ghr in humans (19). We recently observed a 3-fold increase of plasma D-Ghr 3 h after sc A-Ghr administration (200 µg) in rats (Barazzoni, R., G. Guarnieri, unpublished data). Therefore, it is also plausible that A-Ghr administration can result in simultaneous increments of the two ghrelin forms that could contribute to positive metabolic effects reported in animal models.

Calculated and measured D-Ghr values lead to the same conclusions in terms of differences among groups and associations with insulin resistance in the current study population. However, it should be noted that directly measured D-Ghr values were lower than calculated ones. This observation is in agreement with previous reports (12) in which it was suggested that circulating ghrelin fragments could account for these discrepancies. It is also possible that the use of enzyme immunoassay and RIA assays contributed to differential values. However, this possibility does not influence the study conclusions based on differences between groups and on associations with insulin resistance for each ghrelin form or their ratios.

In conclusion, the current data demonstrate that different ghrelin forms are differentially associated with insulin sensitivity in metabolic syndrome. Obesity differentially affects T-Ghr, D-Ghr, and A-Ghr in metabolic syndrome patients. Lower T-Ghr and D-Ghr and relative increments of A-Ghr could negatively modulate insulin action, and contribute to the association between obesity and insulin resistance in metabolic syndrome.


   Footnotes
 
Disclosure Statement: The authors have nothing to declare.

First Published Online July 24, 2007

Abbreviations: A/D-Ghr, Acylated to desacylated ghrelin; A-Ghr, acylated ghrelin; BMI, body mass index; D-Ghr, desacylated ghrelin; F, female; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; HOMA-IR, HOMA of insulin resistance; M, male; NS, nonsignificant; T-Ghr, total plasma ghrelin; WC, waist circumference.

Received November 16, 2006.

Accepted July 17, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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