The effects of laparoscopic sleeve gastrectomy vs. gastric bypass in circulating adiponectin, testosterone and their associations with carotid intima-media thickness in men.

doi:10.21203/rs.3.rs-1399169/v1

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The effects of laparoscopic sleeve gastrectomy vs. gastric bypass in circulating adiponectin, testosterone and their associations with carotid intima-media thickness in men.

https://doi.org/10.21203/rs.3.rs-1399169/v1

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Background: Obesity increases cardiovascular risk in men through several pathophysiological mechanisms. Among them, low adiponectin (APN) and possibly obesity-associated hypogonadism have been described. As obesity surgery is a proven therapy to decrease cardiovascular risk, we aimed to study the association of the latter with changes in circulating adiponectin by comparing laparoscopic Roux-en-Y gastric bypass (RYGB) with sleeve gastrectomy (SG).

Methods: We included 60 men, 20 submitted to RYGB, 20 to SG, and 20 to life-style modification (controls). Serum APN, total testosterone (TT), and sex hormone binding globulin (SHBG) were measured at baseline and six months after surgery. Free testosterone (FT) was calculated, and carotid intima-media thickness (cIMT) measured by ultrasonography.

Results: Circulating APN increased after both surgical techniques, whereas no changes were observed in controls (P<0.001 for the interaction, P=0.005 for RYGB vs. controls, P=0.001 for SG vs. controls, P=0.695 for RYGB vs. SG). The increase in APN correlated positively with TT (r=0.518, P<0.001) and FT (r=0.320, P=0.013) and inversely with cIMT (r=-0.283, P=0.028). The increase in TT and FT inversely correlated with changes in cIMT (r=-0.428, P=0.010 and r=-0.269, P=0.038). After multivariate linear regression only weight loss was associated with cIMT (R²=0.245, P<0.001).

Conclusions: Both RYGB and SG induced a similar increase in APN in men which paralleled TT, FT and SHBG. The decrease in cIMT after surgery inversely correlated with APN but was mainly associated with weight loss.

Obesity

cardiovascular risk

carotid intima-media thickness

adiponectin

testosterone.

Obesity is a global pandemic with major consequences in health as it increases the risk of cancer, metabolic diseases such as diabetes mellitus (DM), and cardiovascular diseases (CVD) [1, 2]. Nowadays, the most effective treatment of severe obesity is surgical, as it maintains long-term weight loss and resolves many of its associated comorbidities, reducing cardiovascular risk and increasing patients’ survival [3–5]. We have shown that both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) decrease the cardiovascular risk as measured by the carotid intima-media thickness (cIMT) in both men and women with obesity, and this effect was higher than that observed with life-style modification [6, 7].

Adiponectin (APN) is a protein hormone secreted by adipose tissue with an anti-inflammatory role that also regulates glucose and lipid metabolism [8]. Low circulating APN concentrations are associated with obesity, type 2 DM and CVD [9, 10]. It has been shown that obesity surgery induces an increase in APN concentrations which drives an improvement in insulin sensitivity and type 2 DM remission rates [11–13]. Conversely, other published data found no association of APN concentrations with diabetes or myocardial infarction after obesity surgery [14].

Regarding the association of circulating APN with cIMT conflicting results have also been reported, with either a significant or a non-significant association between low circulating APN and the severity of cIMT [15, 16]. We previously showed that circulating APN increased in women after obesity surgery in parallel with a beneficial metabolic effect, but we failed to demonstrate an association with the decrease in cIMT [17]. Conversely, a recent meta-analysis has shown suggestive but not conclusive evidence for a negative association between circulating APN and cIMT [18], so there remains some conflicting results. Furthermore, no direct comparisons between different surgical techniques have been published regarding the association of APN and cIMT in men, or with circulating androgens.

Aims and setting of the study

To evaluate the changes in circulating APN in men after RYGB vs. SG and its possible association with the changes in cIMT. We also aimed to characterize its association with circulating testosterone, as APN and its receptors are expressed by different cell types of the male gonad [19] and previous studies showed a relationship between these two hormones [20, 21]. We selected a homogenous group of men with severe obesity and high cardiovascular risk to avoid interference of sexual dimorphism [22, 23]. The study was performed at the Unit of Metabolic Surgery of a tertiary university teaching hospital.

Patients and Study Design

We included sixty men with severe obesity and high cardiovascular risk (according to the American Heart Association) [24]. Twenty were submitted to RYGB, 20 to SG, and the other 20 patients were treated with life-style modification. This was not a randomized study and the indication for each surgical technique was in accordance to our center’s protocol. The latter is in line with current international guidelines and allocates patients with more metabolic complications to RYGB. The main characteristics of the employed surgical techniques have been reported previously [6, 7]. Exclusion criteria included severe psychiatric condition or substance abuse, active neoplasia, and incurable pre-existing comorbidities.

Patients were evaluated at baseline and 6 months after surgery or life-style modification. Anthropometric variables were recorded and body mass index (BMI) was calculated. Excess body weight (EBW) was the difference between baseline body weight and ideal weight, the latter considered as the weight corresponding for a BMI of 25 kg/m². Data of the change in carotid intima-media thickness of these patients were reported before [7].

APN was measured by ELISA in serum samples in duplicate with a commercial kit (Human adiponectin ELISA kit, Thermofisher Scientific, BenderMedSystems GmbH, Vienna, Austria) with an analytical sensitivity of 100 pg/mL and an intra- and inter-assay CVs of 3.5% and 5.8% respectively. Assays and reference ranges for TT, sex hormone–binding globulin (SHBG), insulin and lipids profiles were previously reported [25].

Statistics

A priori sample size analysis was performed as reported before [7]. For the changes in APN a total sample size of 24 subjects was enough to detect a mean difference of 3 ng/dL with a SD of 5 in the follow-up period, with 1-β = 0.80 and α = 0.05.

Results are expressed as means ± SD unless otherwise stated. The Kolmogorov–Smirnov statistic was applied to continuous variables. Logarithmic or square root transformations were used as needed to ensure normal distribution. One-way analysis of variance with Tukey tests compared the central tendencies of the different groups. Kruskal–Wallis test followed by Wilcoxon tests was used in the case of non-normal variables. For discontinuous variables the χ2 test and Fisher’s exact test were employed.

Comparisons of continuous variables before and after bariatric surgery were performed by repeated measures general linear model analysis, and the group of subjects (controls, SG and RYGB) was introduced as the between-subject effect. Bivariate correlation analyzed the association between two continuous variables by Pearson or Spearman’s tests. Multiple linear regression was used to find the effects of several dependent variables and their interactions on the decrease of cIMT, and other metabolic independent variables. We used SPSS 18 (SPSS Inc, Chicago, Illinois) and P < 0.05 was considered statistically significant.

Sixty patients with an age of 48 ± 9y (controls n = 20, age 48 ± 8y, SG n = 20, age 46 ± 9y, RYGB n = 20, age 51 ± 9y, P = 0.190) were evaluated (Table 1). At baseline, patients submitted to RYGB showed lower concentrations of LDL cholesterol because of a more frequent use of statins, and a higher proportion of hypertension due to the lack of randomization of the surgical technique. At follow-up the effects of obesity surgery was higher than those of life-style modification on total weight loss, BMI, cIMT, blood pressure, fasting glucose and insulin (Table 1).

Table 1

Baseline and follow-up characteristics of the men included in the study.
	Controls (n = 20)		SG (n = 20)		RYGB (n = 20)
	Baseline	6 months	Baseline	6 months	Baseline	6 months
BMI (Kg/m²)	44.0 ± 5.4	45.2 ± 7.1	45.0 ± 6.9	33.2 ± 4.1^*†	43.7 ± 7.2	31.6 ± 6.5^*†
EBW (kg)	59.4 ± 17.4	3.7 ± 14.1	61.6 ± 21.2	57.4 ± 18.2^*†	56.7 ± 20.8	69.4 ± 26.2^*†
Hypertension (%)	10 (50)	10 (50)	10 (50)	1 (0.5)^*	18 (90)^†‡	7 (35)^*‡
Type 2 DM (%)	8 (40)	8 (40)	6 (30)	4 (20)^*	10 (50)	2 (10)^*
cIMT (mm)	0.66 ± 0.10	0.67 ± 0.11	0.65 ± 0.11	0.60 ± 0.09^*†	0.66 ± 0.13	0.60 ± 0.12^*†
Systolic BP (mmHg)	145 ± 16	151 ± 12	141 ± 17	130 ± 12^*†	144 ± 16	129 ± 17^*†
Diastolic BP (mmHg)	87 ± 9	89 ± 8	85 ± 11	84 ± 8^†	87 ± 11	76 ± 12^*†
LDL (mg/dL)	116 ± 31	125 ± 26	117 ± 36	113 ± 31	82 ± 29^†‡	74 ± 27
HDL (mg/dL)	43 ± 17	39 ± 13	40 ± 6	44 ± 8^*†	39 ± 9	48 ± 17^*†
Glucose (mg/dl)	119 ± 42	126 ± 53	107 ± 34	97 ± 17^†	129 ± 60	99 ± 31^*†
Insulin (µU/mL)	30 ± 16	27 ± 14	19 ± 9^†	10 ± 6^*†	21 ± 14^†	7 ± 3^*†
HOMA-IR	9.5 ± 8.0	15.2 ± 28.6	5.1 ± 3.1^†	2.4 ± 1.6	6.4 ± 5.7^†	3.2 ± 5.8
SG: sleeve gastrectomy, RYGB: Roux-en-Y gastric bypass, BMI: body mass index, EBW: excess body weight, DM: diabetes mellitus, cIMT: carotid intima-media thickness, BP: blood pressure, LDL: low density lipoprotein cholesterol, HDL: high density lipoprotein cholesterol, HOMA-IR: insulin resistance calculated by the homeostatic model assessment, TT: total testosterone, SHBG: sex hormone binding globulin, FT: free testosterone. *P < 0.05 from baseline, †P < 0.05 vs. controls, ‡P < 0.05 vs SG.

APN concentrations increased after obesity surgery, more after RYGB than SG, with no changes in controls (Wilks' λ = 0.835, P < 0.001 for the interaction, P = 0.005 for RYGB vs. controls, P = 0.001 for SG vs. controls, P = 0.695 for RYGB vs. SG) (Fig. 1). When correcting for the presence of diabetes the results were similar (Wilks' λ = 0.999, P = 0.803 for the interaction). TT, SHBG, and FT increased after obesity surgery compared with controls, and the effect of RYGB was higher than SG (Fig. 1).

Then patients submitted to surgery and controls were pooled together for further analyses. The changes in cIMT at follow-up showed negative correlations with the changes in circulating APN, TT, SHBG and FT (Table 2). In addition, a positive correlation was found between the increase in APN and the changes in TT (r = 0.518, P < 0.001), SHBG (r = 0.446, P < 0.001) and FT (r = 0.320, P = 0.013) and a negative correlation with BMI (Table 2). Both TT and FT also showed negative correlations with the changes in BMI, systolic and diastolic BP, glucose, insulin and HOMA-IR and positive correlation with the changes in HDL (Table 2).

Table 2

Correlation of the changes in circulating adiponectin and androgens with cardiovascular and metabolic variables.
	Δ Adiponectin		Δ TT		Δ SHBG		Δ FT
	r	P	r	P	r	P	r	P
Δ cIMT	-0.283	0.028	-0.428	0.010	-0.347	0.007	-0.269	0.038
Δ BMI	-0.266	0.040	-0.583	< 0.001	-0.691	< 0.001	-0.337	0.009
Δ Systolic BP	-0.211	0.106	-0.394	0.002	-0.205	0.117	-0.419	0.001
Δ Diastolic BP	-0.059	0.656	-0.291	0.024	-0.185	0.156	-0.342	0.008
Δ LDL	-0.230	0.077	-0.099	0.060	-0.060	0.647	-0.035	0.793
Δ HDL	0.046	0.727	0.442	< 0.001	0.355	0.005	0.324	0.011
Δ Glucose	-0.135	0.303	-0.421	0.001	-0.273	0.035	-0.379	0.003
Δ Insulin	-0.158	0.228	-0.516	< 0.001	-0.405	0.001	-0.399	0.002
Δ HOMA-IR	-0.157	0.231	-0.508	< 0.001	-0.378	0.003	-0.395	0.002
TT: total testosterone, SHBG: sex hormone binding globulin, FT: free testosterone, cIMT: carotid intima-media thickness, BMI: body mass index, BP: blood pressure, LDL: low density lipoprotein cholesterol, HDL: high density lipoprotein cholesterol, HOMA-IR: insulin resistance calculated by the homeostatic model assessment.

Multivariate linear regression was performed introducing first the change in cIMT as the dependent variable, and changes in BMI, systolic and diastolic BP, LDL, HDL, adiponectin, glucose, insulin and FT (total testosterone and SHBG were not introduced to avoid collinearity) as the independent variable. Only the change in BMI was retained as a significant variable associated with the changes in cIMT (Table 3). Other multivariate linear regression models were performed to explore for associations between circulating APN and FT with other cardiovascular and metabolic variables. FT was associated with changes in circulating APN, and changes in systolic BP and insulin were also associated with changes in FT (Table 3).

Table 3

Models of multivariate linear regression analysis.
Dependent variables	Independent variables*	R²	F		β	P
Δ cIMT	Δ BMI	0.245	9.229		0.378	< 0.001 0.003
Δ Systolic BP	Δ BMI Δ FT Δ Diastolic BP	0.402	12.571		0.360 -0.240 0.251	< 0.001 0.002 0.041 0.032
Δ Diastolic BP	Δ FT Δ Systolic BP	0.241	9.0.31		-0.475 0.265	< 0.001 0.011 0.044
Δ HDL	Δ FT	0.082	5.159		0.286	0.027 0.027
Δ Adiponectin	Δ FT	0.097	6.251	0.312		0.015 0.015
Δ Glucose	Δ BMI	0.132	4.333	0.274		0.018 0.031
Δ Insulin	Δ BMI Δ FT	0.214	7.759	0.276 -0.295		0.001 0.030 0.021
Δ FT	Δ Systolic BP Δ Insulin Δ Adiponectin	0.375	6.241	-0.311 -0.254 0.258		< 0.001 0.009 0.028 0.020
cIMT: carotid intima-media thickness, BMI: body mass index, FT: free testosterone, BP: blood pressure, HDL: high-density lipoprotein cholesterol.
*Only independent variables retained by the model are shown. The following variables were introduced as independent variables when not considered the dependent variable in the model: changes in cIMT, BMI, systolic and diastolic BP, LDL, HDL, adiponectin, glucose, insulin and FT (total testosterone and SHBG not introduced to avoid collinearity). LDL showed no association with any independent variable.

We have found that in men with obesity both RYGB and SG induce an increase in APN concentrations in parallel with the decrease in cIMT. To our knowledge, this is the first time that the relationships of cIMT with APN and also with testosterone are explored concomitantly in obese men after obesity surgery. These changes also correlated with beneficial effects in the lipid profile, blood pressure and glucose metabolism. However, although we hypothesized that the changes in APN could be associated with the observed decrease in cIMT, multivariate analysis could not confirm this result.

The cIMT is a strong predictor of major cardiovascular events [26, 27], and low APN concentrations seemed to independently predict the progression of carotid atherosclerosis and cardiac remodeling [28, 29]. However the association of APN with cIMT could not be demonstrated in a 5-year prospective study with first-degree relatives of patients with type 2 DM and normal individuals [16]. Further, the prospective controlled Swedish Obese Subjects study [14], with more than 3299 patients, showed that the observed 2-year increases in APN after obesity surgery were not associated with the risk of myocardial infarction or stroke [14]. In agreement, we were not able to demonstrate an association between circulating APN with cIMT in a prospective study with women evaluated at baseline and 1 year after obesity surgery, albeit the observed increase in APN was associated with a reduction in insulin resistance [18]. Therefore it seems that the consistent increase in circulating APN found after obesity surgery is associated with beneficial metabolic changes, such as the reduction in insulin resistance, the resolution of type 2 DM [11, 13, 30, 31], improvements in lipid profiles and reduction of inflammatory markers [32–35], but it does not seem to have a consistent direct effect on the observed decrease in cIMT.

Regarding the relationship of APN with the male gonadal axis, there is evidence of the expression of APN receptors by Leydig cells, spermatozoa, and epididymis [19]. Functionally, APN can regulate the expression of different steroidogenic genes [36], and in addition, it has been shown to promote spermatogenesis and sperm maturation [19]. However, previous studies exploring the association of circulating APN with androgens in men have yielded conflicting results. Elsaied et al described a positive correlation in 87 patients, 58 with type 2 DM and 29 nondiabetics [37], and Rasul et al found the same association in 62 elderly diabetic men [38]. Conversely, Frederiksen et al reported a decrease in APN concentrations after 6 months of testosterone therapy in a group of 38 aged men [39], and similar findings were shown in another two studies [21, 40]. Therefore, the associations of APN and androgens are complex and may be confounded by the presence of type 2 DM and the degree of adiposity.

Severe obesity in men is known to be associated with secondary hypogonadism in as much as 64% of the cases and its resolution can be achieved in an 87% of the patients after obesity surgery [41, 42]. Furthermore, male hypogonadism is associated with dyslipidemia, atherosclerosis, CVD and DM, and testosterone supplementation therapy in hypogonadic men improves lipids, glycemia and insulin sensitivity [43]. In agreement, we found a significant increase in TT and FT concentrations in men after obesity surgery which inversely correlated with blood pressure, lipids and insulin resistance and positively with APN. However, as in the case of APN, no association was found with the decrease of cIMT, as we previously communicated [7].

Our present study has the major limitation of the lack of randomization in the allocation of the patients to the different groups of interventions. In addition, the generalizability of the results is limited because we here evaluated the patients after a short-term period of 6 months, so long-term beneficial effects of obesity surgery on cIMT and cardiovascular events could not be evaluated.

In conclusion, both RYGB and SG induce a significant increase in circulating APN in men which parallels TT, FT and SHBG. These changes were associated with beneficial effects in blood pressure, lipid profiles and insulin sensitivity. However, the decrease in cIMT after surgery was mainly associated with weight loss, with no association with either the increase in APN or testosterone.

APN: adiponectin.

BMI: body mass index.

BP: blood pressure.

cIMT: carotid intima-media thickness.

CV: coefficient of variation.

CVD: cardiovascular disease.

DM: diabetes mellitus.

EBW: excess body weight.

FT: free testosterone.

HDL: high density lipoproteins.

HOMA-IR: insulin resistance by homeostasis model assessment.

LDL: low density lipoproteins.

RYGB: Roux-en-Y gastric bypass.

SD: standard deviation.

SG: sleeve gastrectomy.

SHBG: sex hormone binding globulin.

TT: total testosterone.

Ethics Approval and Consent to Participate

All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board of Hospital Universitario Ramón y Cajal (study code: PI18/00132). Written informed consent was obtained from every participant.

Consent for Publication

Not applicable.

Availability of Data and Materials

Restrictions apply to the availability of data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will, on request, detail the restrictions and any conditions under which access to some data may be provided.

Competing Interests

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript, or in the decision to publish the results.

Funding

This research was funded by the Instituto de Salud Carlos III, grant number AES/ISCIII - PI18/00132 and co-funded by the European Union (ERDF, “A way to make Europe”). CIBEROBN is also an initiative of the Instituto de Salud Carlos III.

Author contributions

P.C., R.P., A.O., J.M.G.-M., M.C.-A., D.P., J.G. and J.I.B.-C. read and approved the final manuscript. P.C., R.P., J.G. and J.I.B.-C. drafted and revised the manuscript. P.C., R.P., A.O., J.M.G.-M., M.C.-A., D.P., J.G. and J.I.B.-C. contributed to collection, analysis, and interpretation of the data. J.G. and J.I.B.-C. contributed to the conception and design of the experiments.

Acknowledgments

The nursing staff at the Department of Endocrinology and Nutrition helped with the anthropometric and blood sampling of the patients.

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The effects of laparoscopic sleeve gastrectomy vs. gastric bypass in circulating adiponectin, testosterone and their associations with carotid intima-media thickness in men.

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