Insulin Resistance, Inflammation, and the Metabolic Syndrome Following Roux-en-Y Gastric Bypass Surgery in Severely Obese Subjects

A total of 36 Caucasian, severely obese subjects about to undergo RYGBP surgery (8) were evaluated (Table 1). Twenty normal-weight healthy volunteers, matched for sex and age with the obese subjects, served as controls (Table 1). The study was approved by the hospital ethics committee. Written informed consent was obtained from all participants. The 36 obese, operated subjects were evaluated within 8 weeks before RYGBP and again at 6 and 52 weeks after RYGBP. Control subjects were evaluated on a single occasion.

The diagnosis of the metabolic syndrome was based on the revised Adult Treatment Panel III criteria (9). Anthropometrical and blood pressure measurements were performed as previously described (10). Venous blood was collected after an overnight fast. Plasma glucose, total cholesterol, HDL cholesterol, triglyceride levels, insulin, adiponectin, and insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR]) were assessed as previously described (10). The leukocyte count was measured using an Advia 2400 analyzer (Bayer Diagnostics, Tarrytown, NY). High-sensitive C-reactive protein (CRP) was determined using an inmunonefelometric method (Boehring Nephelometer analyzer; Dade Boehring, Marburg, Germany). Soluble tumor necrosis factor-α receptors 1 (p55/p60) and 2 (p75/p80) (HyCult Biotechnology, Uden, Netherlands) and resistin (Linco Research, St. Charles, MO) were measured by an enzyme-linked immunosorbent assay.

All data are expressed as means ± SEM. Statistical analyses were carried out using SPSS software (version 11.5; SPSS, Chicago, IL). χ² and nonparametric test (Mann-Whitney U, Friedman, or Kruskall-Wallis) were used for comparisons between groups. Correlations were analyzed using Spearman rank correlation analysis or partial correlation analysis. Statistical significance was set at P < 0.05.

The time course of the prevalence of the metabolic syndrome and its individual components is shown in Table 1.

Before surgery, a significant correlation was found between HOMA-IR and the number of metabolic syndrome components (r = 0.570, P < 0.005). HOMA-IR significantly correlated with fasting plasma glucose (FPG) (r = 0.659, P < 0.001) and tended to correlate with systolic blood pressure (P = 0.071) and waist circumference (P = 0.074), albeit it did not reach statistical significance. HOMA-IR significantly declined following RYGBP (Table 1). At 6 weeks, HOMA-IR significantly correlated with FPG (r = 0.589, P < 0.005), triglycerides (r = 0.367, P < 0.05), and HDL cholesterol (r = −0.339, P < 0.05). At 52 weeks, HOMA-IR significantly correlated with the number of metabolic syndrome components (r = 0.366, P < 0.05) and with FPG (r = 0.394, P < 0.05). The correlations between HOMA-IR and components of the metabolic syndrome remained significant even after controlling for the different inflammatory parameters.

Before surgery, no significant correlation was found between inflammatory markers and the individual metabolic syndrome components, the number of metabolic syndrome components present in one particular individual, or HOMA-IR. At 6 weeks, changes in some of the inflammatory markers were observed (Table 1). The leukocyte count was the only showing significant correlations with metabolic syndrome components (waist circumference and systolic blood pressure), but these associations lost significance when HOMA-IR was considered. At 52 weeks, we observed a significant decline in the evaluated proinflammatory markers (except for resistin) and an increase in plasma adiponectin relative to baseline. Again, we did not find a significant correlation between the number of metabolic syndrome components and the inflammatory parameters. However, the leukocyte count significantly correlated with systolic and diastolic blood pressure (respectively, r = 0.384, P < 0.05; and r = 0.387, P < 0.05) and triglycerides (r = 0.393, P < 0.05). Adiponectin significantly correlated with the waist circumference (r = −0.365, P < 0.05), diastolic blood pressure (r = −0.387, P = 0.05), triglycerides (r = −0.345, P < 0.05), and HDL cholesterol (r = 0.355, P < 0.05). High-sensitivity CRP significantly correlated with FPG (r = 0.34, P < 0.05). These correlations were barely affected when HOMA-IR was considered. Noteworthy, at 52 weeks after surgery most inflammatory markers remained altered when operated subjects were compared with the normal-weight cohort (Table 1).

Marked reductions in the prevalence of the metabolic syndrome have been observed after RYGBP at ≥1 year of follow up (1–3). Noteworthy, our data show that the improvement in the metabolic syndrome following RYGBP occurs shortly after the surgical procedure, at a time when the attained weight loss is still modest. This is consistent with reports showing an early amelioration of altered glucose homeostasis (11) and blood pressure (12) following this type of surgical technique.

It has been proposed that systemic low-grade inflammation is critical for the appearance of the metabolic sydrome and that an improvement in the inflammatory process is important for the beneficial effects of weight loss (4–6,13). However, our data would suggest a different scenario, at least in severe obesity. Our results are supported by recent findings that increased CRP levels are found in severely obese subjects irrespective of the presence of nonalcoholic steatohepatitis or the metabolic syndrome (14). Likewise, several studies have reported either no change or no association between inflammatory markers and changes in metabolic parameters at short term after RYGBP (15–18). Importantly, our data does not preclude a role of the inflammatory process in the improvement of the metabolic syndrome at longer follow-up. At 1 year after RYGBP, upon massive weight loss, our data and those from others demonstrate that changes in the inflammatory process may help to explain changes in the metabolic syndrome. A significant correlation between CRP plasma concentration (19) or adiponectin (17) and metabolic variables has previously been reported at 6 and 12 months after RYGBP.

The data from the current study suggest that the early changes in the metabolic syndrome following RYGBP are better explained by changes in insulin sensitivity. An early improvement in insulin sensitivity following RYGBP has previously been described (11,20). Interestingly, Petersen et al. (21) reported mechanistic studies on the changes of glucose homeostasis in type 2 diabetic subjects following a dietary intervention resulting in a weight loss similar to the one presented in our cohort at 6 weeks after surgery. The normalization of glucose homeostasis was associated with a marked improvement in whole-body insulin sensitivity, hepatic triglyceride content, and hepatic insulin sensitivity but with no changes in circulating levels of inflammatory markers.

We acknowledge our study has several limitations. The small sample size may not allow definite conclusions to be drawn. Second, the inflammatory process involves a complex interplay of inflammatory mediators (5,6), and we only measured a subset of these markers. Thus, further studies with a more comprehensive evaluation are needed to better understand the contribution of the inflammatory process in the changes in obesity-associated metabolic disturbances following RYGBP.

In summary, our data confirm previous reports on the inflammatory state associated with obesity. Moreover, our data support the view that obesity is an important contributor to the elevation of plasma concentration of inflammatory markers. Finally, we suggest that at short term after RYGBP, the changes in the metabolic syndrome components are better accounted for regarding improved insulin sensitivity than regarding decreased low-grade inflammation. Unraveling the mechanisms responsible for the metabolic disturbances associated with obesity may provide new targets to reduce the burden of obesity epidemics.

This work was supported by grants from the Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III (PI060157 and REDIMET RD06/0,015), Madrid, Spain.