Improved insulin sensitivity after gastric bypass correlates with decreased total body fat, but not with changes in free fatty acids
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- Mor, A., Tabone, L., Omotosho, P. et al. Surg Endosc (2014) 28: 1489. doi:10.1007/s00464-013-3338-0
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Increased plasma free fatty acids (FFAs) are considered one of the key elements in the pathogenesis of insulin resistance (IR) and type 2 diabetes (T2DM). We hypothesize that, in diabetic patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB), a postoperative decrease in FFA will correlate with improved insulin sensitivity (Si).
A total of 30 obese [body mass index ((BMI) >35 kg/m2] patients with a diagnosis of T2DM were studied preoperatively and 12 months after LRYGB in a prospective cohort study. Collected data included intravenous glucose tolerance test (IVGTT), total body composition by dual-energy X-ray absorptiometry and plasma levels of FFA. Si analysis from the IVGTT was estimated from minimal model analysis. Pre- and postoperative variables were compared using a paired sample t test. Relationships between changes in variables were determined with Pearson’s correlation test.
Twelve months after LRYGB the study population showed a significant decrease in BMI (p = 0.001), FFA (p = 0.03), and total body fat (p = 0.03), with an increase in Si (p = 0.001). Postoperative changes in Si significantly correlated (Pearson’s r = –0.53, p = 0.01) with change in total body fat, but not with changes in plasma FFA (Pearson’s r = –0.22, p = 0.31).
Our study challenges the notion that IR is mediated to a significant degree by changes in plasma FFA concentration. Instead, changes in adiposity and consequently changes in adipokine release can be the key players in determining remission of T2DM after LRYGB.
KeywordsBariatric surgeryLaparoscopic Roux-en-Y gastric bypassFree fatty acidInsulin sensitivityInsulin resistanceTotal body fatAdiposity
Obesity often causes insulin resistance (IR) and has been shown to influence the severity of IR in type 2 diabetes mellitus (T2DM) [1–3]. Levels of plasma free fatty acids (FFAs) are considered one of the key elements in the obesity-related pathogenesis of IR and T2DM . Several studies have shown that increased FFA levels were associated with increased levels of IR in obese individuals, although the interpretation of the causal relationship between these two variables is still debated. For some authors, the increased FFA levels seen in obese individuals is due to increases in FFA release  and decreases in FFA clearance . Increased concentrations of FFA have been proven to induce IR through several mechanisms: reduced glucose transport in skeletal muscle , increased hepatic glucose production , inhibition of the insulin receptor substrate-1 signaling pathway [8, 9], and activation of the proinflammatory nuclear factor-κB pathway  in insulin-responsive peripheral tissues. Conversely, for other authors, the increased FFA levels could be the consequence of excessive lipolysis and lipoprotein lipase activity, secondary to the adipose tissue IR and hyperinsulinemia seen in obese individuals [11, 12].
It has been demonstrated that bariatric surgery can achieve excellent long-term weight loss and improve obesity-related comorbidities, quality of life, and survival [13–15]. Two large non-blinded, randomized, clinical trials comparing laparoscopic Roux-en-Y gastric bypass (LRYGB) with medical therapy for the treatment of diabetes, showed that bariatric surgery resulted in better glucose control, with rates of hyperinsulinemia and the homeostasis model assessment-estimated insulin resistance index markedly improved as compared with medical therapy alone [16, 17]. Recently, gastric bypass has been shown to increase both insulin sensitivity (Si) and pancreatic beta-cell function, whereas, despite comparable weight loss, sleeve gastrectomy has been shown to only partially restore the Si, with no improvement in pancreatic beta-cell function . Si improves within days after gastric bypass surgery, likely secondary to reduced stimulation of the entero-insular axis by caloric restriction [19, 20]. However, the mechanisms responsible for the long-term improved Si with resolution of T2DM after gastric bypass are still not well understood, but the preferential loss of fat is considered to play a key role .
Patients undergoing bariatric surgery have also been shown to have decreased FFA levels 1 year after operation [21, 22]. Therefore, it could be hypothesized that the decreased FFA levels after bariatric surgery may play a role in mediating the improved Si with resolution of T2DM through insulin receptor signaling pathways.
The aim of our study was to determine if a postoperative decrease in FFA correlates with the improved Si seen in T2DM patients undergoing LRYGB.
Materials and methods
Study design and data collection
A prospective cohort study was designed. We studied 30 morbidly obese (body mass index [BMI] > 35 kg/m2) patients with a diagnosis of T2DM preoperatively and 12 months after LRYGB as previously described . Inclusion criteria included clinical diagnosis of T2DM according to the American Diabetes Association criteria ; glycosylated hemoglobin (HbA1c) ≤ 10.0 % and BMI ≥ 35 kg/m2 in accord with the 1991 National Institutes of Health (NIH) obesity surgery consensus conference criteria; stable weight for the previous 3 months ; and age between 18 and 60 years. Exclusion criteria were history of cardiovascular heart disease; malignancy; uncontrolled hypertension; previous esophageal, gastric, pancreatic, small bowel, or large bowel surgery; tobacco use; or significant psychiatric disorder.
Collected data included weight, height, 3-h frequently sampled intravenous glucose tolerance test (IVGTT), body composition by dual-energy X-ray absorptiometry (DEXA), and plasma levels of FFA. BMI was calculated as weight (kg) divided by height (m2). DEXA was used to study body composition, and total fat and lean mass were measured. We used the minimal model analysis of Bergman to estimate the Si from the 3-h frequently sampled IVGTT . FFA were assayed by an enzymatic colorimetric method.
The LRYGB procedure was performed using a laparoscopic five/six-port technique. We transected the jejunum at 50 cm distal to the ligament of Treitz and performed a stapled side-to-side jejunojejunostomy anastomosis, creating a 100-cm Roux limb. We then created a 15-ml proximal gastric pouch, and performed an ante-colic, retro-gastric Roux-en-Y gastrojejunostomy with linear stapler technique.
Patient characteristics were summarized using mean ± standard deviation (SD). Pre- and postoperative variables were analyzed by two-sided paired sample Student’s t test. Pearson’s correlation test was used to determine the association between changes in variables. The SPSS statistical software program (version 20) was used for all analyses. p values of <0.05 were considered to indicate statistical significance.
Change in postoperative variables correlated with insulin sensitivity
Correlation with insulin sensitivity
Body mass index
43.4 ± 4.3
31.2 ± 4.6
p = 0.001
p = 0.12
Total fat (kg)
66.7 ± 82.1
27.0 ± 46.2
p = 0.03
p = 0.01
Free fatty acids (μmol/L)
765 ± 251
611 ± 197
p = 0.03
p = 0.31
As shown in Table 1, postoperative changes in Si significantly correlated (Pearson’s r = –0.53, p = 0.01) with change in total body fat, but not with changes in plasma FFA (Pearson’s r = –0.22, p = 0.31).
We have demonstrated that patients with T2DM have a significant decrease in BMI, FFA, and total fat mass and a significant increase in Si 12 months after LRYGB. We have also found a correlation between the increased Si and the decrease in total body fat measured by DEXA 1 year after LRYGB. However, interestingly, and according to the fact that levels of FFA do not mediate the association between adiposity and Si , we have found that 1 year after LRYGB there is no correlation between the increased Si and the decrease in FFA.
We have not found any studies in the literature reporting a relationship between decreased FFA levels and improved Si in the long term after LRYGB.
As highlighted by Miller et al. , in spite of the fact that FFAs have been shown to be associated both with measures of adiposity (BMI, visceral adipose tissue [VAT], and subcutaneous adipose tissue [SAT]) and with Si, this association is not mediated through FFA. They found that adiposity measures explained only approximately 1 % of the variance in FFA, arguing that adiposity is not a strong predictor of FFA in our population and that therefore we should not expect circulating levels of FFA to mediate the relationship between adiposity and Si. Moreover, they underlined how levels of obesity may not strongly correlate with levels of circulating FFA due to the influence of several other factors, such as physical activity, dietary intake, overall FFA trafficking, and metabolism. Miller et al.  did not find that increasing levels of FFA mediated the relationship between obesity and increased levels of adiposity and Si, despite demonstrating a very strong association between adiposity and Si. Likewise, we did not find a correlation between the increased Si and the decrease in FFA after LRYGB, despite demonstrating a correlation between increased Si and the decrease in total body fat after LRYGB. These results challenge the notion that the decreased levels of FFA after LRYGB mediate the improvement of IR and the resolution of T2DM after LRYGB, and indicate that other factors might play a more significant role in the relationship between obesity and Si (i.e. changes in adiposity and changes in gut hormones).
We have found a significant correlation between increased Si and the decrease in total body fat measured by DEXA 1 year after LRYGB. This correlation highlights the crucial role played by fat tissue in both the pathogenesis of obesity-related IR and its resolution after LRYGB, and justifies the relatively recent concept of fat tissue as an endocrine organ . A correlation between changes in fat mass and IR 1 year after bariatric surgery has already been pointed out . Different fat depots have different effects on reducing Si, with intra-abdominal fat having a greater impact than peripheral fat [30, 31], and with visceral abdominal fat having a greater impact than subcutaneous fat [32, 33]. Kelley et al.  suggested that plasma FFA levels might be a link mediating the relationship between VAT and skeletal muscle IR in obesity. In this scenario, an increased local production of FFA by VAT would mediate the IR seen in obese individuals: VAT has a high rate of basal lipolysis and responds poorly to lipolysis restraining insulin, resulting in inappropriately high delivery of FFA to the portal circulation that will lead to peripheral IR and beta-cell dysfunction . As mentioned earlier, Miller et al.  did not find that increasing levels of FFA mediate the association between increased levels of adiposity and Si. However, they found that FFA interact with VAT (but not with SAT) to influence levels of Si. They showed that, in individuals with lower VAT, those with low FFA levels had improved levels of Si relative to those with high FFA levels. Therefore, Miller et al.  added another step in our understanding of the role played by FFA in mediating IR in obesity. VAT has been proven to be more insulin resistant than SAT , such that levels of FFA do not additionally impact IR. Instead, in individuals with low VAT levels, increased FFA levels may additionally contribute to IR through the above-mentioned mechanisms of lipotoxicity. Unfortunately, we did not include in our study design a computed tomography (CT) scan for differentiating between intra-abdominal fat (VAT and SAT) and peripheral fat. We could have divided our obese patients in those with high VAT and those with low VAT and we could have looked for a correlation between decreased FFA levels and increased Si in the first group after LRYGB.
Other limitations of our study were that we did not collect data showing the duration of the diabetes prior to enrollment and that we did not perform an insulin suppression test in our obese patients in order to quantify the IR. It has been demonstrated that circulating plasma FFA levels in obese individuals are not a simple reflection of adiposity, but vary considerably as a function of whether the obese individuals are insulin resistant or insulin sensitive . Studying metabolic changes in obese individuals after sibutramine-assisted weight loss, McLaughlin et al.  showed that, despite comparable decreases in FFA levels with weight loss in both insulin-resistant and insulin-sensitive groups, the insulin response fell significantly in association with weight loss only in the insulin-resistant group. Based on this observation, if we had found a positive correlation between the decreased FFA levels and the increased Si in the insulin-sensitive group after LRYGB, we could have speculated that, at least in insulin-sensitive obese individuals, decreased FFA levels after LRYGB play a role in the improvement of Si and T2DM resolution after LRYGB.
In conclusion, our study has demonstrated that 1 year after LRYGB there is a correlation between increased Si and a decrease in total body fat measured by DEXA and that there is no correlation between increased Si and a decrease in FFA levels. Since we did not divide our obese population based on high/low levels of VAT or based on their response to an insulin suppression test, our findings do not imply that a decrease in FFA level after LRYGB is without a role in mediating the improvement of Si and the resolution of T2DM 1 year after LRYGB. However, these data suggest that other factors produced by adipose tissue, such as adipokines, might play an important role in mediating obesity-related IR. Therefore, we believe that changes in adiposity, and consequently changes in adipokines, such as proinflammatory cytokines, leptin, adiponectin, and resistin, are likely the key players in determining remission of IR and T2DM after LRYGB. Studying the profile of these adipokines after LRYGB was beyond the scope of our study and further studies in this area are necessary.
None of the authors have conflicts of interest or financial ties to disclose relative to this study