A Gut Check Explains Improved Glucose Metabolism after Surgery

Abstract

Biliopancreatic diversion (BPD) surgery leads to more frequent diabetes remission than Roux-en-Y gastric bypass (RYGB). In this issue, Harris et al. (2019) compare each surgery after careful matching for percentage weight loss and find the gut as a major site of difference between the effects of the two surgeries.

All metabolic operations improve glucose homeostasis by restoring insulin sensitivity in close relation to calorie restriction and weight loss following the surgery. Diabetes is more likely to remit after surgeries that lead to the greatest weight loss, such as biliopancreatic diversion (BPD) as compared to Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy, or adjustable gastric banding. However, RYGB, a procedure that excludes a portion of the stomach and the proximal intestine from the alimentary circuit, has been shown to lower glycemia more rapidly and to a greater extent than expected from weight loss alone (Laferrère et al., 2008). Numerous mechanisms of action have been proposed to explain this striking weight-independent metabolic effect (Laferrère and Pattou, 2018), but their respective clinical relevance remains unclear. Most hypotheses converge on the gut, as its surgical modifications differ vastly among bariatric surgeries.

In an elegant clinical study, Harris et al. (2019) compare the metabolic change after identical 20% weight loss following RYGB and BPD in two separate cohorts. Individuals, twelve in each group, were tested with state-of-the-art tracer studies, after a mixed-meal liquid test to assess β cell function and endogenous glucose production, and during a hyperinsulinemic-euglycemic clamp, to assess whole-body insulin sensitivity. Differences between surgeries, independent of weight loss, were identified.

While RYGB and BPD both have gastrointestinal diversion, they differ considerably in the length of the diverted intestinal segment. In BPD a much longer portion of the proximal intestine is excluded from the alimentary circuit and anastomosed more distally to the ileum (Figure 1 in Harris et al., 2019). Both BPD and RYGB are characterized by a reduced portion of intestine where ingested food and biliopancreatic chyme mix together. In BPD, this common channel measures only 50 cm, as compared to more than 300 cm in RYGB. Given the difference of each surgery on the length of intestinal exclusion, with BPD being greater than RYGB, the first difference noted by Harris et al. is, not too surprisingly, at the level of the gut, with a much slower rate of appearance of ingested glucose into the circulation and markedly blunted postprandial increment in plasma glucose, and consequently in insulin concentrations, after BPD than after RYGB. The distinct effect of gastrointestinal diversion on glycemia is inversely correlated with the length of the common limb; that is, operations with a shorter common limb like BPD (Mingrone et al., 2015), long-limb RYGB (Risstad et al., 2016), or one anastomosis gastric bypass (Robert et al., 2019) have a more pronounced effect on glucose metabolism when compared to classical RYGB. The blunted absorption of glucose likely results from a reduction of intestinal sodium-glucose co-transport activity, as ingested food travels in absence of the endogenous sodium contained in bile and pancreatic juice, as demonstrated in minipigs and humans (Baud et al., 2016) (Figure 1). This malabsorption is likely more pronounced for complex carbohydrates ingested as solid food (Baud et al., 2016), and documented for lipids by a flat post-prandial triglyceride profile after BPD (Greco et al., 2002).

Figure 1. Gastrointestinal Diversion Blunts Intestinal Absorption of Glucose by Reducing Intestinal Sodium-Glucose Co-transport Activity.

Ingested food travels in the absence of the endogenous sodium contained in bile and pancreatic juice (Baud et al., 2016). This effect is inversely proportional to the length of the common channel and therefore maximal in biliopancreatic diversion.

The second main difference, perhaps less expected under conditions of matched weight loss, is a 45% greater whole-body skeletal muscle insulin sensitivity after BPD than after RYGB. The difference between surgeries, not apparent with the raw data (Figure 6A in Harris et al., 2019), becomes significant after adjustment for baseline body mass index and glucose disposal rate (Rd). Of note are the clinically non-negligible differences between the two groups at baseline: patients in the BPD group were 14.8 kg heavier, had larger fat mass (+7%), and appeared more insulin resistant than patients in the RYGB group. Moreover, change in fat-free mass (FFM), an important determinant of whole-body insulin sensitivity, differed between surgery groups; FFM was ~4 kg lower after BPD than after RYGB. These baseline and post-surgery differences need to be taken into account in the interpretation of Rd, expressed per kg of FFM. Nevertheless, the chronic blunted post-prandial glucose and insulin response could well be the mechanism of superior effect of BPD on insulin sensitivity, as discussed by Harris et al. (2019).

A third significant difference between the two surgeries, not discussed by the authors, is the insulin clearance during the test meal, which increases twice as much after BPD than after RYGB. It would have been interesting to relate this to change in hepatic fat after the two surgeries.

No difference between surgeries was observed with regard to a change in β cell function. The degree of β cell glucose sensitivity, as measured by the slope of insulin response to increments of glucose, which is a good marker of β cell health (Ferrannini et al., 2003), may have differed between the two surgeries.

Metabolomic analyses of fasted and post-prandial blood showed a shift in metabolites after the two surgeries. Changes in fasted metabolites, likely related to weight loss rather than surgery type, were essentially similar after the two surgeries. The magnitude of the change differed between surgeries for only 14% of fasted metabolites (e.g., bile acids, trimethylamine N-oxide, eicosanoids, and amino acids). The post-prandial shift in metabolites after surgery, perhaps resulting mostly from surgical modifications of the gastro-intestinal track, differed between surgeries for 50 out of 216 metabolites. A greater rebound after initial suppression of free fatty acids, medium-chain acyl carnitine, and eicosanoids was seen after RYGB, possibly related to the more rapid rate of post-prandial appearance of nutrients. The suppression of post-prandial bile acids after BPD, opposite to the rise observed after RYGB, may be secondary to the blunted re-uptake of bile acids due to long intestinal exclusion. Other differences may relate to differential change in microbiome.

While these data are compelling, some limitations need to be mentioned. A three-compartment model to assess FFM, taking into account hydration-associated variance within patients with severe obesity after surgical weight loss, may have been more suitable than dual-energy X-ray absorptiometry for assessment of FFM, the main determinant of peripheral insulin sensitivity (Levitt et al., 2010). The choice of study participants without diabetes makes it difficult to address the main goal of the study; that is, to identify mechanisms of diabetes remission after these two surgeries.

In all, surgical weight loss with the gastrointestinal diversion of BPD and RYGB results in improvement in β cell function, insulin sensitivity, and insulin clearance. The superiority of BPD demonstrated in this elegant study confirms the essential role of the gut as a major determinant of glucose metabolism, as well as the importance of minimizing post-prandial glucose excursion in diabetes.