Physiological and molecular responses to bariatric surgery: markers or mechanisms underlying T2DM resolution?

Abstract

Bariatric surgery is currently the most effective treatment for obesity and associated comorbidities, including rapid resolution of type 2 diabetes mellitus (T2DM). Although the weight loss itself has substantial impact, bariatric surgery also has weight loss-independent effects on T2DM. Several variations of bariatric surgery exist, including the widely studied Roux-en-Y gastric bypass and vertical sleeve gastrectomy. The success of both of these bariatric surgeries was originally attributed to restrictive and malabsorptive modes of action; however, mounting evidence from both human and animal studies implicates mechanisms beyond surgery-induced mechanical changes to the gastrointestinal (GI) system. In fact, with bariatric surgery comes a spectrum of physiological responses, including postprandial enhancement of gut peptide and bile acids levels, restructuring of microbial composition, and changes in GI function and morphology. Although many of these processes are also essential for glucoregulation, the independent role of each in the success of surgery is still an open question. In this review, we explore whether these changes are necessary for the improvements in body mass and glucose homeostasis or whether they are simply markers of the physiological effect of surgery.

Keywords: bariatric surgery; glucose metabolism; type 2 diabetes.

Figure 1.

Bariatric surgery, including both RYGB and VSG, has widespread effects on glucose homeostasis. Early responses to surgery include a reduction in basal glucose and insulin levels (and consequently HOMA-IR) and a reduction in basal endogenous glucose production, as indicated in both human and rodent studies. Although unexplored in humans, rodents also demonstrate an early postoperative improvement in hepatic insulin sensitivity. Peak insulin levels in response to a meal are greater after surgery but then rapidly return to baseline. Last, and only after significant weight loss, peripheral insulin sensitivity and thus glucose uptake are increased. Red arrows, end points that are reduced; green arrows, end points that are increased.

Figure 2.

The variability in the changes in postprandial gut peptide levels after RYGB versus VSG. In general, peptides secreted from the upper GI tract, such as ghrelin, CCK, and GIP, have variable reported changes after RYGB but are increased by VSG. In contrast, peptides secreted from the distal gut, such as GLP-1, GLP-2, oxyntomodulin, and PYY, are increased by both operations.

Figure 3.

Primary bile acids secreted by the liver are hydroxylated by the microbiome in the intestinal tract to yield secondary bile acids. In addition to emulsification of lipids, bile acids act as hormones by activating two different receptors. One is a nuclear transcription factor called FXR. Once activated, FXR produces FGF19/15 (human/rodent analog), which is secreted into the circulation. FGF19/15 then acts on downstream metabolic pathways to regulate glucose and lipid homeostasis. The other receptor activated by bile acids is TGR5. TGR5 is a G protein–coupled receptor that, within the intestine, is known to regulate GLP-1 secretion.