Abstract
Bariatric surgery is widely used to treat obesity, and additionally improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide-YY (PYY) and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains hotly debated. Here we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1R) post-gastrectomy in lean humans using Exendin-9, or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery, but instead we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut, and is a key driver of enhanced insulin secretion.
Highlights
Bariatric surgery is widely used to treat obesity and is effective because it results in dramatic improvements in type 2 diabetes (Sjostrom, 2013)
Five post-gastrectomy patients were enrolled into a randomized, double-blind, placebo-controlled cross-over study, in which they received infusions of the glucagon-like peptide (GLP)-1 receptors (GLP1Rs) antagonist Exendin-9 or placebo on separate visits
peptide YY (PYY) concentrations were higher after Exendin-9 than after placebo (Figure 1I), mirroring the elevated glucagon-like peptide 1 (GLP-1) levels and likely reflecting that PYY and GLP-1 are released from the same EEC type (Billing et al, 2018; Habib et al, 2013)
Summary
Bariatric surgery is widely used to treat obesity and is effective because it results in dramatic improvements in type 2 diabetes (Sjostrom, 2013). Reduced plasma glucose after bariatric surgery can be attributed partly to loss of body weight and adiposity, which in turn improves insulin sensitivity (Sjostrom, 2013). Bariatric patients have elevated post-prandial insulin secretion, and there are increasing reports of bariatric surgery being used to treat type 2 diabetes in patients who are not severely obese (Pok and Lee, 2014), as well as of post-prandial hypoglycemia occurring years after surgery when increased insulin release occurs on a background of improved insulin sensitivity following loss of body weight (Salehi et al, 2018). Post-gastrectomy patients have elevated plasma glucagon-like peptide (GLP) 1, peptide YY (PYY), and insulin levels after an oral glucose tolerance test (OGTT), mirroring the endocrine changes seen in bariatric patients, but because these patients are not generally obese, the excessive insulin secretion is associated with significant rates of post-prandial hypoglycemia (Roberts et al, 2018b). Mice with global GLP-1 receptor (Glp1r) knockout, for example, exhibited similar weight loss and glucose tolerance to wild-type controls after vertical sleeve gastrectomy (VSG) (Wilson-Perez et al, 2013), whereas another group reported that mice with inducible b cell-specific Glp1r knockout had impaired insulin secretion and higher plasma glucose after VSG (Garibay et al, 2016)
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