Mechanisms of gastrointestinal hormones and gastric bypass surgery in the treatment of diabetes
The hypoglycemic effect of gastric bypass surgery is also mediated by glucagon-like peptide-1 (GLP-1) in vivo. Glucose-dependent insulinotropic peptide (GLP-1) and GLP-1 are classic gastrointestinal hormones that can stimulate insulin secretion in vivo. In addition, GLP-1 can stimulate the proliferation of pancreatic β cells and inhibit their apoptosis in vivo. It can also indirectly improve insulin sensitivity.
Therefore, in the treatment of type 2 diabetes, therapies that can enhance the activity of the GLP-1 signaling pathway are very promising. Furthermore, GLP-1 can also delay gastric emptying and reduce food intake. GLP-1 is mainly secreted through the distal intestine after eating; this secretion response is partly caused by the direct stimulation of L cells secreting GLP-1 by intestinal nutrients.
After gastric bypass surgery, ingested nutrients can bypass part of the anterior ileum and reach the hind ileum more directly. The abundant nutrient filling of the distal ileum after meals can promote GLP-1 secretion. Several studies on jejunoileal bypass surgery have also shown that GLP-1 levels are higher both 1 year and 20 years post-surgery compared to pre-surgery levels.
Biliary-pancreatic bypass surgery can also allow food to reach the ileum via a similar shortcut. This procedure can also stimulate L cells to secrete hormones, and its effect on diabetes treatment is similar to that of gastric bypass surgery. A recent study on gastric bypass surgery evaluated the secretion of gastrointestinal hormones after surgery. The results showed that GLP-1 levels gradually increased at 1, 3, and 6 months postoperatively. A study by Le Roux et al. also showed that postprandial GLP-1 levels were elevated in patients who underwent gastric bypass surgery.
If other gastrointestinal hormones also show similar increases after gastric bypass surgery, it will help balance glucose and energy metabolism in the body. Recent studies suggest that tyrosine has an appetite-suppressing effect in humans and a weight-reducing effect in rodents; PYY is mainly a late-gut hormone, and plasma PYY levels in patients after gastric bypass surgery, especially after meals, are significantly elevated, which may help with weight loss.
In other surgeries that accelerate the transport of food to the posterior intestine, including extensive small bowel resections, PYY levels are elevated in both fasting and postprandial plasma 9 months to 20 years after the procedure.
**The Role of the Anterior and Posterior Intestinal Segments in Gastric Bypass Surgery for Diabetes**
While all bariatric surgeries help with weight loss and improve glucose metabolism, gastric bypass and bile-pancreatic diversion are the fastest and most effective in achieving these two ultimate results. More than 80% of patients experience long-term remission of diabetes after these two surgeries, especially in the initial postoperative period.
Unlike other bariatric surgeries, gastric bypass and bile-pancreatic diversion disrupt the continuity of the digestive tract, abandoning the absorptive function of the anterior intestinal tract. Some scholars speculate that the deprivation of hormone-active areas after gastric bypass surgery may be the main mechanism by which bariatric surgery treats diabetes.
As mentioned earlier, the effects of gastric bypass surgery on weight loss and maintaining glucose balance can be explained by the suppression of ghrelin secretion in the anterior intestinal tract postoperatively. Integrating ghrelin data with the anterior intestinal hypothesis, we can predict the following results: standard bile-pancreatic bypass surgery, because it preserves the ghrelin-dense gastric fundus of the digestive tract, is unlikely to effectively suppress ghrelin secretion; while duodenal transposition surgery, by removing most of the ghrelin-dense tissue, can significantly suppress ghrelin secretion.
Rubino and Marescaux conducted experimental studies using GK rats, and their results further supported the "foregut hypothesis." At the same time, the study separated the effects of gastric bypass surgery on the duodenum and proximal ileum from the effects of reducing gastric capacity on improving glucose tolerance.
One of the most interesting findings of this study was that, compared to the control group, despite equal body weight, the group undergoing gastrojejunal bypass surgery showed significantly improved glucose tolerance post-surgery. Neither the rosiglitazone treatment group nor the group that experienced significant weight loss due to strict food restriction achieved the same level of glycemic control as the gastrojejunal bypass surgery group.
This phenomenon suggests that food bypassing the anterior intestinal tract and reaching the terminal ileum earlier may play a role in blood sugar control through a mechanism that we do not yet fully understand, independent of weight loss. Researchers speculate that surgery may cause changes in gastrointestinal hormones, but the hormones that were initially thought to be altered have not shown significant changes in tests.
Glucose-dependent insulinotropic peptides (GIPs) are mainly produced in the foregut. Nutrient intake stimulates their secretion, and they promote insulin secretion in the body. Theoretically, gastric bypass surgery, which bypasses the foregut, should reduce GIP secretion. However, there is currently no consensus on the exact effect of bypass surgery on GIP; most studies suggest that postoperative GIP levels are lower.
Another possible mechanism, known as the "rear gut hypothesis," posits that the rapid arrival of ingested food in the rear gut obstructs the passage of ileal contents, leading to weight loss. The sudden increase in ileal contents inhibits gastrointestinal motility, gastric emptying, and the transport of food in the small intestine, thus preventing nutrient absorption. Like hormones, neural mechanisms are also involved in this response.
Following jejunoileal bypass surgery, basal and postprandial levels of PYY, GLP-1, vasopressin, and enteroglucagon all increase. After gastric bypass surgery, PYY and GLP-1 levels also increase. Enteroglucagon, a biomarker synthesized and secreted by L cells in the small intestine, also shows elevated levels after gastric bypass and bile-pancreatic diversion surgery.
As previously mentioned, the rapid entry of nutrients into the hindgut and subsequent stimulation of GLP-1 secretion seems to explain the hypoglycemic effects of RYGB, JIB, and BPD. Supporting the "hindgut hypothesis" are rodent studies in which part of the ileum was removed and spliced into the middle of the duodenum. This simple ileal insemination, without physiologically restricting the animals or causing malabsorption, resulted in significant weight loss. The theoretical basis for this is likely that the ingested nutrients quickly come into contact with the ileum, rapidly filling it and stimulating the secretion of ileal hormones.
Consistent with this mechanism, the repositioning of ileal interposition increases the levels of PYY, GLP-1, and glucagon, and slows gastric motility and emptying.
The mechanisms by which bariatric surgery improves glucose tolerance and reduces weight can be summarized as follows: ① It reduces stomach volume, resulting in a feeling of fullness early in the meal and suppressing food intake; ② It leaves the anterior intestinal tract unattended, inhibiting ghrelin secretion through some unknown mechanism, leading to long-term nutrient absorption disorders; ③ It accelerates the speed at which nutrients reach the posterior intestinal tract, causing the ileum to fill rapidly and stimulating the secretion of PYY and GLP-1. These two hormones can suppress appetite and promote insulin secretion in the body through secretin.
Some patients may experience dumping syndrome when consuming sugary foods after surgery. Besides the hypotheses mentioned above, many other gastrointestinal hormones are also unclear and related to diabetes treatment. Undoubtedly, elucidating the specific mechanisms by which bariatric surgery treats diabetes presents a tremendous opportunity and challenge for researchers.
Recently, the National Institutes of Health (NIH) launched a six-center longitudinal evaluation of bariatric surgery, aiming to address these questions over the next five years or longer. This study, along with others, holds promise for developing new drugs that can mimic some of the effects of surgery, ultimately allowing patients to avoid surgical treatment.