Multiple possible mechanisms by which bariatric surgery improves diabetes
Another mechanism by which bariatric surgery rapidly alleviates diabetes is the negative energy balance in the body after surgery. In the initial period after surgery, patients consume very little food, significantly reducing the burden on pancreatic beta cells. As they gradually resume normal eating habits after surgery, these patients have already lost weight and are in a negative energy balance, which helps improve glucose tolerance.
In summary, the mechanism of surgical treatment for diabetes can be summarized as follows: bariatric surgery reduces the patient's weight, which in turn increases insulin sensitivity, reduces glucotoxicity and lipotoxicity, and improves pancreatic β-cell function.
Another mechanism by which bariatric surgery can reduce weight is by altering the synthesis and release of gastrointestinal hormones in the body, which can affect the secretion and action of insulin. Ghrelin, also known as "appetite stimulant," is a hormone that can raise blood sugar levels in the body, and its levels are significantly reduced after gastric bypass surgery.
Exogenous injection of ghrelin stimulates the secretion of three stress-response hormones in the body, such as growth hormone, cortisol, and adrenaline, all of which counteract the effects of insulin. Furthermore, ghrelin inhibits insulin secretion even during periods of high blood sugar. In living hepatocytes, ghrelin directly inhibits insulin-mediated signaling pathways related to glucose metabolism.
Therefore, at least at pharmacological doses, ghrelin inhibits the secretion and action of insulin in the body, and long-term injection of ghrelin receptor agonists can lead to impaired glucose tolerance. If ghrelin can antagonize the physiological effects of incretins and inhibit the utilization of fasting and pre-meal peripheral blood glucose, then inhibiting ghrelin levels will help with glucose utilization. In patients undergoing bariatric surgery, lower ghrelin levels are also a factor in maintaining a lower weight.
A common feature of many patients with pathological weight loss, including those with advanced malignant tumors and cachexia, is elevated levels of ghrelin, a substance that stimulates weight gain.
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 various other surgeries that accelerate the transport of food to the hindgut, PYY levels in fasting and postprandial plasma are elevated 9 months to 20 years post-surgery.
The role of the anterior and posterior segments of the intestine 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, thus leading to weight loss. The sudden increase in ileal contents inhibits gastrointestinal motility, gastric emptying, and the transport of food in the small intestine, ultimately preventing nutrient absorption.
Similar to hormones, neural mechanisms are also involved in this bodily response. After 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 stimulates GLP-1 secretion, which seems to explain the hypoglycemic effects of RYGB, JIB, and BPD.
Supporting the "rear intestine hypothesis" are rodent experiments. In these experiments, part of the ileum was removed and reattached to 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 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 during ileal insemination increased levels of PYY, GLP-1, and enteroglucagon, and slowed gastric motility and emptying.