Theoretical Gut Hormone Changes after Gastric Bypass

Theoretic Hormonal Impact of Laparoscopic Roux-en-Y Gastric Bypass Surgery

Roux-en-Y gastric bypass (RYGB) surgery is one of the most commonly performed bariatric procedures, offering significant long-term benefits in terms of weight reduction and remission of obesity-related conditions including type 2 diabetes. These changes are thought to be induced via a combination of mechanisms including reduction in stomach capacity and reduced absorption of fat, in addition to the restrictions placed on consumption of highly osmolar foods such as those high in simple sugars, which can trigger symptoms including nausea, vomiting and dizziness if ingested in excessive quantities. However, these factors alone do not fully account for the success of the procedure. Various hormonal changes have been observed following RYGB surgery, prior to significant weight loss, and it is thought that such endocrine effects could also contribute towards the mechanism of action in RYGB.

How May Gut Hormones change after gastric bypass?

Incretins and Peptide YY

The interrelationship between the gut and insulin-producing pancreas, termed the enteroinsular axis, is governed by a number of gastrointestinal hormones including glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). These hormones can also have a significant impact upon hunger and satiety, acting at a central and peripheral level to mediate appetite.

The appetite-regulating hormones GLP-1 and PYY are produced by L cells located within the distal gut, with secretion typically occurring within 15 to 30 minutes following food intake, triggered by absorption of nutrients from the intestinal tract. They inhibit hunger and increase satiety via a range of mechanisms including decrease in speed of gastric emptying, promotion of insulin release and inhibition of gastric acid secretion.

Obese individuals typically display a blunted rise in postprandial GLP-1 and PYY levels, possibly leading to increased food intake as a result of impaired satiety. Conversely, elevated levels of GLP-1 and PYY have been reported in individuals who have undergone RYGB surgery when compared to pre-surgical RYGB candidates, overweight, obese and non-obese individuals, and those undergoing other forms of bariatric surgery. There is evidence to suggest that increased speed of delivery of nutrients to the distal gut may be responsible for enhanced secretion of GLP-1 and PYY postoperatively. It has been suggested that elevated GLP-1 and PYY levels may contribute to the immediate decrease in appetite following RYGB surgery, and could also be responsible for postoperative changes in dietary preferences, typically leading to decreased consumption of fatty foods.

GIP is produced by the K cells of the proximal and mid-gut mucosa. Alongside GLP-1, it is classed as an incretin; a gastrointestinal hormone able to stimulate insulin secretion by the beta cells of the pancreas in response to enteral intake of carbohydrates and fat. GIP also stimulates insulin-dependent uptake of glucose and lipoprotein activity within adipose tissue. Both incretins are known to mediate pancreatic beta cell proliferation, whilst insulin resistance is associated with high circulating levels of GIP.

Diabetes is known to modulate the effects of incretins, through mechanisms that are not fully understood, with insulin secretion in response to GIP reduced and secretion of GLP-1 reduced. Studies of GIP in diabetic individuals are inconclusive as some show normal levels and others show elevated fasting and postprandial levels.

RYGB frequently leads to resolution or remission of type 2 diabetes, with blood glucose reducing significantly relative to preoperative values within a few days or weeks of surgery, before significant weight loss has chance to take place. It is therefore thought that glycemic control occurs as a direct result of surgery, rather than as a secondary outcome of significant weight loss. Two possible theories account for the success of RYGB in resolution of diabetes:

Enhanced GLP-1 and PYY levels may promote improved glucose tolerance and insulin secretion without directly impacting upon body weight and caloric intake. Alternatively, causing food to bypass the duodenum and proximal jejunum could inhibit secretion of an as-yet unknown factor implicated in the pathogenesis of insulin resistance and type 2 diabetes. This theory is supported by animal models but has yet to be proven.

Ghrelin

Ghrelin is an appetite-stimulating hormone, known to affect food intake, chewing time, taste preferences and food perception, in addition to stimulating growth hormone, cortisol and adrenaline. It is secreted centrally by the hypothalamus and peripherally by the gastric fundus, with levels peaking before food intake and dropping immediately after eating is initiated. Ghrelin is known to increase gastrointestinal motility and decrease insulin secretion.
Levels of ghrelin are lower in obese versus non-obese individuals, and increased ghrelin secretion has been reported in individuals who have lost weight through conventional dieting, suggesting a possible link between ghrelin and difficulty in maintaining diet-induced weight loss. There is some controversy regarding the role of ghrelin in post-RYGB weight loss; some studies have reported ghrelin reduction following RYGB surgery, but most have found either no significant change or a slight increase in ghrelin secretion in the long term.

Adipocyte Hormones

Leptin

Leptin is one of a number of protein hormones secreted by adipose tissue and is thought to play an important part in long-term energy balance, mediating appetite and metabolism. Leptin is implicated in the inhibition of glucose-stimulated insulin production and is therefore associated with insulin resistance.

Levels of circulating leptin within the body are proportional to adipose tissue mass, and decrease with weight loss, whether achieved via dietary interventions or bariatric surgery. It is thought that sustained exposure to high levels of leptin produced by excess adipose tissue can cause leptin desensitization, curtailing its ability to induce satiation in obese individuals.

Several studies have reported a marked decrease in leptin levels within a few weeks of RYGB surgery, prior to significant weight loss and exceeding those observed following restrictive procedures. This may be explained by the fact that a certain amount of leptin is also secreted by the stomach, which undergoes substantial alteration during RYGB surgery.

Adiponectin

Adiponectin is an anti-inflammatory adipocyte, thought to be a key mediator in the relationship between obesity and chronic inflammation. It also involved in glucose metabolism and can improve insulin sensitivity in the liver. It has been hypothesized that circulating levels of adiponectin may be predictive of insulin sensitivity, and there is some evidence to suggest that higher levels of adiponectin are associated with decreased risk of developing type 2 diabetes.

Most studies indicate a postsurgical increase in adiponectin, correlating strongly with weight loss and varying with respect to the specific procedure employed. There are also reports of individuals with normal glucose tolerance experiencing more pronounced improvements in adiponectin than those with impaired glucose tolerance or type 2 diabetes, in spite of equivalent weight loss. The majority of studies agree that adiponectin levels are highest following RYGB, which also delivers the greatest improvements in insulin resistance and type 2 diabetes.   

Reproductive Hormones

Male Fertility

Obesity is known to impact upon male fertility via its effects upon erectile function and sperm quality. Obese males typically have low levels of total and circulating testosterone and follicle stimulating hormone (FSH), and elevated estrogen, leading to the hypothesis that hormonal factors could account for the association between obesity and reduced male fertility. There is also evidence to support a role for leptin in maintaining reproductive health, with leptin receptors present within testicular tissue and on the plasma membrane of sperm.

Studies investigating the impact of weight loss upon male fertility have delivered divergent results, with some reporting increased levels of testosterone and others reporting no effect. Investigations into the effects of bariatric procedures upon male fertility have also produced confounding results, with some studies reporting negative effects upon sperm quality and others reporting increased testosterone, reduced estrogen and general improvements in sexual quality of life.

Following RYGB, decreases in estrogen and increases in free and circulating levels of testosterone have been observed relative to non-surgical controls. Improvements in conditions that can affect male fertility, including hypertension, diabetes and obstructive sleep apnea are also frequently reported following bariatric surgery. Whether the endocrine effects of a specific procedure confer particular benefits in terms of male fertility has yet to be determined.

Female Fertility

Obesity is a well-established risk factor for female infertility, anovulation and menstrual irregularities. Polycystic ovarian syndrome (PCOS), as characterized by anovulation in the presence of elevated testosterone levels and/or enlarged ovaries covered in multiple small cysts, is strongly associated with obesity and insulin resistance. Bariatric surgery can lead to improved fertility in women of reproductive age, with RYGB particularly effective in normalizing insulin levels in women with PCOS. However, the metabolic factors underlying both the pathogenesis of obesity-related female infertility and its resolution following bariatric surgery remain unclear.