Gastrointestinal Hormones and their Relationship to Bariatric Surgery

| April 17, 2009

by Daniel J. Rosen, MD; and Alfons Pomp, MD, FACS

Introduction
When most of us learned about gastrointestinal physiology, cholecystokinin was an enzyme. It turns out that it is actually a powerful endocrine hormone as well. The gastrointestinal (GI) tract produces dozens of peptides that enter the circulation and cause a variety of effects relating to nutrient acquisition and energy balance. Since many of these mechanisms have only been elucidated within the last decade, many practicing surgeons lack complete understanding of how these hormones work and how they may be altered by surgery.

As nutrients pass through the intestines and are brought into contact with the entero-endocrine cells lining the GI tract, a series of hormones are released. Upper intestinal hormones are released as soon as a meal’s contents enter the duodenum. Once nutrients reach the hindgut, additional hormones, originally termed the ileal brake, are released to increase satiation and improve nutrient utilization. Bariatric and metabolic surgeons in particular need a working knowledge of how specific hormones released by specialized entero-endocrine cells lining the GI tract can affect hunger, alter glucose control, and impact energy homeostasis.

In general, patients with obesity and type 2 diabetes tend to have diet-related chronic elevation of foregut and visceral fat hormones (like leptin) with end-organ resistance, usually from receptor down-regulation. This translates into high glucose-dependent insulinotropic peptide (GIP), cholecystokinin (CCK), and insulin levels, without the achievement of satiety or efficient glucose and lipid control. This is coupled with under stimulation of hindgut hormones. Altogether, this unbalances the system of energy homeostasis with increased food intake, an inability to deal metabolically with the resultant hyperglycemia and hyperlipidemia, and an exacerbation of unhealthy fat deposition.

Ghrelin
Ghrelin may be thought of as the hunger hormone. It has been identified to have a significant effect on nutrient acquisition and achieving a positive energy balance.[1] When injected directly, the hormone increases the amount eaten per meal, decreases the interval between meals, and promotes fat deposition. Ghrelin is produced mainly in the stomach, with the highest concentration of ghrelin-producing cells in the fundus. By design, ghrelin is a hormone that stimulates eating and is found to rise prior to the initiation of a meal. Ghrelin mechanically optimizes the stomach for maximal consumption, increasing gastric emptying and intestinal motility to improve nutrient flow. Ghrelin levels drop in response to ingested calories, but the system is primarily tuned to the presence of complex carbohydrates. Early in human evolution, diets consisted primarily of vegetable matter with less protein and rare fat supplementing the regular caloric intake. This led to a feedback mechanism that proportionally suppresses ghrelin less with consumption of fats than with equivalent amounts of carbohydrates. There are nutrient-sensor cells, which may be considered analogous to taste buds, distributed throughout the GI tract. These cells communicate with ghrelin-releasing cells in the stomach through a myenteric plexi of vagal afferent fibers.[2]

Ghrelin acts on more than just the stomach. It directly suppresses insulin release from the beta cells of the pancreas, and pancreatic ghrelin blockade improves glucose-mediated insulin release. The ghrelin effect on insulin negatively impacts the metabolism of ingested glucose and lipid loads, and can contribute to hyperglycemia and elevated triglyceride levels.[3] The current high fat/high protein/high sugar of the typical American meal maintains unnaturally high ghrelin levels, which may contribute to overeating. A high ghrelin level can promote long-term weight gain, as it competes with insulin, which itself is one of the central satiety hormones, at the level of the hypothalamus (Figure 1). Ghrelin reaches the brain through the blood and by ghrelin receptors on the vagus nerve to promote sensations of hunger and lower metabolism. The acquisition of nutrient-rich food has been wired into our pleasure sensors, and within the brain, ghrelin is also involved in the reward component of eating and other addictions.[4,5] For weight maintenance, ghrelin levels must be in balance with an array of peptides produced from the intestines, pancreas, and visceral adipose tissue (Figure 2). This allows calibration of hunger and appetite based on body levels of fat stores and the caloric density of the food ingested.

Ghrelin levels have been shown to rise above baseline with medical weight loss. As a powerful stimulus of hunger and a meal initiator, this can influence subsequent weight gain, and helps explain why diet-induced weight loss is so often unsuccessful.[6] Laparoscopic adjustable gastric banding (LAGB) also seems to increase ghrelin levels over time, in a weight loss-dependent manner,[7–10] though some studies are contradictory.[11] The sleeve gastrectomy, either as part of the biliopancreatic diversion with duodenal switch (BPD-DS) or as a stand-alone laparoscopic sleeve gastrectomy (LSG), achieves drastically lower circulating ghrelin levels by removing the majority of the stomach, including the fundus.

Ghrelin-producing P/D1-cells are found primarily in the fundus of the stomach.[12] The best-proven way to maintain lower ghrelin levels in the face of future weight loss is maximal gastric resection incorporating the fundus. This serves to supplement the restrictive effect of surgery with a profound decrease in hunger. Lowering functional levels of ghrelin has been shown to decrease basal insulin levels, enhance glucose-stimulated insulin secretion, and augment insulin sensitivity.[13] The changes in ghrelin following gastric bypass are not universally agreed upon. Ghrelin after Roux-en-Y gastric bypass (RYGB) seems to be lowered despite ongoing weight loss, compared to dieting, obese, or lean controls.[6,14] However, the gastric remnant still holds the potential for ghrelin production with central impact, either through the vagus nerve, if intact, or systemically. The eventual elevation of ghrelin post-RYGB to levels surpassing obese controls has been reported.[15] Suffice it to say, LSG seems superior to gastric bypass in terms of driving ghrelin to its lowest possible levels and maintaining the reduction of both fasting and post-prandial ghrelin long term.[16] A low ghrelin level may be the key to shift the balance from anabolism toward catabolism, and should be a desired consequence of any surgery designed to deal with the metabolic derangements of obesity and diabetes.

Cholecystokinin
Cholecystokinin (CCK) is produced by the I-cells of the proximal intestine and is released in the presence of complex proteins and fats. This sets in motion the mechanics of digestion by means of receptors throughout the GI tract, the gallbladder, the pancreas, and the brain.[17] CCK releases once food enters the duodenum, and causes the gallbladder to contract and release concentrated bile. This hormone is directly trophic to pancreas beta-cell health and function, and augments systemic insulin release.[18] CCK decreases gastric emptying and parietal cell acid secretion.[19] This may contribute to a feeling of fullness, but the effect is central as well. CCK induces satiation within the brain both via the blood and directly through the vagus nerve. The CCK-activated signaling within the vagus is opposed by ghrelin.[2] Exogenous administration of cholecystokinin decreases meal size. Antagonizing CCK receptors leads to increased hunger, meal size, and caloric intake in humans, likely because ghrelin signaling persists unopposed.[20,21]

CCK has not been effective for long-term weight loss because chronic elevation (as seen in high-fat diets or exogenous administration) rapidly leads to loss of its anorectic effects by receptor down-regulation and a decreased interval between eating.[22,23] The changes in CCK following bariatric surgery are indefinite, and CCK alterations are not likely to be a major contributor to weight loss. In one study following vertical banded gastroplasty (VBG), there was no change in fasting CCK levels, but a dramatic increase in CCK release after an ingested meal.[24] This is contrasted by a study by Kellum et al[25] on CCK after both VBG and RYGB that showed an insignificant decrease in CCK release in response to a mixed meal. Patients following jejunoileal bypass (JIB) showed an increased density of I-cells in the intestines proximal to the anastomosis.[26] It is unclear what, if any, changes affect satiation and weight loss.

Glucose-dependent Insulinotrophic Peptide
Glucose-dependent insulinotrophic peptide (GIP) is a hormone produced by K-cells located in the proximal intestine. GIP is released in the presence of simple, energy-dense nutrients like glucose and free fatty acids, and it promotes nutrient (energy) storage rather than satiety. During the evolution of our enterohormonal axis, the opportunities for consumption of energy-rich foods were rare, and therefore a hormonal response to prioritize fat and muscle deposition over fullness and meal termination would serve a survival benefit during subsequent periods of food shortage. While the name GIP glucose-dependent insulinotrophic peptide is descriptive, it fails to recognize the more clinically relevant role GIP plays in fat metabolism and weight deposition. GIP is known as an incretin, along with the hindgut hormone GLP-1, and as its name implies, it is trophic to pancreatic beta cells and enhances insulin release.[27] The GIP receptor is expressed on various extra-pancreatic tissues as well, including bone, intestine, heart, stomach, brain, and adipose tissue. [28,29] GIP up-regulates the GLUT4 glucose transporter in peripheral tissues and activates lipoprotein lipase and lipogenesis in adipose cells to clear the blood of fatty acids.[30,31] Interestingly, the absence of GIP signaling by receptor blockade appears to protect against obesity and diabetes in a genetically engineered animal model.[32]

Those suffering with obesity and diabetes often have a diet-induced, chronic elevation in GIP levels with peripheral tissue receptor down-regulation that is analogous to insulin insensitivity.[33] This likely contributes to the hyperglycemia and hyperlipidemia seen in these patients. Diet-induced weight loss only serves to increase the GIP response to a nutrient-rich meal.[34] This impairs weight loss attempts, as the body counters the perceived starvation by increasing nutrient deposition in central and peripheral stores. Rubino et al[35] have showed that the hyperglycemia and hyperlipidemia seen in the face of chronic GIP elevations in diabetic, obese patients is reversed by proximal foregut bypass. Laferrère et al[36] demonstrated improved GIP sensitivity one month after RYGB before significant weight loss occurred. Both RYGB and BPD-DS have been proven to produce a significant decrease in GIP levels.[37,38] Though the metabolic syndrome is most reliably reversed by bypass procedures, the role of improved GIP sensitivity secondary to foregut exclusion is difficult to tease out from the significant up-regulation of GLP-1 caused by increased hindgut delivery of nutrients.[39] GIP and other gut hormone levels are not significantly affected by LAGB.[40] LSG has been shown to achieve more than 50-percent resolution of diabetes in the short term.[41] However, because ghrelin is prodiabetic and hindgut hormones seem to be mildly upregulated after LSG, it is unclear to what extent GIP contributes. GIP receptor antagonist medications to treat obesity and diabetes are currently in development. In choosing an operation to reverse the metabolic syndrome, one that decreases circulating GIP levels and improves GIP sensitivity would be optimal.

Insulin
Not classically thought of as a gastrointestinal hormone, insulin is released by beta cells of the pancreas in the presence of nutrients within the duodenum and is up-regulated by both CCK and GIP. Insulin receptors are most abundant on muscle, fat, and liver cells, and binding insulin drives glucose and fatty acid into cells for energy utilization. Low insulin levels promote lipid utilization for metabolic needs. Though insulin is released to facilitate nutrient deposition, it also serves a counter-regulatory function by acting centrally as a satiety hormone. Insulin is a major stimulator of leptin release from visceral fat cells at a proportion to overall adiposity, and both insulin and leptin counter ghrelin to deactivate the hunger center and initiate satiety within the hypothalamus (Figure 2).[42] Like the other foregut hormones mentioned above, insulin is chronically elevated in the obese and type 2 diabetic patients. Beta cells in these patients function at near maximum production with an inability to produce the acute spikes necessary to handle a diet with high sugar and fat content. The chronic hyperinsulinemia leads to insulin resistance at target tissues via receptor down-regulation. In time, beta cell exhaustion leads to worsening diabetes and increasing exogenous insulin requirements.

The hyperglycemia and hyperinsulinemia seen in type 2 diabetes improves with diet-induced weight loss, but the improvement is more consistent and more dramatic following all types of weight loss surgery. Following LAGB, all insulin parameters including insulin resistance as measured by HOMA-IR improve, well before normalization of body weight.[43] Fasting insulin levels and the insulin response to a glucose load both improve significantly after RYGB and BPD-DS prior to any significant weight loss.[33] Any bariatric surgery that is successful in achieving weight loss will improve insulin levels and function, but total diabetes resolution (defined as cessation of oral hypoglycemics and exogenous insulin and/or a HA1C lower than 6.0) occurs following surgery in 48 percent of patients after LAGB, 84 percent after LSG, 84 percent after RYGB, and 99 percent after BPD-DS.[44,45] A 5.5-year longitudinal study showed that bariatric surgery was effective in preventing diabetes, making the progression from glucose intolerance 30 times less likely.[46]

The lower insulin level may be achieved through multiple mechanisms. Limiting oral intake of calories as a function of operatively induced restriction and satiation will directly lower circulating insulin levels. A decreased ghrelin level will improve ghrelin-related suppression of insulin secretion from beta-cells. Finally, the up-regulation of GLP-1, 50 times more potent an incretin than GIP, has a profound effect on all aspects of insulin production and secretion.[18] The incidence of metabolic syndrome, including hyperinsulinemia, hyperlipidemia, and insulin resistance, increases with higher BMI. Weight loss improves insulin sensitivity and restores the function of insulin as a satiety hormone, with sharp increases in response to glucose challenges registering centrally to limit food intake and an appropriate return to normal fasting levels soon after cessation of eating.[47]

Hindgut Hormones: Glugagon-Like Peptide (GLP-1) and Peptide-YY (PYY)
The “ileal brake” was recognized clinically as the strong feeling of satiation that developed once nutrients reached the hindgut. This phenomenon makes evolutionary sense because further ingestion of food in the presence of nutrients within the distal small bowel would only result in calorie loss in the stool. To prevent this, the hindgut L-cells within the terminal ileum and colon produce GLP-1 and peptideYY to stop ingestion and improve nutrient utilization. GLP-1 is a potent stimulator of insulin secretion and is trophic to beta cell function.[2] It is the hormone believed to play a key role in diabetes resolution after gastric bypass and duodenal switch, but is also likely to be the culprit behind the rare hypoglycemic hyperinsulimia reported after these operations.[48] Both peptideYY and GLP-1 have receptors in the central satiety and metabolism centers, where they exert strong effects to terminate hunger and increase the basal metabolic expenditure rate. Obese and diabetic patients seem to release less circulating GLP-1 and peptide YY in repsonse to a meal than their lean counterparts.[35,49] This is likely because many obese people are “early-intestine dominant” with an excessively long small bowel that is too efficient at processing and absorbing calories. This leaves little residual intraluminal nutrients downstream to stimulate the release of hindgut hormones.[50]

Many diet modifications and metabolic surgical techniques have relied on the up-regulation of GLP-1 and peptide YY to exert a strong satiating effect. Exenatide is the first of the antidiabetic drugs related to GLP-1 to receive FDA approval, and its use has shown improvement in diabetes as well as modest weight loss.[51] Intestinal resection or bypass in patients is accompanied by a GLP-1 and PYY surge to meal stimulus that contributes to decreased food intake and improved glucose homeostasis.[35,39] In a model of direct glucose delivery to the hindgut, the length of foregut bypassed directly correlated with degree of GLP-1 increase and ghrelin decrease.[52] Clinically, this correlates to operations with a “malabsorptive” component achieving greater overall weight loss and diabetes resolution.[50] Sleeve gastrectomy seems unique in that increased gastric emptying contributes to less mechanical breakdown of food and resultant greater hindgut stimulation than seen with other purely restrictive procedures.[16]

Conclusion
A working understanding of GI hormones and their roles within the gastrointestinal tract is important for a metabolic surgeon hoping to counsel patients toward the appropriate operation to address their disease. Obesity and metabolic surgeries initially were thought to restore balance to the system primarily by minimizing intake of excess calories through restriction or malabsorption. However, while these operations can limit the quantity of food consumed, they each bring on a different change in GI hormone profiles following surgery. As more enterohormonal mechanisms are discovered and understood, operations or drug therapies may be tailored to maximize the treatment of obesity and diabetes, achieving optimal results with minimal metabolic complications.

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Category: Metabolic Perspective

Comments (2)

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  1. Ann says:

    Son, 6’8″ tall, had bariatric surgery about 15 months ago. Now has orthostatic hypotension, headaches, speech impairment & hypoglycemia. His is a truck driver and needs to find help to get his life back to what it was pre-surgery. Has had numerous brain CT’s and MRI’s which reportedly are normal. Also has had many cardioloy studies, all which are normal.

    He could use some expert help, please

  2. Richard says:

    As a physician, I am shocked with regard to the lack of appropriate guidelines for post-bariatric surgical patients’ nutritional needs–something as simple as protein requirements–including what types of protein–and mumbo-jumbo about carbonated drinks, etc. I lay odds that your son is suffering from a disrupted metablosism, which will not be detected by MRIs or CT scans. I have tried to self-educate because my wife had a Roux-en-Y and has had severe weakness and muscle wasting in spite of whatever I can do to help keep protein intake up. However, you should be able to tell whether your son has lost too much of his own muscle by looking at him, and at least be certain his serum vitamin levels–folate, B12, Thiamine– as well as thyroid functions, an iron panel–TIBC, ferritin, Fe–are monitored. I would certainly have him seen by a neurologist who knows something about nutritional deficiencies, and if needs be, an academic biochemical geneticist. Good luck.