Exploring Bariatric Surgery’s Impact on Weight Loss and Diabetes: Sodium and Glucose Receptor Modulation

Abstract

Sodium-glucose cotransporters (SGLT) and glucose transporters (GLUT) have been shown to influence diabetes management by modulating glucose uptake by the intestine. Therefore, alterations in gastrointestinal anatomy during bariatric surgery can change SGLT and GLUT receptor activity. These changes offer an additional mechanism for weight loss and may explain the differential impact of the various bariatric surgical procedures. This review examines the current literature on SGLT and GLUT receptors and their effects on weight loss through genetic studies, pharmacologic inhibition, and how SGLT/GLUT receptors impact surgical physiologic modulation. A better understanding of Type I sodium-glucose cotransport receptors (SGLT-1), GLUT-2, and GLUT-5 could provide insight for improved procedures and allow us to determine the best method to tailor operations to a patient’s individual needs.

INTRODUCTION

In the context of glucose absorption from the gastrointestinal tract into the vascular system, two distinct mechanisms exist: sodium-glucose cotransporters (SGLT) and glucose transporter (GLUT) receptors. Among these mechanisms, the SGLT receptors represent the predominant mode of glucose uptake into circulation.

SGLT RECEPTOR

There are 12 different members of the SGLT family, among which the SGLT-1 receptors are the primary mode of glucose uptake into the systemic circulation. These receptors are primarily expressed on the enterocytes of the small intestine, with a higher concentration observed in the duodenum and proximal jejunum.1,² However, SGLT-1 expression has also been found in other tissues such as the trachea, kidney, heart, brain, testes, prostate, pancreatic α cells, and the L and K cells of the intestine.³

SGLT-1 receptor works in conjunction with sodium (Na) ion gradient to actively transport glucose across the apical membrane of enterocytes. During this process, two Na ions and an SGLT-1 receptor cooperate to transport one glucose molecule across the enterocyte apical membrane. Once inside the enterocyte, the glucose molecule is transported into the systemic circulation through facilitated diffusion via GLUT-2 transporters.

THE ROLE OF Na

The role of sodium ions is critical in driving glucose transport across the apical membrane of enterocytes. Interestingly, the Na ions that are required for this process do not originate from the diet. Instead, research by Baud et al. suggests that the necessary Na ions are sourced from the bile and, to a lesser extent, the fundus of the stomach.⁴

Studies investigating the effects of Roux-en-Y gastric bypass (RYGB) in rats have shown that the luminal content of Na in the alimentary limb is negligible despite the presence of food, leading to reduced carbohydrate digestion in Roux limb due to a lack of Na ions.⁴ Moreover, Cavin et al. further elaborated on the role of Na in glucose absorption by studying glucose absorption before and after sleeve gastrectomy (SG).⁵ They noted that post-SG rats exhibited decreased glucose transport, which they attributed to a decrease in sodium bicarb secretion from the fundus of the stomach. Thus, fundus resection reduces available Na for glucose transport through SGLT-1 receptors.⁵

The major endogenous sources of Na in the body are bile and gastric juices. The stomach produces approximately 1.5 L per day of gastric fluid, which contains a Na concentration of 45 meq per liter. Thus, the total Na secretion from the stomach is 67.5 meq on average per day. In addition, the liver produces approximately 600 mL of bile per day, which has a Na concentration of 145 meq/L, contributing 87 meq for Na utilization for glucose absorption. Thus, the bile contributes 56%, and the stomach contributes 44% of the daily Na utilized for glucose absorption.^6–8

Since SGLT-1 and Na are central to glucose metabolism, Albaugh et al. decided that, in theory, bile acid diversion to the distal small bowel should promote weight loss without intestinal division. Using mice, they created an anastomosis from the fundus of the gallbladder to the ileum of the small intestine and ligated the common bile duct right below the gallbladder. This procedure led to wild-type mice with no change in diet having statistically significant weight loss.⁹ This further enhances the idea that the withdrawal of Na from the proximal intestine leads to glucose malabsorption.

GLUT RECEPTORS

GLUT, notably GLUT-2 and GLUT-5, are the secondary but still significant receptors involved in glucose absorption. Unlike SGLT-1, GLUT-2 and GLUT-5 receptors facilitate the passive diffusion of glucose across cell membranes, driven solely by the concentration gradient.

GLUT receptors are extensively studied for their role in facilitating glucose absorption in the intestine. In a low carbohydrate meal, GLUT-2 and GLUT-5 receptors typically remain on the basement membrane, allowing for the passive diffusion of glucose into the systemic circulation. However, when intestinal glucose concentrations are high, GLUT-2 receptors are transported to the apical surface to increase glucose absorption beyond the capacity of SGLT-1, leading to a surge in absorption from a single meal.¹⁰ In mice, glucose concentrations below the Km of SGLT-1 cause GLUT-2 to disappear entirely from the apical membrane in the intestine.¹⁰ It is worth noting that GLUT-2 is evenly distributed throughout the intestinal tract and not localized to any specific section of the small intestine.

During prolonged exposure to high glucose diets, mice upregulate their expression of GLUT-2 mRNA, leading to increased glucose absorption following meals.¹¹ In mice with insulin resistance, GLUT-2 is transported to the apical membrane of enterocytes at higher levels than in control mice, contributing to rapid spikes in blood glucose.¹²

GLUT-5 is another important GLUT receptor involved exclusively in the absorption of fructose from the diet. Unlike GLUT-2, GLUT-5 is located on both apical and basal surfaces of enterocytes. It is highly concentrated in the jejunum, with little expression in the ileum and none in the duodenum.¹⁰ When mice are exposed to a high fructose diet, GLUT-5 mRNA expression is significantly upregulated compared to control mice.¹³ The role of fructose absorption in the development of metabolic syndrome is well recognized. Fructose can be metabolized similarly to glucose, or it can be transported to the liver, where it is phosphorylated by fructokinase. This metabolic pathway leads to the formation of citrate and uric acid, which can inhibit fat oxidation, encourage lipogenesis, and promote insulin resistance.

THE ABERRANT EXPRESSION OF SGLT AND GLUT

Obesity is a complex metabolic disorder characterized by excessive adiposity and abnormal upregulation of the expression of SGLT-1, GLUT-2, and GLUT-5 receptors, which promotes fat accumulation.

Regarding SGLT-1, upregulation in obesity mainly occurs in the duodenum.¹⁴ In mice models, with an SGLT-1 receptor knockout, glucose, and galactose were not absorbed. Suckling mice showed no malabsorption symptoms until exposed to a high-glucose and galactose diet. Upon exposure to a starch and sugar diet, they experienced diarrhea, weight loss, and mortality within 7–12 days.2,¹⁵

Similarly, humans with glucose-galactose malabsorption disorder have a genetic defect in the SGLT-1 receptor.¹⁶ At birth, these individuals experience intractable watery, hypernatremic diarrhea from lactose in human milk. Elimination of glucose and galactose leads to the cessation of diarrhea. These individuals are supplemented with fructose-based formula and live on a very low carbohydrate diet for their entire lives.^17,18

THE PHARMACOLOGIC MANAGEMENT OF OBESITY VIA RECEPTOR MODULATION

The use of SGLT-1 inhibitors as a strategy for weight loss has been previously investigated. Two distinct randomized clinical control trials evaluating licogliflozin, a dual SGLT-1 and SGLT-2 inhibitor, reported a significant 5.7% reduction in body weight, in contrast to the modest 1%–1% reduction seen with SGLT-2 inhibitors alone, which increases glucose excretion in urine.^19,20 Longer randomized clinical control trials demonstrated a modest weight loss with licogliflozin at 24 weeks.²¹ Additionally, sotagliflozin, another dual SGLT-1 and SGLT-2 inhibitor, was found to be associated with statistically significant weight loss.²²

There appears to be a correlation between SGLT-1 inhibition and dosage levels. In a 29-day study, greater and more frequent medication administration resulted in higher weight loss.²³ This finding is consistent with earlier studies which also reported approximately 6% weight loss.

In contrast, some randomized controlled trials have failed to demonstrate a statistically significant difference between SGLT-1 and SGLT-2 combined inhibition and SGLT-2 therapy alone. In a 12-week study comparing licogliflozin (dual inhibitor) and Empagliflozin (SGLT-2 inhibitor alone), both drugs were found to cause significant weight loss, but no significant difference was observed between the two treatments. However, it is important to note that SGLT-1 inhibition is associated with various side effects, such as osmotic diarrhea, renal tubular dysfunction, and nephrocalcinosis.^16,24

SGLT-1 receptors are also found in high concentrations in enteroendocrine cells, particularly L and K cells. L cells are primarily found in the distal jejunum, ileum, and colon. They secrete GLP-1 and PYY. K cells are mainly found in the duodenum. They secrete GIP.²⁵ The activation of SGLT-1 results in the secretion of GLP-1, PYY, and GIP. In a study involving mice with removed SGLT-1 receptors, glucose gavage failed to trigger GIP secretion and caused blunted early GLP-1 secretion.² In humans, administration of an SGLT-1 inhibitor followed by a glucose tolerance test resulted in lower levels of GLP-1 and GIP compared to control subjects.²⁶

THE SURGICAL MANAGEMENT OF OBESITY VIA RECEPTOR MODULATION

For many years, it was commonly believed that most bariatric surgeries facilitated weight loss through caloric restriction or fat malabsorption. However, this notation does not adequately account for the variation in weight loss observed between SG and gastric imbrication procedures of similar size and restriction.²⁷ Likewise, why do long-term studies show that alimentary limb lengths (Roux limbs) in the RYGB and duodenal switch do not affect outcomes?

SG is currently the most popular bariatric surgical procedure worldwide. Despite its relative simplicity in design, the weight loss and diabetes resolution outcomes associated with SG far surpass those achieved through simple caloric restriction. Notable, procedures such as an endoscopic sleeve or gastric imbrication, which rely solely on restriction mechanisms, do not yield similar outcomes. When viewed using the receptor hypothesis, the rapid weight and changes in diabetes resolution could be the result of a decrease in sodium available for SGLT-S receptors (from fundus resection), thus decreasing glucose uptake.^5,10,28 Thus, SG is truly a metabolic operation, while the imbrication and endoscopic sleeve are purely restrictive. This idea would also explain why bougie size does not seem to make a large difference in weight loss, as the sodium excreting portion of the fundus is almost entirely resected regardless of the bougie size. However, the SG long-term success is less than either the RYGB or single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S), which makes sense since all the SGLT-1, GLUT-2, and GLUT-5 receptors have not been bypassed, and you have only decreased the sodium needed for glucose absorption by at most 44%.^29,30 Furthermore, the GLUT-2 and GLUT-5 receptors will upregulate through time to compensate for the lack of glucose absorption from SGLT-1 receptors. This explains the higher long-term failure rate when comparing SG to RYGB.

The SADI-S is a novel bariatric surgical procedure developed to simplify the technical complexity associated with the traditional BPD-DS. One of the rare complications of SADI-S is diarrhea. Contrary to popular opinion, diarrhea following SADI-S is not necessarily related to fat malabsorption. Rather, it appears that the primary underlying factor is the interaction of simple carbohydrates with the gastrointestinal microbiome.

The pathophysiology of diarrhea in SADI-S patients appears to be comparable to those with defective or inhibited SGLT-1 receptors, wherein carbohydrate intake leads to diarrhea and malabsorption.^21,24 In SADI-S, almost all of the small bowel, except for the distal one-third, is bypassed, which has a minimal concentration of SGLT-1 receptors (predominantly present on L cells) and no GLUT-5 receptors. Additionally, the SADI-S has further reduced sodium available for carbohydrate absorption with the performance of the fundectomy and the bile salt resorption in the long common channel. As a result, when patients who have undergone SADI-S consume a large amount of carbohydrates, a receptor overload occurs, and a significant amount of carbohydrates remain unabsorbed. The unabsorbed carbohydrates move to the colon and are metabolized by colonic bacteria, resulting in flatulence and osmotic diarrhea.

The RYGB procedure works in many ways different than SADI-S, which explains its long-term weight loss inferiority. Specifically, in RYGB, all the sodium produced by the stomach and bile salts are available for SGLT-1 receptors that are exposed to glucose, since the fundus is not resected and typical biliopancreatic limbs are 50 cm in length, not giving enough length to have much bile salt reabsorption. This operative effect is demonstrated by the direct proportionality of long-term outcomes of RYGB to biliopancreatic limb length.³¹

To further support the bile salt absorption hypothesis, Baud et al. used a minipig model of RYGB. The study revealed that immediately after an RYGB procedure, glucose absorption occurred only in the common channel and not in the alimentary limb. They also found that the uptake of glucose was fully restored in the portions of the intestine exposed to bile.⁴ The reasons for this are simple. Most of the sodium required by SGLT-1 to move glucose across the enterocytes is found in bile or comes from the fundus. As there is no Na for the glucose to enter the enterocytes, it waits until the common channel, where it is exposed to SGLT-1, and Na to finally be absorbed.

GLUT-2 and GLUT-5 also play a role in long-term weight loss after RYGBP. The standard 150 cm Roux limb and 50 cm BPL limb do not bypass the jejunum, only the duodenum. Therefore, the GLUT-5 receptors are left totally in contact with the flow of food thus; fructose absorption remains intact in the RYGB, while in the SADI-S with a 300 cm common channel, the GLUT-5 receptors are totally bypassed. Also, since GLUT-2 receptors are found equally throughout the small bowel, the RYGB has more exposure to them than Duodenal Switch-based procedures.

Another factor in long-term weight loss failure is the upregulation of the GLUT-2 receptors in the Roux limb of gastric bypass patients. We can see this example using dumping syndrome. Initially, surgeons postulated that the cause was related to central neurochemical or neurohormonal responses. If true, you would expect that dumping syndrome should follow shortly after surgery. However, it usually presents a year or more from the index surgery. This demonstrates the upregulation of glucose receptors and that there are translational changes in the Roux limb. Exposure to repetitive stimuli from food alters genetic expression to upregulate these receptors. This was demonstrated in 2014 by Nguyen et al. when the biopsied Roux limb and controls showed that SGLT-1, and GLUT-2 receptors were upregulated in Roux limbs.³²

While emphasizing the significance of the pathways delineated in this paper for weight loss, it is imperative to acknowledge that our assertions rest predominantly on inferences drawn from basic science articles rather than direct studies involving weight loss patients. An illustrative instance of this inference is evident in the disparate rates of diarrhea observed between SADI-S and BPDDS. This discrepancy may be attributed to a reduction in the number of SGLT-1 and GLUT-2 receptors. However, it is essential to underscore that our conclusion is based on inference rather than direct proof.

CONCLUSIONS

In conclusion, recent research on SGLT-1, GLUT-2, and GLUT-5 receptors in the intestine has shed new light on the mechanisms underlying weight loss after bariatric procedures.

Different weight loss procedures can now be characterized as having a low or high degree of carbohydrate malabsorption. These effects may explain part of an intricate web of reasons for weight loss. These results may allow surgeons to offer different solutions to weight loss plateaus. First among these would be the introduction of an SGLT-1 inhibitor after SG or GBP failure. Second, developing a simple bile acid diverting procedure could also have the same effect on Na as a SADI-S. Third, an SGLT-1 inhibitor with a longer common channel SADI-S to decrease the incidence of vitamin malnutrition while retaining similar long-term efficacy could be developed.