Weight and type 2 diabetes after bariatric surgery systematic review,value gbp eur,glucose levels and type 2 diabetes symptoms - 2016 Feature


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Understanding the Effects of Roux-en-Y Gastric Bypass (RYGB) Surgery on Type 2 Diabetes MellitusRaymond G.
Why there is this discordant finding between HOMA-IR measures and insulin clamp studies is unclear.
Scientists have found that weight-loss surgery has a dramatic effect on type 2 diabetes and can even eliminate symptoms. Some patients with type 2 diabetes may see an end to insulin injections (left) after having weight-loss surgery that involves stapling (right) the stomach. To treat type 2 diabetes, doctors usually recommend lifestyle modifications such as dietary changes and more physical activity. Doctors have performed bariatric surgery to help people lose weight since the 1950s, and for years they have observed that the operation has a beneficial side effect on patients’ blood sugar levels. Although scientists do not know what causes type 2 diabetes, figuring out why this surgery alleviates the disease could help them better understand it. Type 2 diabetes is a complex disease in which cells in the body are deaf to the crucial insulin signal in a process known as insulin resistance. Many people see diabetes as a disease that worsens over a lifetime, but bariatric surgery is changing that view. As a surgical resident, Rubino of Weill Cornell Medical College never planned to pursue a career in bariatric surgery.
In 1999, while trying to figure out ways to simplify a complicated procedure, Rubino came across some interesting literature in which the authors noted that their bariatric surgery patients’ diabetes seemed to disappear about a month after the operation. All comments are moderated, your comment will not appear on the site until it has been approved. I’m 27 I have heard many stories of this operation working I watched my grandma die from this disease.
I had a RNY Gastric Bypass one year ago, specifically hoping to get my Type II Diabetes under control.
The benefits of weight loss surgery for mildly obese people with type 2 diabetes can last at least five years, according to a new study.
It's still to early to say whether mildly obese people with diabetes live longer after weight loss surgery than those who receive non-surgical treatments, however. Weight loss operations, or bariatric surgery, use various methods to shrink the size of the stomach. Over the years, bariatric surgeries have proved effective for treating type 2 diabetes, but most studies were done in people who are morbidly obese, with a body mass index (BMI) of 35 or above. For the new study, researchers from Taiwan's Min-Sheng General Hospital used data collected since 2007 in a trial comparing two kinds of bariatric surgery - gastric bypass and sleeve gastrectomy - to medical treatments for type 2 diabetes in people who were mildly obese.
The average BMI among those who had surgery fell from 31 to 24.5 by the end of their fifth year in the study. Among those who had surgery, diabetes resolved completely in 36 percent and partially in 28 percent. The researchers also monitored patients' blood levels of hemoglobin A1c, which reflect blood sugar levels over time.
While the new study does not show a survival benefit or surgery after five years, there is evidence from a study of heavier people in Sweden that surgery does lead to a longer life, says Blackstone, of the University of Arizona College of Medicine–Phoenix. In the Swedish study, obese people who had bariatric surgery were about 29 percent less likely to die over 15 years, compared to a group who tried more conventional methods. Though the new study didn't show a benefit in survival among surgery patients, Blackstone said it's reassuring for people with a BMI under 35 interested in the procedure. Blackstone added that people and their doctors should start taking weight seriously once the patient's BMI falls between 27 and 30.
The information presented on this website is not intended as specific medical advice and is not a substitute for professional medical treatment or diagnosis.
While many consider Type 2 Diabetes (T2D) irreversible, fasting has also been long known to cure diabetes. So, yes, even gastric banding these 500 pound patients with 20 years of diabesity can reverse within weeks even before the weight comes off. Returning to the point that bariatrics is simply a surgically enforced fast, you can directly compare the effects of fasting and bariatrics. The reduction in liver size would make working in the abdominal cavity much easier, with better vision.
In the meantime, you could compare both sugar control and weight loss during the fasting period and also during the post surgical period.
If all the benefits of bariatric surgery accrue because of fasting, why not simply do the fasting and skip the surgery? The standard answer is that people cannot do the fasting without the surgical enforcement. Manage your email preferences and tell us which topics interest you so that we can prioritize the information you receive. AARP is a nonprofit, nonpartisan organization that helps people 50 and older improve the quality of their lives. Weight loss over 15 years between control groups (blue), gastric banding (orange), vertical banded gastroplasty (purple), and gastric bypass (green).3. Are there available studies that compare effective calorie restriction versus RYGB in terms of diabetes improvement? Although HOMA-IR is an index of insulin sensitivity, it may also be used as a surrogate for hepatic insulin sensitivity.
Relationship Between Obesity and Diabetes in a US Adult Population Findings from the National Health and Nutrition Examination Survey, 1996-2006. Reduction in Weight and Cardiovascular Disease Risk Factors in Individuals with type 2 diabetes: one year results of the look AHEAD trial.
Comparison of Glucostatic Pamaeters After Hypocaloric Diet or Bariatric Surgery and Equivalent Weight Loss.
Effect of Weight Loss by Gastric bypass Surgery Versus Hypocaloric Diet on Glucose and Incretin Levels in Patients with Type 2 Diabetes.
Propsective Study Of Gut Hormone and Metabolic Changes after Adjsutable Gastric Banding and Roux-en-Y Gastric Bypass.
Re-emergence of diabetes after gastric bypass after gastric bypass in patients with mid to long term follow up. Refractory and new-onset diabetes more than 5 years after gastric bypass for morbid obesity.
Improvement of Type 2 Diabetes Mellitus After Bariatric Surgery-Who Fails in the Early Postoperative Course? Now, researchers are attempting to find out what is behind this diabetes “cure” and are even looking for alternative ways to mimic the surgery’s results. But recently, the American Diabetes Association endorsed a new, more drastic treatment — bariatric surgery, also known as gastric bypass surgery. Many patients with type 2 diabetes, a disease in which the body can no longer regulate blood sugar levels, saw their diabetes disappear. The surgery focuses on an organ that has been somewhat neglected in diabetes research — the upper intestine — and suggests that the hormones secreted by this section of gut could contribute to the disease, and might even play a role in causing it. Francesco Rubino, chief of gastrointestinal metabolic surgery at Weill Cornell Medical College in New York City. Insulin is a hormone produced by the pancreas that helps the cells of the body absorb glucose, which is their main energy source. The surgery appears to have a powerful anti-diabetic effect that has yet to be replicated with traditional treatment methods.
Although he was studying under a clinician with a large bariatric surgery practice, Rubino was more interested in adrenal diseases — disorders caused by the improper production of hormones from the adrenal gland, which secretes stress hormones, such as cortisol and adrenaline. He thought back to the obese patient he had operated on that morning, “And in my mind, I say, well there’s no way this gentleman is going to be much leaner in a month,” Rubino recalls.
Performing operations on rats, he accumulated evidence that all pointed in one direction — the surgery was the cure.
I have a script from my doctor to get the surgery how ever my insurance calls it weight loss and will not help me pay for it at all. Robin Blackstone, a weight loss surgery expert who wrote an editorial on the new study in JAMA Surgery.
A BMI of 25 or higher indicates that someone is overweight, and people with a BMI over 30 are considered obese. Meanwhile, the BMI among those receiving non-surgical diabetes treatments stayed about the same at 29. In the medically-treated group, by comparison, diabetes resolved completely in only 1 percent and partially in only about 2 percent. Patients randomized to the gastric band showed a significant and pretty damn good drop in their fasting blood sugars. Her husband was so impressed that he also started our program and has recently come off all his insulin, too. Well, remember that there was still massive confusion about Type 1 and Type 2 diabetes back then. In a fascinating study, patients who were waiting to undergo bariatric procedures were given a period of fasting beforehand. Since many of these procedures are done laparascopically, being able to see better is a huge benefit. Since bariatrics is considered the heavy weight champ, this was a real David vs Goliath battle (Fasting vs Surgery). Brathwaite1 and Louis Ragolia3[1] Department of Bariatric Surgery, Winthrop University Hospital, Mineola, New York, USA[2] Department of Endocrinology and Metabolism, Winthrop University Hospital, Mineola, New York, USA[3] Department of Vascular Biology, Winthrop University Hospital, Mineola, New York, USA1. While most accurate in assessment of glucose uptake of in vivo systems, it requires experienced and skilled personnel often not readily available.
Therefore, one may observe there are more rapid improvements of hepatic insulin sensitivity than that seen with peripheral insulin sensitivity.
For this procedure, surgeons staple the stomach to make it into a small pouch and rearrange the gut so the middle portion of the intestines is connected to the stunted stomach. Because type 2 diabetes is highly correlated with obesity, doctors assumed that this outcome was due to the substantial weight loss patients experience after surgery. Investigating the mystery could also lead to new diabetes treatments that mimic the surgery’s effects, such as a device placed inside the intestine or drugs that target intestinal hormones. In people with type 2 diabetes, the cells can’t use the insulin, and glucose builds up in the bloodstream. This surgery has researchers all over the world turning to the gut for answers on what might cause or even cure the disease. After surgery, the average hemoglobin A1c level fell from about 9 percent to about 6 percent. While extreme, these surgeries have proven the point that the metabolic abnormalities that underlie T2D (hyper insulinemia, insulin resistance) can often be fully reversed after a short (weeks) period of intensive treatment with bariatrics. There are many hypotheses – which we will consider in a later post, but it is the sudden severe restriction of all calories that causes this beneficial effect.
How can this lady, with her 27 year history of T2D, suddenly reverse all her disease and become non-diabetic?
Fasting would not be particularly useful for Type 1, and type 2 was still quite unusual back then. In the interwar period, as people went back to their accustomed eating habits, it went back up. The second graph shows the overall ‘glycemia’ or the total amount of sugar in the blood over the day. How do you know that you cannot fast for an extended period of time if you have never tried it?
One such study by Plum et al demonstrated greater improvement in diabetes in RYGB subjects when compared to low calorie diets over three months [13]. The small body of literature that uses clamp data in gastric bypass subjects supports that insulin sensitivity in the post-operative period correlates with weight loss [31, 33], and therefore, is not a weight independent event in both diabetics and non-diabetics. It is possible glycemic variability is a precursor to the metabolic complication post-gastric bypass hypoglycemia. But recent studies show that many patients see their diabetes go away months before they lose the pounds. And scientists are taking this opportunity to reexamine what we know about this old disease.
In these rats, surgery to bypass part of the upper intestine caused a huge decrease in their blood sugar levels, meaning that the rodents were essentially cured of diabetes. Many early studies were done with the heavy-duty Roux-en-Y surgery, which is the heavyweight champions of surgeries. In fact, he thought that it was soobvious that fasting was helpful that studies would not even be necessary.
After the discovery of insulin in the early 1920’s, all the focus turned to it as the ‘cure’ for diabetes.
Therefore, it was decided to try a period of fasting for these patients before getting their actual surgery. Rather than the chronic and progressive disease that we have been promised, instead T2D turns out to be a treatable and reversible condition.
Both groups had similar amounts of weight loss, suggestive that RYGB has weight independent effects on diabetes.The surgical obesity procedure known as the gastric band may be perceived as a superior “control group” to dietary weight loss. Only Kashyap et al [34] demonstrated a slight increase of insulin sensitivity using clamp studies at one week following surgery for subjects that underwent gastric bypass as compared to gastric banding.
HOMA-IR and peripheral insulin sensitivity were assessed through clamp studies, with individuals undergoing RYGB one month following surgery by Lima et al [36]. Our laboratory is involved in trials studying this effect.There are a greater number of studies examining the changes of insulin resistance in those that undergo RYGB and caloric restriction. Here are their findings, which were presented at the annual meeting of the American Society for Metabolic and Bariatric Surgery.The scientists looked at remission of diabetes in 139 patients, ages 48 to 57, whoa€™d had gastric bypass surgery.
Now when the patient eats, food will bypass part of the stomach and the small intestine, and go straight to the middle of the gastrointestinal tract.
This paradox led some scientists to wonder if something intrinsic to the surgery itself was “curing” the diabetes. Eventually, however, the pancreas can’t secrete enough insulin to overcome the resistance, and the body is left with a lot of glucose that can’t get inside the cells. However, rats that received a pretend operation, or simply a restriction in diet, did not see significant changes in their diabetes. She had T2D for 27 years and had been progressively using higher and higher doses of insulin in an effort to control her blood sugars. It’s been over a year now, and she continues to be off all insulin and medications with a HgbA1C of 5.9%. This, from the guy that Harvard University used to name its world famous Joslin Center for Diabetes. Since T2D is essentially a disease of excessive sugar in the body, reducing intake of sugars and carbohydrates should cause less disease.
If you could somehow reduce this fatty liver and reduce their weight somewhat, the risk of surgical complications would be reduced. On both counts you can see that the fasting was actually significantly better than the surgery! The gastric band is an anatomically enforced form of caloric restriction and can be difficult to “cheat.” Diabetes remission in subjects who had the gastric band has been shown to be directly related to weight loss, and was superior to conventional therapy programs [8].
However, as with all control groups, it is unclear if the oral intake of gastric band subjects was equivalent to the RYGB study group. They demonstrated that there was no improvement of peripheral insulin resistance despite weight loss, although HOMA-IR did improve. There are far fewer studies comparing these two groups and assessing for differences in beta cell function. Why would scientists recommend such extreme measures for a disease traditionally treated with more subtle steps?
Similarly, when Rubino performed a different type of gut surgery on the rats, one that did not bypass the upper intestine and still allowed nutrients to flow freely across this area, he saw that the diabetes remained the same.
However, most of the interest in fasting disappeared as doctors focused on what would be their mantra for the next century – drugs, drugs, drugs. It contributes to significant morbidity and mortality including heart disease, stroke, cancer, arthritis and sleep apnea. However, prospective longitudinal studies comparing RYGB to gastric banding have demonstrated that RYGB promotes greater insulin sensitivity along with superior weight loss at one year [16]. Further molecular studies in rodent models that have undergone RYGB support the notion that insulin sensitivity is weight dependent. Dunn et al used more dynamic and definitive methods for assessing hepatic insulin resistance using hyperinsulinemic euglycemic clamp studies with isotropic tracers, while also collecting data to asses for peripheral insulin resistance. One study by Hofso D et al [50] compared RYGB to “intensive lifestyle intervention” as the nearest appropriate control.


High levels of glucose in the bloodstream can also damage some organs, including the kidneys and the heart, and can lead to blindness.
Then he set up a new set of experiments that strongly suggested that part of the upper intestine played a role in the disease remission. Additional other types of studies have validated the potency of RYGB on diabetes through the use of other controls.
GLUT4 mRNA expression in skeletal muscle and adipose tissue of rodents that have undergone RYGB, does not increase until 28 days after surgery [35]. They also demonstrated that there was also improvement in hepatic insulin sensitivity as compared to no improvement of peripheral insulin sensitivity at one month [37]. However, as expected, RYGB achieved superior weight loss, with significantly improved beta cell function. Patients try to control their glucose levels with diet and exercise, but some require insulin injections.
He once again performed a gastric bypass on rats and once again saw the diabetes disappear. One such study by Adams et al [17] was a large retrospective study of several thousand, comparing RYGB subjects to weight matched controls.
The reason for this requires further research.Although RYGB and insulin secretion will be discussed in a later section, there are few studies that have measured hepatic glucose output in subjects that have undergone RYGB. There are no available or appropriate weight matched trials to compare diet to RYGB on beta cell function.The anatomic and histologic changes brought on by RYGB on the pancreas are also not well studied, due to the inability to easily access pancreatic tissue. Results from various studies have shown that weight reduction significantly reduces the risk of developing T2DM in obese individuals [3], as well as improving glycemic control in those already with T2DM [4,5].
Because insulin clamp studies are the gold standard in assessment of peripheral insulin sensitivity, the rapid glycemic improvement seen immediately following surgery appears not due to increased peripheral glucose uptake. Dunn et al [37] demonstrated decreased hepatic glucose production using clamp studies as described earlier. The body of literature of known histologic or molecular changes within the pancreas that have been observed are restricted to rodent models, or those afflicted with post-gastric bypass hypoglycemia. Perugini said the findings seem to be saying that they key factor is how far along a persona€™s diabetes has progressed at the time the surgery was done.Scientists know that weight loss helps improve diabetes. Long term medical therapy for obesity is often unsuccessful for the majority of patients in clinical practice. Despite the overall lack of prospectively randomized control trials, there has been compelling data to demonstrate RYGB effectively treats hyperglycemia and the diabetic state. One may expect hyperinsulinemia, especially in the setting of a marked peak in the postprandial insulin level. Bariatric weight loss surgery has remained the most effective means of achieving and maintaining weight loss. Only in 2012 were the first prospectively, randomized, non blinded controlled studies made available, comparing weight loss surgery to medical weight loss therapy. Contrary to these findings, Camastra et al [33] showed no improvement of endogenous glucose production one week following surgery against BMI matched controls. However, if the AUC of postprandial insulin levels are unchanged from prior to surgery, it is difficult to assess what cellular changes would occur if the same quantity of insulin was made by the beta cell. Schauer et al [18] compared the RYGB and gastric sleeve surgical procedures to medical therapy in the STAMPEDE study (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently). Because of these discrepant findings, the precise characterization of how RYGB affects hepatic glucose output also requires additional studies.The clinical observation amongst practitioners in bariatric surgery is that in the immediate post-operative period after gastric bypass there is a rapid decrease of fasting glucose levels.
In rodents that have undergone RYGB, there has been a demonstrated increase in pancreatic beta cell area [51], less beta cell apoptosis [52], and increased beta cell proliferation [53]. The Roux-en-Y gastric bypass (RYGB) is a type of bariatric surgery that involves the creation of a smaller stomach with a connection to the middle portion of the small intestine, bypassing the duodenum and a portion of the jejunum (see figure 1).
Mingrone et al [19] compared RYGB and biliopancreatic diversion (BPD) procedures to medical therapy. However, dietary caloric restriction alone has been shown to decrease hepatic glucose output without affecting whole body glucose disposal [38-39].
In response to the nutrients, the gut is busy releasing hormones of one stripe or another, with a variety of effects on brain and body.A In one theory, called the a€?hindgut hypothesis,a€? the key factor after surgery is the faster delivery of food to farther-along stretches of small intestine.
The two studies had similar findings of greater “normalization” of glucose levels in the surgical patients as compared to medical therapy.
People who undergo RYGB often have a post-operative decrease in appetite, anatomically imposed caloric restriction, and healing gastrointestinal anastomoses that require smaller nutrient boluses to allow for healing. That leads to increased release of certain hormones, such as one called GLP-1.In another theory a€” the a€?foregut hypothesisa€? a€” whata€™s key is the fact that the foregut is bypassed. One limb, referred to as the alimentary or Roux limb, is where nutrient boluses pass from the stomach pouch.
However, there was still greater weight loss in the surgical groups, contributing to the greater glycemic improvement.
In caloric restriction, the improvement of the endogenous glucose production (EGP) appears to be due to reduced glycogenolysis [40].
Much may also be learned of how RYGB affects the pancreas by the associated complication known as post-gastric bypass hypoglycemia (reviewed further in”Antidiabetic effect gone too far? The other limb, which is the bypassed portion of the gastrointestinal tract, is known as the biliopancreatic limb.
Schauer et al [18] further demonstrated that the post-operative weight loss appeared to have no correlation with glucose control. This finding is consistent with a study by Isbell et al [30] demonstrating comparable liver improvements (HOMA-IR) between RYGB subjects and calorie restricted subjects.
Maugh II wrote about the various kinds of weight loss surgery in a 2011 Los Angeles Times article. Therefore, the rapid alterations in hepatic metabolism seen immediately following gastric bypass may be from calorie reduction alone and not alterations brought on by the surgery itself.Further molecular studies have supported the notion that RYGB does not induce a weight independent effect on peripheral insulin sensitivity.
Meier et al [54] demonstrated in human subjects who are afflicted with hyperinsulinemic post-gastric bypass hypoglycemia, the pancreatic beta cell area was not increased as compared to obese or even lean control subjects.
Note that lap band surgery, in which there is no bypass of bits of the small intestine, does not resolve diabetes until significant weight is lost. Most remarkably, many obese diabetic patients who undergo RYGB are relieved of their anti-diabetic medications in a matter of days. Time-dependent GLUT4 expression in skeletal and adipose cells in rodents after RYGB and weight loss was discussed earlier [35].
They did demonstrate increased beta cell nuclear diameter in those afflicted with post-gastric bypass hypoglycemia compared to BMI-matched controls, suggestive of altered insulin production and secretion. Before discussing the antidiabetic mechanisms behind RYGB, a further discussion of the meaning of diabetes remission will be explored.
Intramuscular lipid content has also been noted to decrease one year following surgery by as much as 44%, which also contributes to enhanced insulin action [41].
One may therefore hypothesize that the decreased weight in response to the elevated insulin levels in RYGB subjects may be the responsible factor that improves glycemic control. A seemingly simple concept, we wish to elaborate on the meaning of “diabetes remission,” as well as discuss the associated complexities. These observations alone suggest why peripheral insulin sensitivity is delayed and appears to be affected only by the presence of adiposity. Despite these studies, further characterization is needed to understand how the pancreas responds to RYGB in T2DM independent of weight loss. Alteration in gut hormone levels have been strongly implicated as a cause for the metabolic improvement seen in RYGB subjects, but has not clearly been associated with the changes in altered insulin sensitivity. Beta cell dysfunction is considered a hallmark of T2DM, often with hyperinsulinemia and gradual insulinopenia.
Roux-en-Y gastric bypass and remission of type 2 diabetes mellitusMany subjects who undergo RYGB surgery and have T2DM observe a rapid normalization of their glucose levels, leading them to believe they have been “cured” of their diabetes. The effect of GLP-1 on peripheral tissue has demonstrated some effect on glucose uptake in adipocytes and skeletal muscle cells [42-43]. The altered post-prandial insulin profile seen after RYGB suggests beta cell function has only been altered, and not necessarily restored to appropriate physiologic function.
Improvement or remission of T2DM was thought to be due to weight loss in obese subjects [3, 5]. While these authors feel the term “cure” is incorrect, we cannot deny, and in fact pleasantly enjoy, watching the marked improvement in hyperglycemia following surgery. However, the authors feel the effect of GLP-1 has more clinically significant effects on pancreatic function.
This was further supported by studies with gastric banding, a form of enforced caloric restriction [8].
The role of GLP-1 is discussed further in the section “Identifying anti-diabetic factors of gastric bypass.”It is of interest that RYGB and other weight loss surgeries have differential effects on insulin sensitivity and insulin secretion. Identifying anti-diabetic factors of gastric bypassAlterations of insulin secretion itself is a contributing factor that ameliorates the diabetic state in RYGB. However, clinicians began to observe that glucose levels were significantly lower in RYGB subjects as compared to weight matched controls [7].
Buse et al had [20] recently defined prolonged diabetes remission as hyperglycemia that is below the diagnostic threshold for diabetes for at least five years, while on no active pharmacologic therapy for diabetes.
The biliopancreatic diversion (BPD), a more malabsorptive surgery with a more extensive bypass, is often reserved for the super-obese population. Although malabsorption also likely contributes to the improved dysglycemia, there are other hormonal changes that are likely contributing to this effect.
The increasing number of diabetes remissions after RYGB surgery has caused practitioners to revisit the definition.Mingrone and Schauer’s studies included similar definitions of diabetes remission in their trials, although their studies were less than five years in duration. However, this surgery been suggested to improve glycemia through normalization of insulin sensitivity [44].
Several investigators have proposed various intestinal mediators that may induce euglycemia, none of which have fully explained the clinical potency of RYGB. This contrasts to RYGB, which we have discussed here, in that it does not appear to rely on insulin sensitivity for rapid improvement of hyperglycemia. Earlier studies suggested that exclusion of the proximal gut was responsible for the improvement of hyperglycemia, implying a potential “diabetogenic factor.” Rubino et al [55] was the first to support this concept, by performing a duodenal-jejunal exclusion in diabetic rodents known as Goto-Kakizaki rodents. These are hormones that are secreted by enteroendocrine cells from the stomach, pancreas, and small intestine.
We have demonstrated here that peripheral insulin sensitivity improves as a function of weight loss, independent of RYGB, whereas hepatic insulin sensitivity improves as a function of caloric restriction. This was a surgery that led to preservation of gastric volume, with a pure exclusion of proximal intestinal absorptive surfaces. Neural based mechanisms have also been implied as contributors to the glycemic improvement, although much is still not understood. The initial excitement of his findings surrounded the premise that there was greater glycemic control as compared to calorie restricted rodents, simply by removing a portion of the intestine without creating caloric restriction. This is a well accepted phenomenon seen with RYGB subjects, and is believed to contribute significantly to this improvement of hyperglycemia in diabetics.
Born from this procedure was the concept of the “foregut theory.” From this, it was perceived that there was a “diabetogenic factor” in this region of the intestine.
To better understand how RYGB affects those with T2DM, we will review the changes that occur with RYGB in key glucoregulatory organ systems within the body. Are the diabetic microvascular complications also reversed and should practitioners stop following these patients if they do go into remission? Effects of gastric bypass surgery on pancreatic functionT2DM is characterized by both peripheral insulin resistance, as well as pancreatic beta cell dysfunction.
However, this concept was later challenged by the “hindgut theory.” The “hindgut theory,” perhaps more popular, operated on the premise that there were factors in the distal intestine that became elevated and had potent anti-diabetogenic effects. In the ensuing sections, we will discuss in detail, the changes of peripheral insulin sensitivity and insulin secretion brought on by gastric bypass, and their effects on hyperglycemia.
If there is complete reversal, why not use the term “cure?” Most important, has the characteristic pancreatic beta cell dysfunction reversed itself?
For this reason, understanding how RYGB affects the pancreas may allow us to better understand why diabetes improves after the surgery. These are questions proposed by these authors, some of which will be addressed in later sections. The majority of available studies involve dynamic biochemical measurements involving nutrient challenges. Further support for this are studies performed with feeding tubes placed in the gastric remnant of the intestine following RYGB.
We will also discuss the role that caloric restriction and gut hormone elevation may have in this process. Despite these questions, it is very hard to ignore the potent clinical effect the surgery has on diabetes. The impetus for study of these nutrient challenges, such as mixed meal testing, is based on the link between RYGB and postprandial gut hormone hypersecretion [45].
Hansen et al [56] demonstrated that using gastric feeding tubes led to increased gut hormones, as well as via oral (jejunal) routes. For those physicians and health care practitioners who struggle with uncontrolled diabetic patients, it is a seemingly effective and attractive solution.
Exaggerated gut hormone secretion appears to occur because of the altered transit of nutrient boluses caused by the gastric bypass, and is a well accepted phenomenon.
The similar alterations in insulin sensitivity between the two nutrient routes suggest the exclusion of nutrients from the foregut is not significant.
Cumulatively, this will permit the reader to develop an understanding of the relationship of how RYGB affects diabetes.
The metabolic potency of RYGB has even been addressed by the International Diabetes Federation (IDF) in a statement published in 2011 [21]. Several gut hormones have been suggested to also alter insulin secretion, and are termed “incretins.” The incretin effect relates to the ability of an oral glucose load to result in an enhanced insulin response as compared to a similar intraveous glucose load.
Instead, distal gut factors such as GLP-1 may more likely be the cause.GLP-1 physiology will not be covered here in depth. The distal gut hormone GLP-1 has been shown to be primarily responsible for mediating this effect, although other possible contributing anti-diabetic factors have yet to be characterized.
Its anti-diabetic effect in gastric bypass has been demonstrated in rodent models that underwent RYGB [57]. While a compelling argument can be made for this, we caution practitioners that not all RYGB subjects experience diabetes remission.
There have been surprisingly few studies that have addressed the impact of RYGB on the release of insulin secretion and its relation to other gut hormones.
There are a small, but significant number of patients that have T2DM and undergo RYGB, but remain hyperglycemic post-operatively.
We will first characterize the pancreatic secretory alterations brought on by the surgery, and then further explain associated hormonal and pancreatic cellular changes.Le Roux CW, Aylwin SJ, Batterham RL et al.
Roux-en-Y Gastric Bypass (RYGB) and its weight independent effect on T2DMSince the early portion of the 21st century, there has been a growing interest in bariatric surgeries and their effect on ameliorating the diabetic state. In a retrospective review by DiGiorgi et al [22], as much as 24% of T2DM who had undergone RYGB had recurrence of their diabetes over a three year period, while a longer five year study demonstrated 31% recurrence [23]. Gut Hormone Profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Pories et al was arguably the first to describe remission of diabetes following gastric bypass.
Use of GLP-1 agonists or GLP-1 continuous infusions increased basal insulin secretion, often leading to an improved second phase of insulin secretion [58, 59]. He reported gastric bypass not only caused weight loss, it also led to normalization of blood sugars in over 80% of his diabetic patients [9]. Because fasting GLP-1 levels do not increase following surgery, many questions remain regarding its postprandial effects.
Initially, the normalization of blood sugars was thought to be directly caused by the weight loss. Higher BMI’s, age, prior use of antidiabetic medications, and male gender were identified as factors associated with diabetes recurrence [23, 24]. The majority of studies also demonstrate a postprandial rise of insulin concentration that has a higher and earlier peak than seen pre-operatively [32-34, 46-48].
Perhaps the most important evidence that there are other factors besides GLP-1 in RYGB that contribute to the anti-diabetic effect, is that the pharmacologic use of GLP-1 agonists have not led to the equivalent potency of RYGB surgery alone.
However, it has subsequently been noted that blood glucose control improves immediately following the surgery, prior to any significant weight loss.
A similar study in Chinese subjects demonstrated that diabetes duration, BMI, and fasting C-peptide were predictors for diabetes remission at one year. While this suggests a possible restoration of the first phase of insulin secretion, this remains unclear. The concept that weight loss alone was not the reason for diabetes improvement after RYGB was a paradigm shift in the world of weight loss surgery, as well as the world of diabetes.


These investigators were the first to suggest predictors and possible cutoffs in assessing the glycemic responses to RYGB. The insulin peak also does not appear to be as marked as the postprandial GLP-1 elevations. Roux-en-Y gastric bypass, satiety, and the central nervous systemThe importance in assessment of decreased caloric intake with diabetes remission has already been discussed, in particular those that undergo gastric banding [8].
Determining how to use RYGB in diabetes management is still in the early stages of development.
The insulin peak is typically followed by a rapid decrease of insulin and glucose levels following the peak. Similarly, the RYGB involves creation of a small stomach size, causing similar restriction. It is remarkable that subjects that undergo RYGB actually appear to have a markedly decreased appetite as compared to their gastric band counterparts. However, the insulin area under the curve (AUC), based on these prior studies, is either unchanged or decreased as compared to pre-operative measurements. Because postprandial elevation of gut hormones is a distinguishing factor of RYGB from gastric banding, investigation of their orexogenic and anorexogenic tendencies have recently begun to be characterized.
Figure 4 demonstrates an example of post-prandial insulin levels in subjects that underwent gastric band and RYGB, as compared to control obese and lean subjects. Earlier prospective studies generally demonstrated RYGB induced altered satiety [45, 60-62], although the field appears to be lacking trials that are appropriately controlled.The evidence continues to mount for this gut brain communication effect, with several biochemical mechanisms that affect neural signaling of hunger and satiety being discovered.
The SOS trial is one of the largest prospective data collections to date that studies the clinical effects of various types of bariatric surgery. Since 1991, the National Institutes of Health used both BMI and the presence of obesity-related comorbidities as the criteria for surgical weight loss.
The control obese subjects were matched to the pre-operative BMI of the surgical patients, and the subjects that underwent either operation had an equivalent post-operative BMI. Therefore, RYGB has effects on satiety that are independent of the physical limitations imposed by the formation of the gastric pouch. The SOS data demonstrates durable weight loss by as much 25% reduction at 10 years with various surgery types.
Here, RYGB subjects exhibit the largest post-prandial insulin peak as compared to the gastric band and the remaining non-surgical subjects. The effect gut hormones have on the neural circuitry are most studied specifically within the hypothalamus [63], with the balance of orexogenic and anorexogenic hormones. The greatest weight loss is observed with RYGB [6] as compared to gastric banding, and a modified restrictive surgery known as vertical banded gastroplasty, (see figure 3). Prime hormonal candidates for these changes include insulin, leptin, GLP-1, peptide YY (PYY), and ghrelin [61-62, 64-65]. Since SOS, additional studies of obese subjects that have undergone RYGB have verified that weight loss from the surgery is durable and long lasting [10, 11]. We have already pointed out that post-operative weight loss does not always seem to correlate with glycemic control [18].
Decreased insulin levels following RYGB was generally believed to be the case with the perceived notion that insulin sensitivity was improved.
While findings with ghrelin have been mixed, there is growing evidence that the other aforementioned hormones may play a significant role. While durability of the surgery continues to be validated in ongoing trials, its weight independent effect on diabetes was initially uncertain during the infancy of bariatric surgery. However, as mounting evidence shows that peripheral insulin sensitivity is not immediately improved, these alterations in insulin secretion may hold more significance.
This uncertainty was at least partially due to the absence of appropriate “control groups” in various studies. Potential changes in alpha cell secretion of glucagon was then investigated to see if that had a possible role in these glycemic changes, namely if levels were decreased.
Origins of these mediators come from multiple different organ systems, which subsequently affect neurons within the arcuate nucleus and other hypothalamic regions.
For instance, the SOS data demonstrated reduced incidence of diabetes in surgically treated groups, but this was compared to non-standardized medically treated groups [12]. Seeing such high rates of diabetes remission in a lower BMI range reinforces the concept of weight-independent effects of surgery on diabetes.
Medical weight loss therapy can be difficult to implement effectively, and therefore, comparison to surgical subjects is often imbalanced. As most obese individuals fall within this BMI range, clinicians may even consider recommending surgery at an earlier BMI. Why hyperglucagonemia would be present during the glycemic improvement seen after RYGB is unclear, and needs further studies to validate these findings.Based on the postprandial insulin concentration profile demonstrated in figure 4, the glycemic effects do not clearly show why there would be an improvement of hyperglycemia.
Research into these anti-obesity mechanisms for pharmacologic uses are still being investigated. Increasing evidence shows that BMI alone is not an adequate measure to predict successful health outcomes after RYGB. Available studies do not demonstrate consistently how postprandial glucose levels behave in response to these insulin secretory changes. Some have demonstrated significantly elevated postprandial glucose levels with a subsequent decrease [32], while others mostly show the postprandial decrease [8]. Roux-en-Y gastric bypass, type 2 diabetes mellitus, and the central nervous systemAutonomic nerve regulation has often been the target for pharmacologic weight loss therapy. We have mentioned that assessing for adequate beta cell function [25] could be used as criteria for successful diabetes remission. Inconsistency may have to do with varying nutritional content of test meals and timing after the surgery. Therefore, there has been renewed interest in the role of the vagus nerve within bariatric surgical procedures to determine its role in weight loss. Additional evidence has suggested that those who have most benefited from surgery have elevated insulin levels, or insulin resistance [28, 29]. Using other methods in assessment of glycemic changes with RYGB, continuous glucose monitoring (CGM) has revealed unusual patterns. The simultaneous improved cardiovascular effects observed from the surgery [28] may also highlight the intrinsic relationship between insulin resistance and cardiovascular disease, often referred to as the metabolic syndrome. In a group of RYGB subjects, CGM revealed increased glycemic variability using a calculation parameter known as “mean amplitude of glycemic excursions” (MAGE) [49].
An intact vagus nerve with RYGB appears to have a significant and improved effect on food intake and weight loss [70]. As clinicians and scientists, it is critical for us to evaluate the effects of RYGB surgery beyond simple weight loss. However, the beneficial effect appears to carry over to improved glucose metabolism that also appears to be weight independent. Obese and diabetic rodent models studies have demonstrated that hepatic vagotomy will worsen glucose metabolism [71-72]. In the remaining portion of this chapter we will characterize the basic driving forces for T2DM and how the surgery brings about an improved glucose effect. This further highlights the necessary role of the vagus for helping attain euglycemia via hepatic-mediated mechanisms. This is not without some conflicting studies such as by Shin et al [73], although their focus was on food intake, body weight, and energy expenditure.
Effects of gastric bypass surgery on insulin resistanceInsulin action has a key role in regulating glucose homeostasis, facilitating glucose uptake in various tissue types. The source of this neuroendocrine regulation may suggest that hepatic glucose metabolism is uniquely regulated by a hypothalamic source.Pocai A et al [74] demonstrated that activation of potassium-ATP channels within the hypothalamus appears to lower blood glucose through hepatic gluconeogenesis. Its inability to cause glucose uptake is believed to be a key step in the pathogenesis of T2DM. This was a significant advance in better understanding the mechanisms that may mediate hepatic gluconeogenesis. Similarly, insulin presence near the hypothalamus has also been demonstrated to suppress lipolysis [75], which directly affects insulin resistance and T2DM. Additional characterization of the hypothalamic and vagal mediated effects may also help us to better understand the role of the nervous system in glucose and lipid regulation. Glucose transport is maintained primarily through insulin-regulated glucose transporters, such as GLUT4.
Commonly proposed theories that may mediate insulin resistance include impaired insulin signaling defects, GLUT transporter dysfunction, as well as increased availability of circulating free fatty acids. PYY) may not only have anorexogenic effects that modify caloric intake, but they may also directly mediate glucose regulation via central nervous system mechanisms. Both environmental and molecular factors may contribute to the development of insulin resistance. Further identification of where gut hormone receptors exist are needed to better understand this potentially significant glucose-governing mechanism. Obesity, as an environmental source, is believed to be a very common contributor.Insulin resistance has been significantly observed at the level of the liver, skeletal muscle, adipose tissue, and pancreas. But it is skeletal muscle and adipose tissue that account for over 80% of total body glucose uptake.
Because the reversal of diabetes immediately following gastric bypass is so profound, an alteration of peripheral tissue insulin sensitivity was thought to be the mechanism for achieving normoglycemia.
Postgastric bypass hypoglycemiaPerhaps best described by the title of the article by Patti ME et al “Hypoglycemia following gastric bypass surgery-diabetes remission in the extreme?”[76] the condition of post-gastric bypass hypoglycemia has been an increasingly observed phenomenon.
With RYGB having superior weight loss, it has been well accepted that improved insulin sensitivity in surgical patients is also superior.
Contrasting mechanisms of how this occurs have been proposed, with the initial reports suggesting islet cell hyperplasia [77]. However, the timing of when peripheral insulin sensitivity improves has been an area of uncertainty.
However, follow up studies suggested there was no change in beta cell mass, although there was an increase in beta cell nuclear diameter [54].
Answering when peripheral insulin sensitivity begins after RYGB will also help to elucidate if it is a weight independent event.The most frequently used measure of insulin resistance is the Homeostasis Model Assessment Insulin-Resistance (HOMA-IR).
The increase in beta cell diameter may be more of a function of increased nuclear transcriptional activity of insulin production. The ease of obtaining measurable glucose parameters have made this a popular method for quantifying insulin sensitivity. This would coincide with those afflicted with this condition may have hypersecretion of insulin. Several sources cite RYGB improves HOMA-IR from four days to two weeks following surgery in diabetic and non-diabetic subjects [30-31]. Hypersecretion of insulin at disproportionate levels to the decreased BMI following surgery may potentially lead to clinically significant hypoglycemia. In a non-weight controlled study, HOMA-IR was also decreased at three days following surgery [32]. If we recall the changes in peak of insulin secretion discussed earlier brought on by RYGB [32-34, 46-48], a comparison to BMI-matched subjects afflicted with hypoglycemia demonstrated a greater post prandial peak of insulin secretion [78]. However, these same sources demonstrate that HOMA-IR in RYGB subjects has comparable improvement to that of diet controlled subjects at similar time intervals while on calorie restriction [30-31]. This may lead to increased glycemic variability, which has been demonstrated in subjects who are afflicted with post-gastric bypass hypoglycemia [40]. While this is suggestive that RYGB may induce hypoglycemia via pancreatic mediated mechanisms, the question of the contribution of peripheral insulin sensitivity to hypoglycemia was answered by Kim et al [79]. These findings are suggestive that immediate changes in HOMA-IR following RYGB are possibly related to caloric restriction alone.
Using intravenous glucose infusions in BMI matched controls, Kim et al [80] showed that those who are afflicted with hypoglycemia demonstrated appropriate insulin secretion rates in response to intravenous glucose challenges.
Therefore, it appears the hypoglycemia is only brought on by ingestion of nutrient boluses which elicits an abnormal insulin response. While the response may be effective in mediating improved glucose control, it is unclear why some subjects develop hypoglycemia and others do not. Possible causes may have to do with prior history of diabetes and residual insulin resistance. Because of the increasing number of bariatric surgeries being performed, this is an area that is in urgent need of further study. Understanding how this condition develops will also likely shed light on how the surgery helps improve hyperglycemia.
Currently, our laboratory is involved with ongoing clinical trials to better understand the mechanisms behind this clinically significant phenomena.
The growing popularity of the bariatric weight loss surgery known as the sleeve gastrectomy is worthy of discussion. The procedure involves the removal of the antrum of the stomach, with a creation of a sleeve-like structure. The potency of the sleeve gastrectomy on diabetes has been demonstrated by Schauer et al [18]. While the improvement of hemoglobin A1c reduction was greater in those that underwent RYGB, the sleeve gastrectomy had a similar reduction of almost 3% at one year following surgery. The question remains if there is a weight-independent effect of diabetes improvement with this surgery?Earlier prospective studies of the sleeve gastrectomy, as compared to the RYGB, demonstrated that weight loss and glucose homeostasis was also similarly improved between the two [80-81]. However, they also demonstrated increased postprandial elevation of GLP-1, PYY, and insulin levels, although generally slightly less than RYGB. Short term (6 weeks) and long term (1 year) follow up demonstrated comparable GLP-1 responses to mixed meal challenges [82-83].
The alterations of GLP-1 and PYY secretion is confusing and remains not well explained within the literature. RYGB has been associated with earlier transit of nutrients to the distal intestine, stimulating an elevation of the “hindgut hormones.” These elevations may potentially explain the glycemic improvement. However, these observations do not explain why the postprandial hormone elevation with the sleeve gastrectomy occurs. The literature still lacks a satisfactory mechanism of the stimulating mechanism for these elevations. However, the clinical effects of the sleeve gastrectomy on diabetes remains difficult to ignore.
The mechanism remains elusive, and many questions remain about the effects of the sleeve gastrectomy. The lack of an intestinal bypass prevents associated malabsorption and the plethora of micronutrient deficiencies. Despite these appealing features, we would advise practitioners to evaluate their patients carefully when considering a bariatric surgical method for weight loss. Little to no long-term studies are currently available on their clinical potency, and the lack of understanding how the surgery affects diabetes should give practitioners pause.
However, the surgery is still very promising with apparently little metabolic complications. The authors are excited about the growing role of the sleeve gastrectomy in weight loss procedures.6. ConclusionRYGB unquestionably ameliorates the hyperglycemic state in many of those with T2DM. Many who undergo the surgery gain significant health benefits, and achieve remission of their diabetes. Investigators are attempting to understand the clinical impact of diabetes remission on RYGB patients, as well as the mechanism of how this is achieved. The improvement of peripheral insulin sensitivity appears to be weight dependent, while hepatic insulin sensitivity seems to be a function of caloric restriction.
However, alterations in pancreatic function are reflected in the robust postprandial insulin secretion profile, and appear to be a direct result of RYGB.
Understanding the condition of the pancreas’ endogenous insulin producing ability and the whole body insulin resistance may allow us to predict who will achieve diabetic remission.The increasing clinical phenomenon of post-gastric bypass hypoglycemia may be a result of an undesired overenhancement of the alterations brought on by surgery. This condition needs further study to better aide those afflicted with this potentially debilitating condition.
As a possible alternative, the sleeve gastrectomy may potentially be an alternative weight loss surgery that appears to have lesser metabolic complications than are associated with RYGB. However, understanding of how it mediates its effect on diabetes is still not understood, and also is in great need of additional research.7.



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Comments

  1. Raul_505

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    31.07.2014

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    31.07.2014