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Our studies were designed to understand the role of the gut hormones incretins GLP-1 and GIP on diabetes remission after gastric bypass surgery (GBP).
Morbidly obese patients with type 2 diabetes (T2DM) were studied before and 1, 6, 12, 24 and 36 months after GBP. A matched group of patients were studied before and after a diet-induced 10 kg weight loss, equivalent to the weight loss 1 month after GBP. All patients underwent an oral glucose tolerance test and an isoglycaemic glucose intravenous challenge to measure the incretin effect.
Post-prandial GLP-1 and GIP levels increase after GBP and the incretin effect on insulin secretion normalizes to the level of non diabetic controls. In addition, the pattern of insulin secretion in response to oral glucose changes after GBP, with recovery of the early phase, and post-prandial glucose levels decrease significantly. These changes were not seen after an equivalent weight loss by diet. The changes in incretin levels and effect observed at 1 month are long lasting and persist up to 3 years after the surgery. The improved insulin release and glucose tolerance after GBP were shown by others to be blocked by the administration of a GLP-1 antagonist in rodents, demonstrating that these metabolic changes are, in part, GLP-1 dependent.
Although sustained and significant weight loss is likely to be the key mediator of diabetes remission after GBP, the changes of incretins improve the early phase of insulin secretion and post-prandial glucose levels, and contribute to the better glucose tolerance.
One of the major benefits of surgical weight loss is the resolution of type 2 diabetes (T2DM) in 50–80% of cases [1,2]. The rapidity of the onset and the magnitude of the effect of gastric bypass surgery on diabetes remain largely unexplained.
Some determinants of impaired insulin secretion in T2DM, such as glucose or lipid toxicity [3,4], likely improve as a result of weight loss per se. In contrast, the change of the gut hormone incretins after GBP [5,6], and their resulting effect on insulin or on glucagon secretion, could be the mediator of the greater improvement of glucose levels after GBP [5,6] compared to diet or to gastric banding.
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), secreted respectively from the upper (duodenum K cells) and the lower intestine (ileum L cells) [7–9], are the two incretins responsible for approximately 50% of post-prandial insulin secretion [10–13]. The incretin effect is described as the greater insulin response after oral glucose compared to an equivalent dose of intravenous glucose [11,14]. In addition to its insulinotropic effect, GLP-1 delays gastric emptying , decreases appetite and promotes weight loss [15,16], inhibits glucagon , and improves insulin sensitivity . GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV). The incretin effect on insulin secretion is impaired in patients with T2DM . GLP-1 analogues and DPP-IV inhibitors are currently used as anti-diabetic agents .
Reports of increase incretin levels after bypass surgeries started in the late 1970’s early 1980’s, at a time when no commercial assays were available. GLP-1 consistently increased after jejuno ileal bypass, biliopancreatic diversion or gastric bypass [21–23]. More recent reports, including ours, confirm a significant increase of GLP-1 levels by a factor 5 to 10 after a meal  or oral glucose  after GBP. The results of bypass surgeries on changes of GIP levels are less consistent with either elevated or decreased levels after the same types of surgery [21,23,25–27]. In morbidly obese patients with T2DM, we reported an increase of GIP levels 1 month after GBP . In addition to the increase post-prandial levels of incretins, we have shown that the incretin effect on insulin secretion, blunted in patients with diabetes, normalized to the levels of non-diabetic controls as early as 1 month after gastric bypass surgery . These patients had diagnosed diabetes for less than 5 years, were well controlled (mean HbA1c 6%) and on minimum therapy. Recent data in Gato-Kakizaki (GK) rats show that the increased GLP-1 secretion and improved glucose tolerance after duodeno jejunal bypass (DJB), is reversed by the administration of a GLP-1 receptor antagonism. This proof-of-concept study provides direct evidence that improvement of glucose tolerance following a gastric bypass-like surgery is mediated, at last in part, by enhanced GLP-1 action .
Previous data suggested that a diet-induced weight loss (−18.8 kg) increase the incretin levels in response to a test meal . To address the question of the possible role of weight loss on the change in incretin levels and effect after GBP surgery, we designed a prospective study with a surgical group studied before and 1 month after GBP and a matched diet group studied before and after a diet-induced equivalent weight loss. Our working hypothesis was that the increase in incretin levels and incretin effect would be greater after GBP surgery than after equivalent weight loss by diet.
The inclusion criteria for the surgical group and the diet group were identical: morbidly obese patients with BMI >35kg/m2, with T2DM of less than 5 years duration, not on insulin, thiazolidinedione, exenatide or DPP-IV inhibitor, with HbA1c < 8%, age < 60 years, of all ethnic background. The GBP group was studied first. Participants in the diet group were recruited afterwards, fit the same inclusion criteria, and were matched for body weight, BMI, age, diabetes control and duration with patients from the surgical group. The diet consisted of meal replacement, about 1000 to 1200 kcal/d, given on weekly outpatient visits. The duration of weight loss was not set but the expectation was that the participants would lose 10 kg of weight in 4 to 8 weeks. The patients were kept on negative energy balance while retested after diet weight loss. The diabetes management during diet included self glucose monitoring by the patients and the adjustment of medications to avoid hypoglycaemia. At baseline and after weight loss, patients were studied off diabetes medications for 72 hours. The results of these experiments have been published elsewhere . In brief, patients in GBP and diet group lost the same amount of weight (~ 10 kg). Diabetes medications were discontinued at the time of surgery for all GBP patients, and were decreased or stopped for diet patients, using algorithm based on American Diabetes Association (ADA) criteria of target glucose control. There was a significant and similar decrease of fasting glucose and fasting insulin after diet and after GBP. However, the recovery of the early phase insulin secretion in response to oral glucose and the improvement in incretin levels and effect were observed only after GBP and not after diet. Recent clinical studies of various types of bypass surgeries and/or ileal transposition in humans with BMI less than 35 kg/m2 suggest that the diabetes can be improved without weight loss . Data on gut hormones in these patients has not been provided.
Do the incretin changes observed early after gastric bypass persist overtime? Cross sectional data from Naslund show a persistent increase fasting and post-prandial GLP-1 and GIP levels 20 years after DJB compared to obese non-operated controls . Our own data show persistent increased GLP-1 response to oral glucose and GIP up to 3 years after GBP, after ~30kg weight loss, in patients with diabetes remission and normal incretin effect (Fig. 1). Off notes, the incretin levels and effect, the early phase insulin release during the OGTT and the insulinogenic index all improve rapidly (1 month) after GBP without further change at 6 and 12 months, in spite of continuous weight loss. On the contrary, other variables such as glucose levels improve as a function of weight loss up to one year. This suggests that some changes occur as a result of the surgery, independently of weight loss, while other changes are clearly weight loss related.
Whether the improved post-prandial insulin and glucose levels observed one month after GBP is responsible for the later development of hyperinsulinemic hypoglycaemia with [32,33] or without  nesidioblastosis is unknown. Although GLP-1 has been shown to preserve human islet in vitro  and prevent beta cell apoptosis in rodents  there is no human data to suggest that GLP-1 increases beta cell mass after gastric bypass in humans.
As a result of GBP, a small gastric pouch of about 30cc is anastomosed directly to the distal part of the ileum (alimentary limb). The rest of the stomach, including the pylorus, with the duodenum and part of the jejunum is shunted from the nutrients and reattached to the very distal par of the ileum to allow gastrointestinal and pancreatic juice to be excreted (biliopancreatic (BP) limb). Elegant studies in a rat model of diabetes suggest that the exclusion of the upper gut (foregut hypothesis), rather than weight loss, benefits glucose tolerance [37,38]. Rats after gastrojejunal bypass have better glucose tolerance than sham-operated pair-fed control animals with equivalent body weight . The hindgut hypothesis suggests that the rapid stimulation of the distal ileum by nutrients is responsible for increased GLP-1 and beneficial effect on glucose tolerance, as suggested by studies of ileal transposition in rodents [39–41]. There are few data in humans to support these hypotheses. After GBP, the emptying of the gastric pouch is faster for liquids but delayed for solids [24,42]. The increased GE and intestinal transit time for liquid  may result in rapid release of GLP-1 by the distal ileum rapidly in contact with nutrients GLP-1. It is likely that both duodenal exclusion (foregut hypothesis)  and the rapid exposure of the distal ileum to undigested nutrients (hindgut hypothesis) [39,40] are possible mechanisms that may contribute to incretin levels increase after GBP, but this has not yet been studied in humans.
What is the place of incretins in the remission of type 2 diabetes after gastric bypass surgery? Data show clearly beneficial changes of incretin levels and effect after GBP, resulting in better profile of insulin secretion and decreased post-prandial glucose. However it is likely that weight loss by its magnitude (~40%) and its duration (years) is the major contributor to glucose control after GBP, via mechanisms other than incretins, such as decreased inèammation, decreased liver fat, intramyocellular fat, insulin resistance and changes in adipokines.
This work was funded by grants from the American Diabetes Association CR-7-05 CR-18, NIH R01-DK67561, GCRC 1 UL1 RR024156-02, ORC DK-26687, DERC DK-63068-05, Merck and Amylin Investigator Initiated Studies Program.
Conflicts of interests
The authors have reported no conèict of interests.