GLP-1—A Candidate Humoral Mediator for Glucose Control After Roux-en-Y Gastric Bypass

Abstract

The worldwide increase in obesity is associated with a higher prevalence of type 2 diabetes (T2D), and severe obesity occurs with the greatest risk (1). Bariatric surgery is currently the most effective treatment not only for weight loss but also for prevention or treatment of T2D in such patients (2). It leads to remission or improvement of T2D in the majority of morbidly obese (3,4). Roux-en-Y gastric bypass (RYGB) is one of the most frequently performed procedures. With RYGB, the stomach is reduced to a small proximal pouch (30-50 mL) and anastomosed to the jejunum, thereby bypassing the majority of the stomach and duodenum. After RYGB, T2D improves rapidly often before significant weight loss occurs. The mechanisms behind this phenomenon are not clearly resolved. Caloric restriction contributes. Extreme caloric restriction to the limit just tolerated in patients after surgery improved insulin resistance in obese subjects similarly as found in after the first week after RYGB (5). Of interest, the malabsorptive component of the RYGB procedure approximately accounts only for up to 11% of the total reduction in combustible energy absorption (6). Changes of adipokine-induced inflammation and insulin resistance (7) and reduction of branched-chain amino acids correlating with insulin resistance (8) have been proposed as further mechanisms operating after bariatric surgery complementing the sole weight loss.A popular hypothesis points to an antidiabetic effect after RYGB of postprandially exaggeratedly released gut peptides, such as glucagon-like peptide 1 (GLP-1), already starting early after surgery. The release of GLP-1 depends on gastric emptying (GE) velocity (9). It lowers postprandial glycemia by stimulation of insulin, inhibition of glucagon secretion, and delay of GE. For example, Laferrère et al. (10) reported a sixfold increase in GLP-1 plasma levels and a fivefold increase of the incretin effect in obese patients with T2D 1 month after RYGB. In this issue, Shah et al. (11) addressed the contribution of endogenous GLP-1 to the meal-induced glucose metabolism, islet secretion, and GE after RYGB in 12 nondiabetic obese patients 5 6 0.9 years after RYGB and 8 weightmatched control subjects twice using the GLP-1 receptor (GLP-1R) antagonist exendin(9-39). After ingestion of a 220 kcal mixed-meal, glucose metabolism was measured using the isotope dilution method. Indices of insulin action and b-cell glucose responsitivity and the resulting glucose disposition indices were calculated using the oral minimal model. GE was measured by scintigraphy. As expected, GE (gastric pouch in the post-RYGB subjects) was greatly accelerated, leading to a several-fold increase in postprandial GLP-1, insulin, and C-peptide responses after RYGB. The GLP-1R antagonist increased the postprandial glucose excursions in both groups. Exendin(9-39) decreased insulin and C-peptide concentrations in subjects post-RYGB by about 30% with no effect in control subjects. The calculated b-cell response to glucose was significantly reduced in b...

Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery

“…This assumption is based on previously published results, and the Ex-9 dosage used in this study has been shown to result in a 95% inhibition of the insulinotropic effect of pharmacological concentrations of GLP-1 (33,48). In our study, however, peak values of intact GLP-1 on the Ex-9/sitagliptin day reached even higher concentrations than reported previously, where the effectiveness of Ex-9 infusion has not been evaluated.…”

“…The peptide had Ͼ99.5% purity by high-performance liquid chromatography. The Ex-9 infusion rate of 900 pmol·kg Ϫ1 ·min Ϫ1 was chosen since this dosage has previously been reported to block the GLP-1R by 95% (33,48). Sita (Januvia; 100 mg) was purchased from MSD (Ballerup, Denmark) and was dispensed in capsules similar to placebo capsules by the Capital Region of Denmark Central Pharmacy (Herlev, Denmark).…”

Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes

“…Certainly, our ex vivo data illustrate the ability of metformin to directly induce L cell secretion, but such an effect will be modified in vivo due to reduced dosage upon reaching the ileum and colon and by the potential for other factors to affect this response. Finally, a residual effect of GLP-1 may persist due to the submaximal GLP-1 receptor antagonism (~90%) at the chosen Ex9-39 dose, which could potentially underestimate the effect of metformin-induced GLP-1 secretion (64).…”

“…The forearm used for blood sampling was wrapped in a heating pad (50°C) for arterialization of venous blood during the experiment. Continuous isovolemic infusions of either saline or Ex9-39 were then started at a rate of 10 ml/hour by the use of a pump (Terufusion Infusion Pump, TE-171, Terumo), for Ex9-39 corresponding to a rate of 450 pmol × kg body weight -1 × min -1 , since this dose has previously been shown to block the insulinotropic effect of synthetic GLP-1 by ~90% (64). After 30 minutes, at time 0 minutes, the patients ingested a 200 ml, 1,264 kJ (302 kcal) mixed liquid meal (chocolate-flavored Nutridrink, 36.8 g carbohydrates, 12.0 g protein and 11.6 g fat; Nutricia) mixed with a dispersion of 1,500 mg of acetaminophen in 100 ml of water (for evaluation of gastric emptying) and metformin 1,500 mg or placebo.…”

Diabetes, Neurodegenerative Diseases, GLP-1 & Surgery: Evidence Calls for Exploration

“…The main actors in metabolic control and the reversion of complications could be the elevated concentrations of GIP, GLP-1 and PYY, resulting from an early contact between the L cell and raw nutrients [48][49][50] as well as the interaction between biliary salts and pancreatic juices, all which are promoted by procedures such as biliary pancreatic derivation, gastric bypass [51], duodenojejunal bypass [52] and adaptive enterectomy. Although it was considered a mixed procedure (restrictive and malabsorptive), in gastric bypass the malabsoptive component seems to contribute to only 11% of the overall decrease in energetic absorption [53], suggesting that it holds its main activity as a metabolic procedure.…”