Altered bile acid kinetics contribute to postprandial hypoglycaemia after Roux-en-Y gastric bypass surgery.

BACKGROUND/OBJECTIVES: Bile acids (BA) act as detergents in intestinal fat absorption and as modulators of metabolic processes via activation of receptors such as FXR and TGR5. Elevated plasma BA as well as increased intestinal BA signalling to promote GLP-1 release have been implicated in beneficial health effects of Roux-en-Y gastric bypass surgery (RYGB). Whether BA also contribute to the postprandial hypoglycaemia that is frequently observed post-RYGB is unknown. METHODS: Plasma BA, fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), GLP-1, insulin and glucose levels were determined during 3.5 h mixed-meal tolerance tests (MMTT) in subjects after RYGB, either with (RYGB, n = 11) or without a functioning gallbladder due to cholecystectomy (RYGB-CC, n = 11). Basal values were compared to those of age, BMI and sex-matched obese controls without RYGB (n = 22). RESULTS: Fasting BA as well as FGF19 levels were elevated in RYGB and RYGB-CC subjects compared to non-bariatric controls, without significant differences between RYGB and RYGB-CC. Postprandial hypoglycaemia was observed in 8/11 RYGB-CC and only in 3/11 RYGB. Subjects who developed hypoglycaemia showed higher postprandial BA levels coinciding with augmented GLP-1 and insulin responses during the MMTT. The nadir of plasma glucose concentrations after meals showed a negative relationship with postprandial BA peaks. Plasma C4 was lower during MMTT in subjects experiencing hypoglycaemia, indicating lower hepatic BA synthesis. Computer simulations revealed that altered intestinal transit underlies the occurrence of exaggerated postprandial BA responses in hypoglycaemic subjects. CONCLUSION: Altered BA kinetics upon ingestion of a meal, as frequently observed in RYGB-CC subjects, appear to contribute to postprandial hypoglycaemia by stimulating intestinal GLP-1 release.

Diminished Counterregulatory Responses to Meal-Induced Hypoglycemia 4 Years After RYGB.

PURPOSE: Post-bariatric hypoglycemia is a complication of bariatric surgery, especially Roux-en-Y gastric bypass (RYGB). The counterregulatory hormonal and sympathetic neural responses were measured during a previously reported meal test in which 48% had an almost asymptomatic hypoglycemic event. MATERIALS AND METHODS: Forty-four randomly selected patients 4 years after RYGB. A liquid meal test (MMT) after overnight fasting. Based on the glucose nadir during the MMT, patients were divided in a hypo group (glucose < 3.3 mmol/L) and a non-hypo group (glucose ≥ 3.3 mmol/L). Cortisol, epinephrine, norepinephrine, blood pressure, and heart rate were measured up to 180 min after ingestion of the meal. Incremental areas under the curve (iAUC), peak, and delta hormone responses after the glucose nadir were calculated. Parameters were compared between the hypo and non-hypo groups. RESULTS: A total of 21/44 (48%) had an almost asymptomatic hypoglycemic event. Cortisol and epinephrine responses in the hypo group were not increased compared to the non-hypo group, and there were no signs of increased sympathetic nerve activity. Peak and delta cortisol were lower in the hypo compared to the non-hypo group. Norepinephrine was higher in the hypo group especially in the time frame 60-120 and 120-180 min after start of the meal. CONCLUSION: No increase in epinephrine and a lower cortisol response to hypoglycemia were observed compared to normoglycemia during a meal test in patients after RYGB. Norepinephrine levels were higher in the hypo group. These findings may suggest that possible recurrent hypoglycemia after RYGB results in blunting of counterregulatory responses indicative of hypoglycemia-induced autonomic failure. CLIN TRIAL REGISTER ID: ISRCTN 11738149.

Cholecystectomy increases the risk of dumping syndrome and postbariatric hypoglycemia after bariatric surgery.

BACKGROUND: Dumping syndrome (DS) and postbariatric hypoglycemia (PBH) are frequent complications of bariatric surgery. Bile acids (BA) have been implicated in their pathogenesis because both bariatric surgery and cholecystectomy (CCx) are known to modulate human BA metabolism. OBJECTIVES: Our investigation aimed to compare the prevalence of self-reported complaints of DS and PBH in postbariatric patients with and without CCx. SETTING: A large peripheral hospital in the Netherlands. METHODS: All patients who underwent bariatric surgery in 2008-2011 received standardized questionnaires on DS/PBH complaints. The relative risk (RR) of CCx was calculated as the risk of perceived DS and PBH in patients with and without CCx. RESULTS: Of 590 participants, 146 (25%) had CCx before assessment of DS/PBH complaints. Participants were mostly female (82%) with median age of 46 years (interquartile range, 39-53). The RR for DS after CCx was higher in patients with body mass index <30 kg/m2 at the study (RR, 1.59; 95% CI, 1.04-2.42; P = .007) and in primary Roux-and-Y gastric bypass surgery patients (RR, 1.63; 95% CI, 1.10-2.42; P = .018). Detailed analysis of the latter group associated women, age younger than 50 years, without diabetes and (most prominently) with excess weight loss ≥70% (RR, 2.73; 95% CI, 1.57-4.77; P = .0004) with greater risk of DS. The RR for PBH was higher after CCx in sleeve gastrectomy patients (RR, 4.5; 95% CI, 1.00-20.3; P = .036). CONCLUSION: High suspicion of DS and PBH after CCx is increased after bariatric surgery in certain subgroups, suggesting involvement of altered BA metabolism in their pathophysiology.

Prevalence and pathophysiology of early dumping in patients after primary Roux-en-Y gastric bypass during a mixed-meal tolerance test.

BACKGROUND: Early dumping is a poorly defined and incompletely understood complication after Roux-en-Y gastric (RYGB). OBJECTIVE: We performed a mixed-meal tolerance test in patients after RYGB to address the prevalence of early dumping and to gain further insight into its pathophysiology. SETTING: The study was conducted in a regional hospital in the northern part of the Netherlands. METHODS: From a random sample of patients who underwent primary RYGB between 2008 and 2011, 46 patients completed the mixed-meal tolerance test. The dumping severity score for early dumping was assessed every 30 minutes. A sum score at 30 or 60 minutes of ≥5 and an incremental score of ≥3 points were defined as indicating a high suspicion of early dumping. Blood samples were collected at baseline, every 10 minutes during the first half hour, and at 60 minutes after the start. RESULTS: The prevalence of a high suspicion of early dumping was 26%. No differences were seen for absolute hematocrit value, inactive glucagon-like peptide-1, and vasoactive intestinal peptide between patients with or without early dumping. Patients at high suspicion of early dumping had higher levels of active glucagon-like peptide-1 and peptide YY. CONCLUSION: The prevalence of complaints at high suspicion of early dumping in a random population of patients after RYGB is 26% in response to a mixed-meal tolerance test. Postprandial increases in both glucagon-like peptide-1 and peptide YY are associated with symptoms of early dumping, suggesting gut L-cell overactivity in this syndrome.

Prevalence of hypoglycaemia in a random population after Roux-en-Y gastric bypass after a meal test.

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) is an effective way to induce sustainable weight loss and can be complicated by postprandial hyperinsulinaemic hypoglycaemia (PHH). To study the prevalence and the mechanisms behind the occurrence of hypoglycaemia after a mixed meal tolerance test (MMTT) in patients with primary RYGB. DESIGN: This is a cross-sectional study of patients 4 years after primary RYGB. METHODS: From a total population of 550 patients, a random sample of 44 patients completed the total test procedures. A standardized mixed meal was used as stimulus. Venous blood samples were collected at baseline, every 10 min during the first half hour and every 30 min until 210 min after the start. Symptoms were assessed by questionnaires. Hypoglycaemia is defined as a blood glucose level below 3.3 mmol/L. RESULTS: The prevalence of postprandial hypoglycaemia was 48% and was asymptomatic in all patients. Development of hypoglycaemia was more frequent in patients with lower weight at surgery (P = 0.045), with higher weight loss after surgery (P = 0.011), and with higher insulin sensitivity calculated by the homeostasis model assessment indexes (HOMA2-IR, P = 0.014) and enhanced beta cell function (insulinogenic index at 20 min, P = 0.001). CONCLUSION: In a randomly selected population 4 years after primary RYGB surgery, 48% of patients developed a hypoglycaemic event during an MMTT without symptoms, suggesting the presence of hypoglycaemia unawareness in these patients. The findings in this study suggest that the pathophysiology of PHH is multifactorial.

Satiety and gastrointestinal hormones during a Mixed Meal Tolerance Test after gastric bypass surgery: association with plasma amino acid concentrations.

BACKGROUND: Circulating amino acids have been associated with both appetite and the secretion of anorexigenic hormones in healthy and obese populations. This effect has not been investigated in subjects having undergone Roux-en-Y gastric bypass surgery (RYGB). OBJECTIVE: To investigate the association between postprandial plasma concentrations of amino acids and the anorexigenic hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY), the orexigenic hormone ghrelin, and satiety and hunger in post-RYGB subjects. SETTING: A Dutch surgical department. METHODS: Participants after primary RYGB were studied during a Mixed Meal Tolerance Test (MMTT). Satiety and hunger were assessed every 30 minutes on visual analogue scales. Blood samples were collected at baseline, every 10 minutes during the first half hour and every 30 minutes until 210 minutes after the start. The samples were assessed for 24 amino acids and 3 gastrointestinal hormones. Incremental areas under the curve (iAUCs) were calculated. Exploratory analyses were performed in which subjects were divided into high and low responders depending on the median iAUC. RESULTS: 42 subjects, aged 48 ± 11 (mean ± SD) years, 31 to 76 months post-RYGB and with total weight loss of 30 ± 9% completed the MMTT. Subjects with high satiety scores had more than a 25% higher net iAUC of PYY and GLP-1 and at least a 10% higher net iAUC of 10 amino acids compared to subjects with low scores (P < 0.05). The net iAUC of five of these amino acids (i.e. arginine, asparagine, histidine, serine and threonine) was more than 10% higher in subjects with high responses on GLP-1 and/or PYY (P < 0.05). CONCLUSIONS: Certain postprandial amino acids were associated with satiety and anorexigenic hormones and could therefore play a role in appetite regulation after RYGB; either by a direct effect on satiety, indirectly through gastrointestinal hormones, or both.

Influence of dietary protein and its amino acid composition on postoperative outcomes after gastric bypass surgery: a systematic review.

CONTEXT: Bariatric surgery is an effective method to reduce morbid obesity. Nutritional counseling is essential to achieve maximal treatment success and to avoid long-term complications. Increased dietary protein intake may improve various postoperative results. OBJECTIVE: The aim of this systematic review is to examine the relationship between intake of dietary protein or supplementation with amino acids and postoperative outcomes after gastric bypass surgery. DATA SOURCES: A systematic literature search was conducted in 4 electronic databases: Cochrane, Embase, PubMed, and Scopus. STUDY SELECTION: The initial search retrieved 7333 hits, which included 2390 duplicates. DATA EXTRACTION: Tweny-three studies with varying study designs, interventions, and outcomes were included. RESULTS: Studies did not provide convincing evidence of a beneficial effect on any postoperative outcome. CONCLUSIONS: The study of the influence of protein and its amino acid composition represents an important developing domain of knowledge and warrants further attention considering the popularity of bariatric surgery. Future studies should include a clear description of the quantity and composition of proteins and amino acids in the diet or supplement.