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Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1β.
Hepprich, M, Wiedemann, SJ, Schelker, BL, Trinh, B, Stärkle, A, Geigges, M, Löliger, J, Böni-Schnetzler, M, Rudofsky, G, Donath, MY
Cell metabolism. 2020;(4):699-709.e5
Abstract
Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1β leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pvallikelihood ratio test (LRT) = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18-2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31-3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43-3.55, pvalLRT = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.
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Biliopancreatic Diversion Induces Greater Metabolic Improvement Than Roux-en-Y Gastric Bypass.
Harris, LA, Kayser, BD, Cefalo, C, Marini, L, Watrous, JD, Ding, J, Jain, M, McDonald, JG, Thompson, BM, Fabbrini, E, et al
Cell metabolism. 2019;(5):855-864.e3
Abstract
Diabetes remission is greater after biliopancreatic diversion (BPD) than Roux-en-Y gastric bypass (RYGB) surgery. We used a mixed-meal test with ingested and infused glucose tracers and the hyperinsulinemic-euglycemic clamp procedure with glucose tracer infusion to assess the effect of 20% weight loss induced by either RYGB or BPD on glucoregulation in people with obesity (ClinicalTrials.gov number: NCT03111953). The rate of appearance of ingested glucose into the circulation was much slower, and the postprandial increases in plasma glucose and insulin concentrations were markedly blunted after BPD compared to after RYGB. Insulin sensitivity, assessed as glucose disposal rate during insulin infusion, was ∼45% greater after BPD than RYGB, whereas β cell function was not different between groups. These results demonstrate that compared with matched-percentage weight loss induced by RYGB, BPD has unique beneficial effects on glycemic control, manifested by slower postprandial glucose absorption, blunted postprandial plasma glucose and insulin excursions, and greater improvement in insulin sensitivity.
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Laparoscopic Roux-en-Y gastric bypass surgery influenced pharmacokinetics of several drugs given as a cocktail with the highest impact observed for CYP1A2, CYP2C8 and CYP2E1 substrates.
Puris, E, Pasanen, M, Ranta, VP, Gynther, M, Petsalo, A, Käkelä, P, Männistö, V, Pihlajamäki, J
Basic & clinical pharmacology & toxicology. 2019;(2):123-132
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Abstract
There is a lack of information about the changes in drug pharmacokinetics and cytochrome P450 (CYP) metabolism after bariatric surgery. Here, we investigated the effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery on pharmacokinetics of nine drugs given simultaneously which may reveal changes in the activities of the main CYPs. Eight obese subjects undergoing LRYGB received an oral cocktail containing nine drugs, substrates of various CYPs: melatonin (CYP1A2), nicotine (CYP2A6), bupropion (CYP2B6), repaglinide (CYP2C8), losartan (CYP2C9), omeprazole (CYP2C19/CYP3A4), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A). The 6-hours pharmacokinetic profiles in serum and urine of each drug or corresponding metabolite as well as their metabolic ratios were compared before surgery with those at a median 1 year later. LRYGB exerted variable effects on the pharmacokinetics of these drugs. The geometric mean AUC0-6 (90% confidence interval) of melatonin, bupropion, repaglinide, chlorzoxazone and midazolam after LRYGB was 27 (19%-41%), 54 (43%-67%), 44 (29%-66%), 160 (129%-197%) and 74 (62%-90%) of the pre-surgery values, respectively. The pharmacokinetics of losartan, omeprazole and dextromethorphan did not change in response to surgery. Nicotine was not detected in serum, while geometric mean of AUC0-6 of its metabolite, cotinine, increased by 1.7 times after surgery. There were 3.6- and 1.3-fold increases in the AUC ratios of 6-hydroxymelatonin/melatonin and hydroxybupropion/bupropion, respectively. The cocktail revealed multiple pharmacokinetic changes occurring after LRYGB with the greatest effects observed for CYP1A2, CYP2C8 and CYP2E1 substrates. Future studies should be focused on CYP1A2, CYP2A6, CYP2C8 and CYP2B6 to clarify the changes in activities of these enzymes after LRYGB.
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Sleeve gastrectomy surgery: when 2 alcoholic drinks are converted to 4.
Acevedo, MB, Eagon, JC, Bartholow, BD, Klein, S, Bucholz, KK, Pepino, MY
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2018;(3):277-283
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BACKGROUND While it is well established that Roux-en-Y gastric bypass (RYGB) causes a rapid and heightened peak blood alcohol concentration (BAC), results from previous studies on the effects of sleeve gastrectomy (SG) on alcohol pharmacokinetics are conflicting. Data from 2 studies found SG did not affect BAC, whereas another study found SG caused a heightened peak BAC after alcohol ingestion. Moreover, these 3 studies estimated BAC from breathalyzers, which might not reliably estimate peak BAC. OBJECTIVES The aims of this study were to evaluate (1) the effect of SG, relative to RYGB and a presurgery group, on alcohol pharmacokinetics and subjective effects, and (2) whether breathalyzers are reliable in this population. SETTING Single-center prospective nonrandomized trial. METHODS We performed alcohol challenge tests in 11 women who had SG surgery 1.9 ± .1 years ago (body mass index = 35.1 ± 6.6 kg/m2), 8 women who had RYGB surgery 2.2 ± .4 years ago (body mass index = 30.0 ± 5.2 kg/m2), and 9 women who were scheduled for bariatric surgery (body mass index = 44.1 ± 4.0 kg/m2). BACs were estimated from breath samples and measured by gas chromatography at various times after consuming approximately 2 standard drinks. RESULTS BAC increased faster, peak BAC was approximately 2-fold higher, and feelings of drunkenness were heightened in both SG and RYGB groups relative to the presurgery group (P values<.001). BAC estimated from breath samples underestimated BAC by 27% (standard deviation = 13%) and missed peak BACs postsurgery. CONCLUSIONS SG, similar to RYGB, causes marked alterations in the response to alcohol ingestion manifested by a faster and higher peak BAC. The breathalyzer is invalid to assess effects of gastric surgeries on pharmacokinetics of ingested alcohol.
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Roux-en-Y Gastric Bypass Surgery Has Unique Effects on Postprandial FGF21 but Not FGF19 Secretion.
Harris, LLS, Smith, GI, Mittendorfer, B, Eagon, JC, Okunade, AL, Patterson, BW, Klein, S
The Journal of clinical endocrinology and metabolism. 2017;(10):3858-3864
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CONTEXT Fibroblast growth factor (FGF)19 and FGF21 are secreted by the intestine and liver in response to macronutrient intake. Intestinal resection and reconstruction via bariatric surgery may alter their regulation. OBJECTIVE We tested the hypothesis that weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery, but not matched weight loss induced by laparoscopic adjustable gastric banding (LAGB), increases postprandial plasma FGF19 and FGF21 concentrations. DESIGN Glucose kinetics and plasma FGF19 and FGF21 responses to mixed meal ingestion and to glucose-insulin infusion during a hyperinsulinemic-euglycemic clamp procedure, with stable isotope tracer methods, were evaluated in 28 adults with obesity before and after 20% weight loss induced by RYGB (n = 16) or LAGB (n = 12). RESULTS LAGB- and RYGB-induced weight loss increased postprandial plasma FGF19 concentrations (P < 0.05). However, weight loss after RYGB, but not LAGB, increased postprandial plasma FGF21 concentrations (1875 ± 330 to 2976 ± 682 vs 2150 ± 310 and 1572 ± 265 pg/mL × 6 hours, respectively). The increase in plasma FGF21 occurred ∼2 hours after the peak in delivery of ingested glucose into systemic circulation. Glucose-insulin infusion increased plasma FGF21, but not FGF19, concentrations. The increase in plasma FGF21 during glucose-insulin infusion was greater after than before weight loss in both surgery groups without a difference between groups, whereas plasma FGF19 was not affected by either procedure. CONCLUSIONS RYGB-induced weight loss has unique effects on postprandial FGF21 metabolism, presumably due to rapid delivery of ingested macronutrients to the small intestine and delivery of glucose to the liver.
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Energy restriction and Roux-en-Y gastric bypass reduce postprandial α-dicarbonyl stress in obese women with type 2 diabetes.
Maessen, DE, Hanssen, NM, Lips, MA, Scheijen, JL, Willems van Dijk, K, Pijl, H, Stehouwer, CD, Schalkwijk, CG
Diabetologia. 2016;(9):2013-7
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AIMS/HYPOTHESIS Dicarbonyl compounds are formed as byproducts of glycolysis and are key mediators of diabetic complications. However, evidence of postprandial α-dicarbonyl formation in humans is lacking, and interventions to reduce α-dicarbonyls have not yet been investigated. Therefore, we investigated postprandial α-dicarbonyl levels in obese women without and with type 2 diabetes. Furthermore, we evaluated whether a diet very low in energy (very low calorie diet [VLCD]) or Roux-en-Y gastric bypass (RYGB) reduces α-dicarbonyl stress in obese women with type 2 diabetes. METHODS In lean (n = 12) and obese women without (n = 27) or with type 2 diabetes (n = 27), we measured the α-dicarbonyls, methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), and glucose in fasting and postprandial plasma samples obtained during a mixed meal test. Obese women with type 2 diabetes underwent either a VLCD or RYGB. Three weeks after the intervention, individuals underwent a second mixed meal test. RESULTS Obese women with type 2 diabetes had higher fasting and particularly higher postprandial plasma α-dicarbonyl levels, compared with those without diabetes. After three weeks of a VLCD, postprandial α-dicarbonyl levels in diabetic women were significantly reduced (AUC MGO -14%, GO -16%, 3-DG -25%), mainly through reduction of fasting plasma α-dicarbonyls (MGO -13%, GO -13%, 3-DG -33%). Similar results were found after RYGB. CONCLUSIONS/INTERPRETATION This study shows that type 2 diabetes is characterised by increased fasting and postprandial plasma α-dicarbonyl stress, which can be reduced by improving glucose metabolism through a VLCD or RYGB. These data highlight the potential to reduce reactive α-dicarbonyls in obese individuals with type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT01167959.
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Comparison of Virtual Nutri Plus® and Dietpro 5i® software systems for the assessment of nutrient intake before and after Roux-en-Y gastric bypass.
Silva, MM, Sala, PC, Cardinelli, CS, Torrinhas, RS, Waitzberg, DL
Clinics (Sao Paulo, Brazil). 2014;(11):714-22
Abstract
OBJECTIVES The assessment of nutritional intake before and after bariatric surgery assists in identifying eating disorders, nutritional deficiencies and weight loss/maintenance. The 7-day record is the gold standard for such an assessment and is interpreted using specialized software. This study sought to compare the Virtual Nutri Plus® and Dietpro 5i® software systems in assessing nutrient intake in obese patients with type 2 diabetes mellitus who underwent a Roux-en-Y gastric bypass. METHODS Nutritional intake was assessed in 10 obese women with type 2 diabetes mellitus before and 3 months after Roux-en-Y gastric bypass. The 7-day record was used to assess food intake and then, the Virtual Nutri Plus® and Dietpro 5i® software systems were used to calculate calorie, macronutrient and micronutrient intake based on validated food chemical composition databases. Clinicaltrials.gov: NCT01251016. RESULTS During the preoperative period, deficits in the ingestion of total fiber and 15 out of 22 estimated micronutrients were observed when using the Virtual Nutri Plus®, compared to deficiencies in total fiber and 4 micronutrients when using the Dietpro 5i®. During the postoperative period, both the Virtual Nutri Plus® and Dietpro 5i® systems detected deficits in the ingestion of total fiber, carbohydrates and 19 micronutrients, but only the Virtual Nutri Plus® detected deficits in complex B vitamins (except B12) and minerals. CONCLUSION Virtual Nutri Plus® was more sensitive than Dietpro 5i® for the identification of deficits in nutrient intake in obese, type 2 diabetes mellitus patients undergoing Roux-en-Y gastric bypass.
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Patient factors associated with undergoing laparoscopic adjustable gastric banding vs Roux-en-Y gastric bypass for weight loss.
Apovian, CM, Huskey, KW, Chiodi, S, Hess, DT, Schneider, BE, Blackburn, GL, Jones, DB, Wee, CC
Journal of the American College of Surgeons. 2013;(6):1118-25
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BACKGROUND Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding are 2 commonly performed bariatric procedures in the US with different profiles for risk and effectiveness. Little is known about factors that might lead patients to proceed with one procedure over the other. STUDY DESIGN We recruited and interviewed patients seeking bariatric surgery from 2 academic centers in Boston (response rate 70%). We conducted multivariable analyses to identify patient perceptions and clinical and behavioral characteristics that correlated with undergoing gastric banding (n = 239) vs gastric bypass (n = 297). RESULTS After adjustment for socio-demographic and clinical factors, we found that older patients (odds ratio [OR] 1.03; 95% CI 1.00 to 1.05) and those with higher quality of life scores and higher levels of uncontrolled eating were more likely to undergo gastric banding as opposed to gastric bypass. In contrast, patients with type 2 diabetes (OR 0.46; 95% CI 0.28 to 0.77), those who desired greater weight loss, and those who were willing to assume higher mortality risk to achieve their ideal weight were less likely to proceed with gastric banding. After initial adjustment, male sex and lower body mass index were associated with a likelihood of undergoing gastric banding; however, these factors were no longer significant after adjustment for other significant correlates such as patients' perceived ideal weight, predilection to assume risk to lose weight, and eating behavior. CONCLUSIONS Patients' diabetes status, quality of life, eating behavior, ideal weight loss, and willingness to assume mortality risk to lose weight were associated with whether patients proceeded with gastric banding as opposed to gastric bypass. Other clinical factors were less important.
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Defining and predicting complete remission of type 2 diabetes: a short-term efficacy study of open gastric bypass.
Yan, H, Tang, L, Chen, T, Kral, JG, Jiang, L, Li, Y, Hu, R, Cui, J, Li, S, Tian, F
Obesity facts. 2013;(2):176-84
Abstract
OBJECTIVE To investigate the metabolic effects of open Roux-en Y gastric bypass (RYGB) on pancreatic endocrine reserve in overweight/obese Chinese patients with type 2 diabetes during postoperative year 1. METHODS Retrospective analysis comparing pre- and postoperative results of oral glucose tolerance tests (OGTT) with determinations of insulin and C-peptide, glycated hemoglobin (HbA1c), insulin resistance (HOMA-IR), and BMI at 1, 3, 6, and 12 months in 99 overweight patients (BMI 26.3 ± 4.0 kg/m(2); 59 men) with type 2 diabetes at the General Hospital of Chengdu Military Region. RESULTS 79 patients (80%) achieved complete remission (maintaining random blood glucose levels < 11.1 mmol/l, fasting blood glucose levels < 7.0 mmol/l, 2-hour OGTT blood glucose levels < 11.1 mmol/l, and glycated hemoglobin < 6.5%). Nine cases (9%) were 'improved' (reduced medication or diet controlled blood sugar), and 11 cases did not meet either criterion ('unchanged'). Patients in complete remission were younger and heavier, more often men, had significantly shorter history of diabetes (4.3 ± 3.8 years vs. 7.6 ± 3.8 years, p < 0.05), and exhibited significantly higher fasting and OGTT levels of C-peptide and insulin, and HOMA-IR than the other 2 groups (p < 0.05-0.01). CONCLUSION Open gastric bypass achieved complete remission of type 2 diabetes in Chinese overweight/obese, heavier, younger, predominantly male patients with shorter duration of disease exhibiting greater pancreatic endocrine reserve.
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The decline in hip bone density after gastric bypass surgery is associated with extent of weight loss.
Fleischer, J, Stein, EM, Bessler, M, Della Badia, M, Restuccia, N, Olivero-Rivera, L, McMahon, DJ, Silverberg, SJ
The Journal of clinical endocrinology and metabolism. 2008;(10):3735-40
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CONTEXT Bariatric surgery is common and may be associated with deleterious effects on the skeleton. OBJECTIVE Our objective was to assess bone metabolism and bone mineral density (BMD) after Roux-en-Y gastric bypass. DESIGN AND SETTING We conducted a 1-yr prospective longitudinal study at a university hospital bariatric surgery practice and metabolic bone disease unit. PARTICIPANTS Participants included 23 obese (mean body mass index 47 kg/m(2)) men and women, aged 20-64 yr. MAIN OUTCOME MEASURES Serum PTH, 25-hydroxyvitamin D, osteocalcin, and urinary N-telopeptide, and BMD were assessed. RESULTS Patients lost 45 +/- 2 kg 1 yr postoperatively (P < 0.01). PTH increased early (3 months, 43-50 pg/ml; P < 0.001) and urinary calcium dropped (161-92 mg/24 h; P < 0.01), despite doubling of calcium intake (1318-2488 mg/d; P < 0.001). Serum 25-hydroxyvitamin D concentrations were unchanged (23-26 ng/ml), although vitamin D intake increased by 260% (658 IU/d at baseline to 1698 IU/d at 12 months; P < 0.05). Markers of bone remodeling rose (P < 0.01 for both urinary N-telopeptide and osteocalcin), whereas BMD decreased at the femoral neck (9.2%, P < 0.005) and at the total hip (8.0%, P < 0.005). These declines were strongly associated with the extent of weight loss (femoral neck: r = 0.90, P < 0.0001; and total hip: r = 0.65, P = 0.02). Lumbar spine and distal radius sites did not change. CONCLUSIONS After Roux-en-Y gastric bypass, there was evidence of calcium and vitamin D malabsorption. Bone turnover increased, and hip bone density rapidly declined. The decline in hip BMD was strongly associated with weight loss itself. Vigilance for nutritional deficiencies and bone loss in patients both before and after bariatric surgery is crucial.