Glycemic Control after Sleeve Gastrectomy and Roux-En-Y Gastric Bypass in Obese Subjects with Type 2 Diabetes Mellitus

Glycemic Control after Sleeve Gastrectomy and Roux-En-Y Gastric Bypass in Obese Subjects with... Background Roux-en-Y gastric bypass (LRYGB) has weight-independent effects on glycemia in obese type 2 diabetic patients, whereas sleeve gastrectomy (LSG) is less well characterized. This study aims to compare early weight-independent and later weight-dependent glycemic effects of LRYGB and LSG. Methods Eighteen LRYGB and 15 LSG patients were included in the study. Glucose, insulin, GLP-1, and GIP levels were monitored during a modified 30 g oral glucose tolerance test before surgery and 2 days, 3 weeks, and 12 months after surgery. Patients self-monitored glucose levels 2 weeks before and after surgery. Results Postoperative fasting blood glucose decreased similarlyinboth groups (LRYGBvs. SG;baseline—8.1 ± 0.6 vs. 8.2 ± 0.4 mmol/l, 2 days—7.8 ± 0.5 vs. 7.4 ± 0.3 mmol/l, 3 weeks—6.6 ± 0.4 vs. 6.6 ± 0.3 mmol/l, respectively, P <0.01 vs. baseline for both groups; 12 months—6.6 ± 0.4 vs. 5.9 ± 0.4, respectively, P <0.05 for LRYGB and P <0.001 for LSG vs. baseline, P = ns between the groups at all times). LSG, but not LRYGB, showed increased peak insulin levels 2 days postoperatively (mean ± SEM; LSG + 58 ± 14%, P <0.01; LRYGB − 8±17%, P = ns). GLP-1 levels increased similarly at 2 days, but were higher in LRYGB at 3 weeks (AUC; 7525 ± 1258 vs. 4779 ± 712 pmol × min, respectively, P <0.05). GIP levels did not differ. Body mass index (BMI) decreased more after LRYGB than LSG (− 10.1 ± 0.9 vs. − 7.9 ± 0.5 kg/m , respectively, P <0.05). Conclusion LRYGB and LSG show very similar effects on glycemic control, despite lower GLP-1 levels and inferior BMI decrease after LSG. . . . . Keywords Obesity Type 2 diabetes Gastric bypass Sleeve gastrectomy Glycemic Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11695-017-3061-3) contains supplementary material, which is available to authorized users. * Ville Wallenius Department of Gastrosurgical Research and Education, Sahlgrenska ville.wallenius@gastro.gu.se Academy, University of Gothenburg, Gothenburg, Sweden Department of Endocrinology, Diabetology, and Metabolism, Eveline Dirinck University of Antwerp, Antwerp, Belgium Eveline.dirinck@uza.be Department of Surgery, Medical Academy, Lithuanian University of Almantas Maleckas Health Sciences, Kaunas, Lithuania Almantas_maleckas@yahoo.com Diabetes Complications Research Centre, Conway Institute, Carel W le Roux University College of Dublin, Dublin, Ireland carel.leroux@ucd.ie Department of Clinical Science at Danderyd Hospital, Karolinska Anders Thorell Institutet and Department of Surgery, Ersta Hospital, anders.thorell@erstadiakoni.se Stockholm, Sweden 1462 OBES SURG (2018) 28:1461–1472 Introduction Swedish language or to adhere to study instructions. At Sahlgrenska Hospital, all patients were randomized to either Obesity is a major risk factor for development of type 2 dia- method (seven LRYGB, five LSG). At Ersta Hospital (12 betes mellitus (T2DM)—and a key target in its treatment. LRYGB, 10 LSG), the patients were designated for either Bariatric surgery, and in particular Roux-en-Y gastric bypass LRYGB or LSG depending on the patients’ preference and (LRYGB), induces marked and well-characterized effects on the surgeons’ judgment, e.g., severe reflux disease was con- glycemic control that are superior to best medical treatment sidered a contraindication for LSG. There was no systematic [1]. Bariatric surgery has therefore recently been recommend- bias for the choice of one or the other method. Patients were ed as part of the diabetes treatment, extending to patients with asked to daily record their fasting (FBG) and 90 min postpran- T2DM with body mass index (BMI) below 35 kg/m [2, 3]. dial glucose levels (PPBG; after individual breakfast), as well The observed effects on glucose control are rapid and obvi- as all use of diabetes medications during 2 weeks before and ously in part non-weight dependent [4]. 2 weeks after surgery. Postoperative adjustments of diabetes A non-weight-dependent mechanism after surgery involv- medications were handled by the physician usually in charge ing bypass of the small intestine is a rapid and pronounced of the patient’s diabetes treatment. Weight, waist circumfer- postprandial increase of incretin hormones, e.g., glucagon-like ence, and height were recorded with patients wearing only peptide (GLP)-1 [5, 6]. Despite its Bsimplistic^ nature without underwear after an overnight fast. The usual 2-week preoper- intestinal bypass and despite incomplete elucidation of the ative low-energy diet (LED) was omitted in order not to influ- underlying mechanisms, laparoscopic sleeve gastrectomy ence preoperative or early postoperative glycemic control (LSG) seems to have good effects on glucose control as well, [12]. Eighteen patients underwent LRYGB and 15 underwent at least in the middle–long term. Some data indicate that gas- LSG. One patient who was not operated on by the intended tric emptying is not delayed after LSG, suggesting that the technique at Sahlgrenska was excluded. One patient was lost operation does not exert its effects solely through to follow-up after the 3-week follow-up. The total follow-up Brestriction.^ [7–9] Supporting this idea is the observation in rate was 94% (see Supplementary Fig. 1 for flow chart of pregnant rat dams showing that they can increase food intake inclusion). Data for GLP-1 and GIP were lost for four patients substantially even after LSG surgery [10]. Despite the lack of in the LSG group at 12 months; therefore, data are shown for intestinal bypass, it seems that release of several incretins, 11 LSG patients in Figs. 6dand 7d. All patients were of such as GLP-1 and peptide YY (PYY), is increased in a sim- Caucasian origin. The study was registered at ClinicalTrials. ilar way after LSG as after LRYGB, at least in non-diabetic gov identifier NCT01984762. patients [11]. A potential mechanism could be, in line with the situation after LRYGB, that, due to the reduced reservoir ca- Study Ethics pacity of the stomach, undigested food enters the small intes- tine more rapidly, which in turn increases stimulation of the This study was approved by the Regional Ethical Review hormone-producing entero-endocrine cells of the intestinal Board of Gothenburg (study reference number 016-12), and mucosa. the study was conducted according to the principles of the The aim of this study was to compare and characterize, in Helsinki declaration. All patients gave written informed detail, the changes in glycemic control in patients with T2DM consent. and obesity who undergo LRYGB or LSG. In order to differ- entiate between weight- and non-weight-dependent effects, Modified Oral Glucose Tolerance Test (MOGTT) measurements were performed at various times after surgery. MOGTT with 30 g of glucose (compared to standard OGTT 75 g) dissolved in 150 ml water was performed Methods at four occasions: 3 weeks preoperatively and 2 days, 3 weeks, and 12 months postoperatively. The glucose Patients dose was reduced in order to, as far as possible, avoid sideeffectssuchasvomitinganddumpinginthepost- Thirty-four subsequent patients with T2DM who fulfilled the operative phase. MOGTT was performed after a 12-h inclusion criteria were asked to participate and were included fast. Patients did not take any antidiabetic medications, from the waiting list for bariatric surgery at two sites in and no long-, intermediate-, or fast-acting insulin was Sweden, the Sahlgrenska University Hospital, Gothenburg, administered on the morning of the test. Glucose, insulin, and Ersta Hospital, Stockholm. The inclusion criteria were glucagon-like peptide (GLP)-1, and gastric inhibitory BMI 35–50 kg/m , age 18–60 years, and T2DM requiring peptide (GIP) levels were measured at 0, 15, 30, 60, any available diabetes medications, but not only dietary regi- 90, 120, 150, and 180 min after intake of the oral glu- men. Exclusion criteria were inability to understand the cose dose. In case the glucose level declined to basal OBES SURG (2018) 28:1461–1472 1463 level at any time before 180 min, the blood sampling cell functioning in the stability of a fasting state and using a wasterminatedatthattime. single mathematical model such as HOMA-B is less reliable than the assessment of a relatively stable factor such as insulin Surgery resistance [15]. All patients underwent a laparoscopic LRYGB or LSG by Statistics experienced bariatric surgeons. LRYGB was performed by a five-port technique with the use of a linear stapler for both the All statistics were performed using Prism 5 and 7 (version gastrojejunostomy and the jejuno-jejunostomy. A running su- 5.0a and 7.0a). Logarithmic transformation was performed ture was used for closure of the remaining defects as previ- where indicated in order to obtain equal variances. Area under ously described [13]. The length of the Roux limb (alimentary the curve for glucose, insulin, GLP-1, and GIP during the oral limb) was typically 120 cm and the biliopancreatic limb glucose tolerance tests was calculated using the trapezoidal 50 cm. For LSG, a linear stapler was used for resection of rule. One-way ANOVA with Dunnett’s post hoc test was used the stomach over a 35–36 F bougie from 3 to 5 cm proximal for analyzing changes from baseline to the different postoper- to the pylorus to 1–2 cm distal to the angle of His. ative times within groups. Paired and unpaired Student’s t test Postoperative dietary recommendations included intake of was used for single comparisons between baseline and post- fluids and semi-solid food for 2 weeks, and solid food there- operative values and between the groups, respectively. χ test after. Patients were instructed to adhere to a diet rich in protein was used to compare numbers of patients on/off diabetes med- and with a calorie content of approximately 800–1000 kcal for ications 12 months after surgery. A P value of < 0.05 was the first six postoperative weeks. considered statistically significant. Glucose, Insulin, GLP-1, and GIP Measurements Results At the Sahlgrenska University Hospital, blood glucose was measured using StatStrip according to the manufacturer’sin- Anthropometry and Diabetes structions (Nova Biomedical, Waltham, MA, USA). At Ersta Hospital, blood glucose was measured using the YSI Model There were no differences in age, gender, weight, BMI, dia- 2300 Stat Plus glucose analyzer according to the manufac- betes duration, or basal HbA1c between the LRYGB and LSG turer’s instructions (Yellow Springs Instruments, OH, USA). groups of patients (Table 1). The reduction in body weight and Insulin was measured by an electrochemiluminescence immu- BMI at 12 months postoperatively was significantly greater noassay BECLIA^ using a Cobas e immunoassay analyzer after LRYGB compared to LSG, whereas the improvement of according to the manufacturer’s instructions (Roche HbA1c did not differ between groups (Table 1). The number Diagnostics, Dublin, Ireland). The intra-assay variation of of patients needing diabetes medications and/or insulin treat- the insulin measurement was 1.1–1.4% (CV) and the inter- ment decreased after surgery and was not different between assay variation 3.5–3.7% (CV). The cross-reactivity with the LRYGB and the LSG group, neither at baseline nor post- IGF-1 was 0.04%. GLP-1 and GIP were measured using operatively up to 12 months (Table 2). The diabetes medica- ELISAs according to the manufacturer’s instructions (Merck tion and insulin doses in the individual patients in the respec- Millipore, Solna, Sweden; Human total GIP ELISA, product tive group at baseline and 12 months postoperatively are number EZHGIP-54K, and Multi Species GLP-1 Total shown in Table 3. ELISA, product number EZGLP1T-36K). The intra-assay variation for GLP-1 was 1–2% (CV) and the inter-assay var- Fasting Glucose, Insulin, and HOMA iation < 12% (CV). For GIP, the intra-assay variation was 3– 8.8% (CV) and the inter-assay variation 1.8–6.1% (CV). Fasting blood glucose (FBG) concentrations were not signif- icantly changed in either group at 2 days after surgery, but Calculation of HOMA-IR and HOMA-B (%) were decreased in both groups at 3 weeks and 12 months after surgery (Fig. 1a). Fasting plasma insulin was decreased as HOMA-IR, an index of insulin resistance, was calculated early as on day 2 in both groups; however, only significantly based on the morning fasting plasma insulin and blood glu- in the LRYGB patients at this time (Fig. 1b). At 3 weeks and cose levels using the formula: HOMA-IR = (insulin (μIU/ 12 months after surgery, fasting insulin was similarly de- ml) × FBG (mmol/l))/ 22.5. HOMA-B (%) is a measure of creasedinbothgroups. HOMA-IR wassignificantlyim- pancreatic β-cell activity and was calculated using the formu- proved compared to baseline from day 2 to 12 months after la: ((20 × insulin (μIU/ml))/(FBG (mmol/l)) – 3.5)% [14]. It surgery within both LRYGB and LSG groups, and did not should be noted that the assessment of the dynamics of beta differ between the groups at baseline, or at any time after 1464 OBES SURG (2018) 28:1461–1472 Table 1 Anthropometric measures of the study groups at baseline and after surgery RYGB SG RYGB SG Mean ± SEM Pbase Mean ± SEM Pbase Pgroups Gender (F/M) 10:8 7:8 0.62 Age (years) Base 51.2 ± 1.6 51.9 ± 1.9 0.78 Body weight (kg) Base 112.9 ± 3.6 109.0 ± 3.4 0.43 12 mo 84.3 ± 3.0 < 0.001 85.2 ± 3.0 < 0.001 0.83 Δ Body weight (kg) 12 mo 29.5 ± 2.6 22.1 ± 1.2 < 0.05 ) Base 38.6 ± 0.8 36.9 ± 0.7 0.14 BMI (kg/m 12 mo 28.8 ± 0.7 < 0.001 28.6 ± 0.6 < 0.001 0.86 Δ BMI (kg/m ) 12 mo 10.1 ± 0.9 7.9 ± 0.5 < 0.05 EWL (%) 12 mo 73.0 ± 5.0 < 0.001 69.1 ± 4.4 < 0.001 0.57 Waist/hip ratio Base 1.00 ± 0.02 1.02 ± 0.02 0.58 12 mo 0.96 ± 0.02 < 0.01 0.94 ± 0.02 < 0.001 0.53 Diab duration (years) Base 5.7 ± 0.6 6.5 ± 1.1 0.54 HbA1c (%) Base 61.8 ± 3.9 55.7 ± 2.1 0.20 6 w 50.3 ± 2.9 < 0.001 48.7 ± 2.0 < 0.001 0.66 12 mo 40.5 ± 2.0 < 0.001 43.9 ± 2.7 < 0.01 0.34 Δ HbA1c (%) 0–12 mo − 15.9 ± 5.2 < 0.001 − 11.5 ± 2.6 < 0.001 0.47 surgery (Table 4). HOMA-B (%) improved both after SG and insulin release in response to the glucose load was blunt and RYGB, but the difference reached significance only in RYGB showed a prolonged peak from 15 to 90 min in both groups compared to baseline at 2 days and 12 months, and there were (Fig. 3a). After surgery, already from day 2 and on, the insulin no significant differences between the groups at any time responses were more rapid and distinct and the peak occurred (Table 4). at 15–30 min in both groups (Fig. 3b–d). Total AUC for insu- lin was not different between the groups and only significantly decreased in the LSG group at 12 months compared to base- MOGTT line (0–180 min; Fig. 3e). However, the seemingly elevated insulin peak area at 2 days in LSG encouraged us to analyze In the LSG group, 3 out of 15 patients were able to ingest only insulin peak AUCs 0–60 min. This revealed a clearly signifi- part of the glucose dose 2 days after surgery because of nausea cant increase in the LSG, but not in the LRYGB group, both at (20 g in two patients and 15 g in one patient). All 2-day day 2 and at 3 weeks postoperatively (Fig. 4c, d). calculations were repeated with exclusion of these three pa- tients, but that did not change the outcomes in any significant way. Glucose and insulin levels during MOGTT in RYGB and Patient Self-Measured Glucose Levels Pre- SG from baseline to 12 months after surgery are shown in and Postoperatively Figs. 2 and 3. Glucose clearance was significantly improved in both groups at 3 weeks after surgery as calculated using Figure 5 shows patient self-measured FBG and 90 min PPBG AUC 0–180 min and continued to improve in both groups after an individual breakfast during the first 2 weeks before until 12 months after surgery (Fig. 2e). The preoperative compared to 2 weeks immediately after surgery. In line with Table 2 Total numbers of T2DM treatment OAD Insulin OAD + insulin All treatm No treatm patients and types of medications n (%) n (%) n (%) n (%) n (%) before and 12 months after surgery RYGB Before 9 (53) 1 (6) 7 (41) 17 (100) – After 6 (35) 1 (6) 0 (0) 7 (41) 10 (59) SG Before 11 (73) 0 (0) 4 (27) 15 (100) – After 5 (33) 0 (0) 1 (7) 6 (40) 9 (60) Total no. of patients on/off medications 12 months after surgery were compared by χ test OBES SURG (2018) 28:1461–1472 1465 Table 3 Diabetes medications in all subjects before and 12 months after surgery Subject number Diabetes treatment, baseline Diabetes treatment, 12 months Metformin (mg) OAD (mg) Insulin (IU) Metformin (mg) OAD (mg) Insulin (IU) RYGB 1 1500 0 2168 0 31500 0 41000 0 5 1000 Glimepiride (1000), liraglutide (1.8) 0 0 6 2000 Liraglutide (1.2) 40 0 0 0 81000 0 91000 0 10 2000 0 11 2000 28 0 0 14 1500 0 16 500 95 –– 19 3000 94 500 0 20 2550 Glibenklamide (1.75) 1000 0 21 1000 0 24 1000 wn 3000 0 26 2000 25 500 0 34 1500 30 1000 0 SG 12 1500 46 0 0 13 3000 Glimepiride (4) 0 0 17 2000 Glimepiride (4) 2000 Glimepiride (2) 18 3000 Glimepiride (2) 1000 0 22 1500 0 23 1000–1500 0 25 1500 Pioglitazone (30) 1000 0 27 3000 80 3000 28 28 1500 Glibenklamide (7) 2000 Glibenklamide (3.5) 29 1000 0 30 500 0 31 1500 0 32 2550 58–70 0 0 33 2000 80 1000 0 39 500 0 Liraglutide was administered by subcutaneous injections wn when needed the data from the MOGTTs, these self-reported glucose mea- Three weeks after surgery, GLP-1 levels, in response to the surements clearly showed significantly decreased FBG and MOGTT, were maintained in the LRYGB patients, whereas 90 min PPBG levels in both groups of patients with no differ- they had started to decline in the LSG patients and declined ences between the groups (Fig. 5). further at 12 months to levels not different compared with baseline (Fig. 6c, d). Although the total AUC at 12 months was not increased compared to baseline in LRYGB, it was still Glucagon-Like Peptide (GLP-)1 Levels after Surgery significantly higher in the LRYGB group compared to LSG group (Fig. 6e). Analysis of peak AUC (0–60 min; hatched The GLP-1 levels during MOGTT were substantially in- area in Fig. 6d) showed an increase in the GLP-1 peak after creased 2 days after both LRYGB and LSG with no differ- LRYGB also at 12 months compared to baseline, whereas ences in AUCs between the groups (Fig. 6a, b, e). there was no increase after LSG (Fig. 6f). 1466 OBES SURG (2018) 28:1461–1472 Fig. 1 a Fasting blood glucose (FBG) and b fasting plasma insulin (fP- intervals for AUCs. The plus sign shows the mean. *P <0.05, **P < Insulin) levels at baseline, 2 days, 3 weeks, and 12 months after LRYGB 0.01, and ***P < 0.001 for ANOVA with Dunnett’s post hoc test for or LSG surgery. The box plots show the median and 95% confidence comparisons within groups at the different times after surgery vs. baseline Gastric Inhibitory Peptide (GIP) Levels after Surgery in patients with obesity and T2DM. Therefore, we performed a comparative study between LSG and LRYGB, to examine GIPlevelsinresponsetoMOGTT weresignificantlyin- the early postoperative effects on glycemic control, supple- creased in both LSG and LRYGB patients at 2 days and mented by the effects after 1 year. 3 weeks after surgery compared to baseline (Fig. 7a–c). The most important finding of the present study in pa- They then started to decline and were not significantly in- tients with T2DM was that the early effect of SG on glucose creased at 12 months in either group compared to baseline control and insulin secretion was equal compared to that of (Fig. 7d, e). AUC GIP was higher in LRYGB compared with RYGB. Although based on a relatively limited number of LSG at baseline, but no differences were noted between patients, we found that RYGB elicited a statistically signif- groups postoperatively (Fig. 7e). icant increase in the GLP-1 response at 3 weeks. However, this did not translate into a greater improvement of glucose metabolism variables in the RYGB group at that moment Discussion compared to the LSG group. This is well in line with exper- imental data from animal studies, showing that even com- Sleeve gastrectomy (LSG) is currently one of the most com- plete absence of GLP-1 does not change the effect of LSG mon bariatric operations worldwide, although the long-term on weight decrease and glucose metabolism [20]. In relation effects on body weight and diabetes have not yet been char- to LRYGB, it has been speculated that decreased release of a acterized in detail. A number of studies focusing on long-term hitherto uncharacterized anti-incretin or Bdecretin^ factor effects are ongoing [16–19], but very few data on the very from the bypassed foregut, which would suppress insulin early weight-independent effects of LSG have been presented release, could be of importance [21]. If this factor is of Table 4 HOMA-IR and HOMA- RYGB SG Paired-samples t test Independent-samples t test B (%) at baseline and 2 days, 3 weeks, and 12 months after RYGB SG surgery Mean ± SD Mean ± SD P value P value P value HOMA-IR Baseline 9.2 ± 6.4 8.4 ± 6.2 –– 0.63 2 days 4.5 ± 2.4 5.4 ± 1.8 < 0.001 < 0.05 0.13 3 weeks 3.8 ± 2.0 4.0 ± 1.6 < 0.001 < 0.001 0.52 12 months 1.9 ± 1.2 2.3 ± 1.1 < 0.001 < 0.001 0.31 HOMA-B (%) Baseline 151 ± 132 130 ± 116 –– 0.63 2 days 87 ± 87 94 ± 46 <0.05 0.387 0.25 3 weeks 107 ± 81 93 ± 40 0.141 0.344 0.99 12 months 56 ± 42 87 ± 56 0.001 0.245 0.11 All statistical analyses were performed with logarithmically transformed values in order to obtain normal distri- bution. Paired-samples t test was performed comparing baseline values with values at 2 days, 3 weeks, and 12 months, respectively. Independent-samples t test was performed between RYGB and SG OBES SURG (2018) 28:1461–1472 1467 Fig. 2 Blood glucose levels (B- glucose) 0–180 min after a modified 30 g oral glucose tolerance test at a baseline, b 2days, c 3weeks, and d 12 months after LRYGB or LSG. Graphs (a)–(d) show means ± SEM. e The box plots show the median and 95% confidence intervals for AUCs for the corresponding times. The plus sign shows the mean. **P <0.01 and ***P <0.001 for ANOVA with Dunnett’s post hoc test for comparisons within groups at the different times after surgery vs. baseline importance after LSG as well, it would most probably be mentioned above, these differences did not translate into dif- released from the area along the major curvature of the ferences in clinically relevant diabetes measures or diabetes stomach, which is removed, rather than from the duodenum medication use between the groups at any time during the first since this is not bypassed in LSG. Moreover, this would also postoperative year. The fact that both groups lost more than fit with the rapid recurrence of diabetes in RYGB patients or 20% of their initial body weight after 1 year corresponds to the diabetic rats where food is reintroduced to the remnant stom- observed improvement in glucose metabolism. These im- ach via a gastrostomy cannula [22, 23]. On the other hand, provements can be equally important when the weight loss many other factors have been suggested to influence the has been achieved by non-dietary measures, as shown in the metabolic response after bariatric surgery, e.g., bile acids Look AHEAD study [28]. and changes of the microbiota [24]. Our study did not focus Postoperative vomiting and nausea (PONV) is more com- on the latter aspects, and as such, a contribution of these monly reported after LSG than after LRYGB. Accordingly, parameters cannot be excluded nor proven. Moreover, calo- three of the LSG patients were not able to ingest the entire rie restriction is known to be a potent insulin sensitizer [25]. 30 g glucose dose at the first 2-day MOGTT. This did, how- The improvement in glucose metabolism, observed in both ever, not influence the data presented in any significant way groups, could be influenced by the preoperative fasting and since the results were the same irrespective if these patients postoperatively decreased caloric intake. The authors assume were included or not. On post-op day 2, HOMA-IR was sig- caloric intake was similarly decreased within the first days nificantly reduced in both groups, whereas fP-insulin and and weeks after SG and RYGB despite the fact that the two HOMA-B (%) were significantly reduced only in the procedures are anatomically completely distinct. LRYGB patients. On the other hand, the peak AUC 0– In corroboration with previous studies [17, 18, 26, 27], the 60 min for insulin was increased only in the LSG patients at weight loss was statistically significantly lower after LSG this time. Although we cannot exclude that the lack of differ- compared to LRYGB 1 year after surgery. Despite this and ences between groups was due to a type II error, these findings might suggest that the anti-diabetes effects of these two despite the subtle differences in the insulin and GLP-1 curves, 1468 OBES SURG (2018) 28:1461–1472 Fig. 3 Plasma insulin levels 0– 180 min after a modified 30 g oral glucose tolerance test at a baseline, b 2days, c 3 weeks, and d 12 months after LRYGB or LSG. Graphs (a)–(d)show means ± SEM. e Box plots show the median and 95% confidence intervals for AUCs for the corresponding times. The plus sign shows the mean. *P <0.05 for ANOVA followed by Dunnett’s post hoc test for comparisons within groups at the different times after surgery vs. baseline operations are distinct, with a somewhat more pronounced The measurements at 1 year postoperatively were per- effect by LRYGB on insulin sensitivity, and by LSG on β- formed in order to evaluate the combined effect of weight- cell activity. dependent and non-weight-dependent mechanisms. There Fig. 4 Within-group plasma insulin levels 0–180 min after a modified 30 g oral glucose tolerance test at baseline, 2 days, 3 weeks, and 12 months after a LRYGB or b LSG. Graphs (a) and (b) show means ± SEM. Box plots show the median and 95% confidence intervals for AUCs 0– 60 min (gray hatched areas in a and b)for c LRYGB and d LSG. The plus sign shows the mean. AUCs *P < 0.05 and ***P < 0.001 for ANOVA followed by Dunnett’s post hoc test for comparisons within groups at the different times after surgery vs. baseline OBES SURG (2018) 28:1461–1472 1469 were no significant differences in glycemic control between LSG and LRYGB at 1 year, as assessed by HbA1c levels, MOGTT measurements, the patients self-reported FBG and PPBG, or the numbers of patients off anti-diabetes medica- tions. The exception being HOMA-B (%), that still was sig- nificantly decreased after LRYGB but not LSG. The effect of LSG, with removal of a major part of the stomach, could be related to the decreased reservoir capacity and the transfer of undigested food to the small intestine where the release of hindgut factors, e.g., GLP-1 and GIP, is stimulated and could exert beneficial effects on insulin and glucagon release. The levels of incretin hormones, in response to a somewhat higher oral glucose load, were previously shown to be relatively sim- ilar in non-diabetic RYGB and SG patients [11]. In the present Fig. 5 Patient self-reported morning FBG (left 4 box plots) and 90 min PPBG (right 4 box plots) measured during 14 days preoperatively (pre) study, however, the GLP-1 stimulatory effect of LSG was and 14 days postoperatively (post) after LRYGB or LSG, showing the transient and started to subside already 3 weeks after surgery. median and 95% confidence intervals. The plus sign shows the mean. The Whether this reflects a true difference in GLP-1 response after patients were not put on LED before surgery to avoid effects of fasting on LSG compared to LRYGB in patients with or without diabetes glucose. White bars represent LRYGB and hatched bars represent LSG. **P < 0.01 and ***P <0.001 for paired t test within groups before and is not entirely clear. An alternative explanation is that the after surgery differences in GLP-1 response are associated with the use of Fig. 6 Plasma GLP-1 levels 0– 180 min after a modified 30 g oral glucose tolerance test at a baseline, b 2days, c 3 weeks, and d 12 months after LRYGB or LSG. Graphs (a)–(d)show mean ± SEM. e Box plots showing median and 95% confidence intervals for AUCs for GLP-1 at corresponding times. The plus sign shows the mean. f Peak AUC for GLP-1 (0–60 min) after LRYGB and LSG. **P < 0.01 and ***P <0.001 for ANOVA followed by Dunnett’s post hoc test for comparisons within groups at the different times after surgery vs. baseline. # ## P <0.01 and P < 0.001 for unpaired t test between LRYGB and LSG. P < 0.05 paired- samples t test within group. N = 18 for LRYGB and 15 for LSG in all panels, except panel (d)where n = 11 for LSG 1470 OBES SURG (2018) 28:1461–1472 Fig. 7 Plasma GIP levels 0– 180 min after a modified 30 g oral glucose tolerance test at a baseline, b 2days, c 3 weeks, and d 12 months after LRYGB or LSG. Graphs (a)–(d)show means ± SEM. e Box plots showing median and 95% confidence intervals for AUCs for GIP at corresponding times. The plus sign shows the mean. *P < 0.05, **P < 0.01, and ***P < 0.001 for one-way ANOVA followed by Dunnett’spost hoc ## test. P < 0.001 for between- groups t test LRYGB vs. LSG. N = 18 for LRYGB and 15 for LSG in all panels, except panel (d)where n =11 for LSG a lower energy load in our study (30 g glucose vs. a liquid test Strengths of this study were the careful monitoring of glu- meal containing 15 g carbohydrates, 25 g protein, and 28 g cose metabolism at several times both very early and up to a fat). year after surgery by MOGTT, and the Breal-life^ self- Limitations of this study include the relatively small num- monitoring data from patients during 2 weeks before and bers of patients, which obviously is associated with a risk that 2 weeks after surgery on glucose levels at fasting and post- we were unable to statistically demonstrate some additional prandially after breakfast. true differences between the groups. Moreover, all patients In conclusion, in this study, LSG exerted early beneficial were not randomized. Anthropometric data were not different effects on glycemia that were nearly indistinguishable from in any aspect between the groups at baseline. To assess glu- those after LRYGB. GLP-1 secretion in response to an oral cose metabolism, ingestion of a low-dose glucose drink was glucose load was only transiently increased after LSG, in con- used. This choice was made to avoid vomiting and dumping, trast to LRYGB where GLP-1 peak levels were still increased despite the fact that this low-dose drink has not been exten- at 1 year postoperatively. The BMI loss after 1 year was lower sively validated. A similar load of glucose has, however, pre- after LSG than LRYGB. Elucidation of other mechanisms that viously been shown to induce a satisfactory response in intes- contribute to the positive glycemic effects of LSG may hold tinal hormones after bariatric surgery [29]. Moreover, using a the key to understanding how patients can be helped to main- glucose drink as opposed to a mixed meal test limits the inter- tain long-term glycemic control after bariatric surgery. pretability as human data indicate proteins are also able to elicit a dose-dependent incretin effect [30]. Detailed food di- aries, in particular during the first 3 weeks after surgery, were Conclusion not collected. Therefore, the authors cannot be certain that patients consumed the recommended post-op diet. Recent LRYGB and LSG induced similar effects on glycemic control, studies suggest that differences in glycemic control between both very early after surgery and up to 1 year after surgery, despite the groups may appear with longer follow-up time [19]. lower GLP-1 levels and inferior decrease of BMI after LSG. OBES SURG (2018) 28:1461–1472 1471 Acknowledgments We would like to thank My Engström, Niclas 8. Melissas J, Daskalakis M, Koukouraki S, et al. Sleeve gastrecto- Björnfot, Anette Bratt, and Hans-Georg Eckhardt for skillful technical my—a Bfood limiting^ operation. Obes Surg. 2008;18(10):1251–6. assistance. This study was started as a collaboration between European https://doi.org/10.1007/s11695-008-9634-4. endocrinologists and bariatric surgeons in the European Obesity 9. Melissas J, Koukouraki S, Askoxylakis J, et al. Sleeve gastrectomy: Academy 2, which was made possible by generous sponsorship from a restrictive procedure? Obes Surg. 2007;17(1):57–62. https://doi. Ethicon Endosurgery/Johnson & Johnson. The study was also funded org/10.1007/s11695-007-9006-5. by the Erling-Persson Family Foundation, the Erik & Lily Philipson 10. Grayson BE, Schneider KM, Woods SC, et al. Improved rodent Memorial Foundation, and the Western Region of Sweden ALF grant maternal metabolism but reduced intrauterine growth after vertical number 94251. sleeve gastrectomy. Sci Transl Med. 2013;5:199ra12. 11. Peterli R, Wolnerhanssen B, Peters T, et al. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Compliance with Ethical Standards roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial. Ann Surg. 2009;250(2):234–41. Conflict of Interest Dr. Wallenius reports grants from Western Region of https://doi.org/10.1097/SLA.0b013e3181ae32e3. Sweden, grants from Erik and Lily Philipson memorial foundation, dur- 12. Pournaras DJ, Nygren J, Hagstrom-Toft E, et al. Improved glucose ing the conduct of the study; personal fees from Johnson & Johnson, metabolism after gastric bypass: evolution of the paradigm. Surg outside the submitted work. Dr. Anders Thorell reports research grants Obes Relat Dis. 2016;12(8):1457–65. https://doi.org/10.1016/j. from the Erling Persson family foundation. Dr. Carel le Roux reports soard.2016.03.020. research grants from Science Foundation Ireland, and the Health 13. Olbers T, Lonroth H, Fagevik-Olsen M, et al. Laparoscopic gastric Research Board, Ireland, during the conduct of the study; other from bypass: development of technique, respiratory function, and long- Novo Nordisk, other from GI Dynamics, personal fees from Eli Lilly, term outcome. Obes Surg. 2003;13(3):364–70. https://doi.org/10. grants and personal fees from Johnson & Johnson, personal fees from 1381/096089203765887679. Sanofi Aventis, personal fees from Astra Zeneca, personal fees from 14. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model Janssen, personal fees from Bristol-Myers Squibb, and personal fees from assessment: insulin resistance and beta-cell function from fasting Boehringer-Ingelheim outside of the submitted work. Eveline Dirinck, plasma glucose and insulin concentrations in man. Diabetologia. Almantas Maleckas, and Lars Fändriks report no conflict of interest. 1985;28(7):412–9. https://doi.org/10.1007/BF00280883. 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Diabetes. 2010;59(3):627–33. https://doi.org/10.2337/ effects of calorie restriction in patients with type 2 diabetes with db09-1239. abdominal obesity: a randomized controlled trial. Diabetes. 29. Wolnerhanssen BK, Meyer-Gerspach AC, Peters T, et al. Incretin 2017;66(1):75–86. https://doi.org/10.2337/db16-0607. effects, gastric emptying and insulin responses to low oral glucose 26. Lee WJ, Chong K, Lin YH, et al. Laparoscopic sleeve gastrectomy loads in patients after gastric bypass and lean and obese controls. versus single anastomosis (mini-) gastric bypass for the treatment of Surg Obes Relat Dis 2015. type 2 diabetes mellitus: 5-year results of a randomized trial and 30. Belza A, Ritz C, Sorensen MQ, et al. Contribution of study of incretin effect. Obes Surg. 2014;24(9):1552–62. https:// gastroenteropancreatic appetite hormones to protein-induced sati- doi.org/10.1007/s11695-014-1344-5. ety. Am J Clin Nutr. 2013;97(5):980–9. https://doi.org/10.3945/ 27. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus ajcn.112.047563. intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567–76. https://doi.org/10.1056/NEJMoa1200225. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Obesity Surgery Springer Journals

Glycemic Control after Sleeve Gastrectomy and Roux-En-Y Gastric Bypass in Obese Subjects with Type 2 Diabetes Mellitus

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Medicine & Public Health; Surgery
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Abstract

Background Roux-en-Y gastric bypass (LRYGB) has weight-independent effects on glycemia in obese type 2 diabetic patients, whereas sleeve gastrectomy (LSG) is less well characterized. This study aims to compare early weight-independent and later weight-dependent glycemic effects of LRYGB and LSG. Methods Eighteen LRYGB and 15 LSG patients were included in the study. Glucose, insulin, GLP-1, and GIP levels were monitored during a modified 30 g oral glucose tolerance test before surgery and 2 days, 3 weeks, and 12 months after surgery. Patients self-monitored glucose levels 2 weeks before and after surgery. Results Postoperative fasting blood glucose decreased similarlyinboth groups (LRYGBvs. SG;baseline—8.1 ± 0.6 vs. 8.2 ± 0.4 mmol/l, 2 days—7.8 ± 0.5 vs. 7.4 ± 0.3 mmol/l, 3 weeks—6.6 ± 0.4 vs. 6.6 ± 0.3 mmol/l, respectively, P <0.01 vs. baseline for both groups; 12 months—6.6 ± 0.4 vs. 5.9 ± 0.4, respectively, P <0.05 for LRYGB and P <0.001 for LSG vs. baseline, P = ns between the groups at all times). LSG, but not LRYGB, showed increased peak insulin levels 2 days postoperatively (mean ± SEM; LSG + 58 ± 14%, P <0.01; LRYGB − 8±17%, P = ns). GLP-1 levels increased similarly at 2 days, but were higher in LRYGB at 3 weeks (AUC; 7525 ± 1258 vs. 4779 ± 712 pmol × min, respectively, P <0.05). GIP levels did not differ. Body mass index (BMI) decreased more after LRYGB than LSG (− 10.1 ± 0.9 vs. − 7.9 ± 0.5 kg/m , respectively, P <0.05). Conclusion LRYGB and LSG show very similar effects on glycemic control, despite lower GLP-1 levels and inferior BMI decrease after LSG. . . . . Keywords Obesity Type 2 diabetes Gastric bypass Sleeve gastrectomy Glycemic Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11695-017-3061-3) contains supplementary material, which is available to authorized users. * Ville Wallenius Department of Gastrosurgical Research and Education, Sahlgrenska ville.wallenius@gastro.gu.se Academy, University of Gothenburg, Gothenburg, Sweden Department of Endocrinology, Diabetology, and Metabolism, Eveline Dirinck University of Antwerp, Antwerp, Belgium Eveline.dirinck@uza.be Department of Surgery, Medical Academy, Lithuanian University of Almantas Maleckas Health Sciences, Kaunas, Lithuania Almantas_maleckas@yahoo.com Diabetes Complications Research Centre, Conway Institute, Carel W le Roux University College of Dublin, Dublin, Ireland carel.leroux@ucd.ie Department of Clinical Science at Danderyd Hospital, Karolinska Anders Thorell Institutet and Department of Surgery, Ersta Hospital, anders.thorell@erstadiakoni.se Stockholm, Sweden 1462 OBES SURG (2018) 28:1461–1472 Introduction Swedish language or to adhere to study instructions. At Sahlgrenska Hospital, all patients were randomized to either Obesity is a major risk factor for development of type 2 dia- method (seven LRYGB, five LSG). At Ersta Hospital (12 betes mellitus (T2DM)—and a key target in its treatment. LRYGB, 10 LSG), the patients were designated for either Bariatric surgery, and in particular Roux-en-Y gastric bypass LRYGB or LSG depending on the patients’ preference and (LRYGB), induces marked and well-characterized effects on the surgeons’ judgment, e.g., severe reflux disease was con- glycemic control that are superior to best medical treatment sidered a contraindication for LSG. There was no systematic [1]. Bariatric surgery has therefore recently been recommend- bias for the choice of one or the other method. Patients were ed as part of the diabetes treatment, extending to patients with asked to daily record their fasting (FBG) and 90 min postpran- T2DM with body mass index (BMI) below 35 kg/m [2, 3]. dial glucose levels (PPBG; after individual breakfast), as well The observed effects on glucose control are rapid and obvi- as all use of diabetes medications during 2 weeks before and ously in part non-weight dependent [4]. 2 weeks after surgery. Postoperative adjustments of diabetes A non-weight-dependent mechanism after surgery involv- medications were handled by the physician usually in charge ing bypass of the small intestine is a rapid and pronounced of the patient’s diabetes treatment. Weight, waist circumfer- postprandial increase of incretin hormones, e.g., glucagon-like ence, and height were recorded with patients wearing only peptide (GLP)-1 [5, 6]. Despite its Bsimplistic^ nature without underwear after an overnight fast. The usual 2-week preoper- intestinal bypass and despite incomplete elucidation of the ative low-energy diet (LED) was omitted in order not to influ- underlying mechanisms, laparoscopic sleeve gastrectomy ence preoperative or early postoperative glycemic control (LSG) seems to have good effects on glucose control as well, [12]. Eighteen patients underwent LRYGB and 15 underwent at least in the middle–long term. Some data indicate that gas- LSG. One patient who was not operated on by the intended tric emptying is not delayed after LSG, suggesting that the technique at Sahlgrenska was excluded. One patient was lost operation does not exert its effects solely through to follow-up after the 3-week follow-up. The total follow-up Brestriction.^ [7–9] Supporting this idea is the observation in rate was 94% (see Supplementary Fig. 1 for flow chart of pregnant rat dams showing that they can increase food intake inclusion). Data for GLP-1 and GIP were lost for four patients substantially even after LSG surgery [10]. Despite the lack of in the LSG group at 12 months; therefore, data are shown for intestinal bypass, it seems that release of several incretins, 11 LSG patients in Figs. 6dand 7d. All patients were of such as GLP-1 and peptide YY (PYY), is increased in a sim- Caucasian origin. The study was registered at ClinicalTrials. ilar way after LSG as after LRYGB, at least in non-diabetic gov identifier NCT01984762. patients [11]. A potential mechanism could be, in line with the situation after LRYGB, that, due to the reduced reservoir ca- Study Ethics pacity of the stomach, undigested food enters the small intes- tine more rapidly, which in turn increases stimulation of the This study was approved by the Regional Ethical Review hormone-producing entero-endocrine cells of the intestinal Board of Gothenburg (study reference number 016-12), and mucosa. the study was conducted according to the principles of the The aim of this study was to compare and characterize, in Helsinki declaration. All patients gave written informed detail, the changes in glycemic control in patients with T2DM consent. and obesity who undergo LRYGB or LSG. In order to differ- entiate between weight- and non-weight-dependent effects, Modified Oral Glucose Tolerance Test (MOGTT) measurements were performed at various times after surgery. MOGTT with 30 g of glucose (compared to standard OGTT 75 g) dissolved in 150 ml water was performed Methods at four occasions: 3 weeks preoperatively and 2 days, 3 weeks, and 12 months postoperatively. The glucose Patients dose was reduced in order to, as far as possible, avoid sideeffectssuchasvomitinganddumpinginthepost- Thirty-four subsequent patients with T2DM who fulfilled the operative phase. MOGTT was performed after a 12-h inclusion criteria were asked to participate and were included fast. Patients did not take any antidiabetic medications, from the waiting list for bariatric surgery at two sites in and no long-, intermediate-, or fast-acting insulin was Sweden, the Sahlgrenska University Hospital, Gothenburg, administered on the morning of the test. Glucose, insulin, and Ersta Hospital, Stockholm. The inclusion criteria were glucagon-like peptide (GLP)-1, and gastric inhibitory BMI 35–50 kg/m , age 18–60 years, and T2DM requiring peptide (GIP) levels were measured at 0, 15, 30, 60, any available diabetes medications, but not only dietary regi- 90, 120, 150, and 180 min after intake of the oral glu- men. Exclusion criteria were inability to understand the cose dose. In case the glucose level declined to basal OBES SURG (2018) 28:1461–1472 1463 level at any time before 180 min, the blood sampling cell functioning in the stability of a fasting state and using a wasterminatedatthattime. single mathematical model such as HOMA-B is less reliable than the assessment of a relatively stable factor such as insulin Surgery resistance [15]. All patients underwent a laparoscopic LRYGB or LSG by Statistics experienced bariatric surgeons. LRYGB was performed by a five-port technique with the use of a linear stapler for both the All statistics were performed using Prism 5 and 7 (version gastrojejunostomy and the jejuno-jejunostomy. A running su- 5.0a and 7.0a). Logarithmic transformation was performed ture was used for closure of the remaining defects as previ- where indicated in order to obtain equal variances. Area under ously described [13]. The length of the Roux limb (alimentary the curve for glucose, insulin, GLP-1, and GIP during the oral limb) was typically 120 cm and the biliopancreatic limb glucose tolerance tests was calculated using the trapezoidal 50 cm. For LSG, a linear stapler was used for resection of rule. One-way ANOVA with Dunnett’s post hoc test was used the stomach over a 35–36 F bougie from 3 to 5 cm proximal for analyzing changes from baseline to the different postoper- to the pylorus to 1–2 cm distal to the angle of His. ative times within groups. Paired and unpaired Student’s t test Postoperative dietary recommendations included intake of was used for single comparisons between baseline and post- fluids and semi-solid food for 2 weeks, and solid food there- operative values and between the groups, respectively. χ test after. Patients were instructed to adhere to a diet rich in protein was used to compare numbers of patients on/off diabetes med- and with a calorie content of approximately 800–1000 kcal for ications 12 months after surgery. A P value of < 0.05 was the first six postoperative weeks. considered statistically significant. Glucose, Insulin, GLP-1, and GIP Measurements Results At the Sahlgrenska University Hospital, blood glucose was measured using StatStrip according to the manufacturer’sin- Anthropometry and Diabetes structions (Nova Biomedical, Waltham, MA, USA). At Ersta Hospital, blood glucose was measured using the YSI Model There were no differences in age, gender, weight, BMI, dia- 2300 Stat Plus glucose analyzer according to the manufac- betes duration, or basal HbA1c between the LRYGB and LSG turer’s instructions (Yellow Springs Instruments, OH, USA). groups of patients (Table 1). The reduction in body weight and Insulin was measured by an electrochemiluminescence immu- BMI at 12 months postoperatively was significantly greater noassay BECLIA^ using a Cobas e immunoassay analyzer after LRYGB compared to LSG, whereas the improvement of according to the manufacturer’s instructions (Roche HbA1c did not differ between groups (Table 1). The number Diagnostics, Dublin, Ireland). The intra-assay variation of of patients needing diabetes medications and/or insulin treat- the insulin measurement was 1.1–1.4% (CV) and the inter- ment decreased after surgery and was not different between assay variation 3.5–3.7% (CV). The cross-reactivity with the LRYGB and the LSG group, neither at baseline nor post- IGF-1 was 0.04%. GLP-1 and GIP were measured using operatively up to 12 months (Table 2). The diabetes medica- ELISAs according to the manufacturer’s instructions (Merck tion and insulin doses in the individual patients in the respec- Millipore, Solna, Sweden; Human total GIP ELISA, product tive group at baseline and 12 months postoperatively are number EZHGIP-54K, and Multi Species GLP-1 Total shown in Table 3. ELISA, product number EZGLP1T-36K). The intra-assay variation for GLP-1 was 1–2% (CV) and the inter-assay var- Fasting Glucose, Insulin, and HOMA iation < 12% (CV). For GIP, the intra-assay variation was 3– 8.8% (CV) and the inter-assay variation 1.8–6.1% (CV). Fasting blood glucose (FBG) concentrations were not signif- icantly changed in either group at 2 days after surgery, but Calculation of HOMA-IR and HOMA-B (%) were decreased in both groups at 3 weeks and 12 months after surgery (Fig. 1a). Fasting plasma insulin was decreased as HOMA-IR, an index of insulin resistance, was calculated early as on day 2 in both groups; however, only significantly based on the morning fasting plasma insulin and blood glu- in the LRYGB patients at this time (Fig. 1b). At 3 weeks and cose levels using the formula: HOMA-IR = (insulin (μIU/ 12 months after surgery, fasting insulin was similarly de- ml) × FBG (mmol/l))/ 22.5. HOMA-B (%) is a measure of creasedinbothgroups. HOMA-IR wassignificantlyim- pancreatic β-cell activity and was calculated using the formu- proved compared to baseline from day 2 to 12 months after la: ((20 × insulin (μIU/ml))/(FBG (mmol/l)) – 3.5)% [14]. It surgery within both LRYGB and LSG groups, and did not should be noted that the assessment of the dynamics of beta differ between the groups at baseline, or at any time after 1464 OBES SURG (2018) 28:1461–1472 Table 1 Anthropometric measures of the study groups at baseline and after surgery RYGB SG RYGB SG Mean ± SEM Pbase Mean ± SEM Pbase Pgroups Gender (F/M) 10:8 7:8 0.62 Age (years) Base 51.2 ± 1.6 51.9 ± 1.9 0.78 Body weight (kg) Base 112.9 ± 3.6 109.0 ± 3.4 0.43 12 mo 84.3 ± 3.0 < 0.001 85.2 ± 3.0 < 0.001 0.83 Δ Body weight (kg) 12 mo 29.5 ± 2.6 22.1 ± 1.2 < 0.05 ) Base 38.6 ± 0.8 36.9 ± 0.7 0.14 BMI (kg/m 12 mo 28.8 ± 0.7 < 0.001 28.6 ± 0.6 < 0.001 0.86 Δ BMI (kg/m ) 12 mo 10.1 ± 0.9 7.9 ± 0.5 < 0.05 EWL (%) 12 mo 73.0 ± 5.0 < 0.001 69.1 ± 4.4 < 0.001 0.57 Waist/hip ratio Base 1.00 ± 0.02 1.02 ± 0.02 0.58 12 mo 0.96 ± 0.02 < 0.01 0.94 ± 0.02 < 0.001 0.53 Diab duration (years) Base 5.7 ± 0.6 6.5 ± 1.1 0.54 HbA1c (%) Base 61.8 ± 3.9 55.7 ± 2.1 0.20 6 w 50.3 ± 2.9 < 0.001 48.7 ± 2.0 < 0.001 0.66 12 mo 40.5 ± 2.0 < 0.001 43.9 ± 2.7 < 0.01 0.34 Δ HbA1c (%) 0–12 mo − 15.9 ± 5.2 < 0.001 − 11.5 ± 2.6 < 0.001 0.47 surgery (Table 4). HOMA-B (%) improved both after SG and insulin release in response to the glucose load was blunt and RYGB, but the difference reached significance only in RYGB showed a prolonged peak from 15 to 90 min in both groups compared to baseline at 2 days and 12 months, and there were (Fig. 3a). After surgery, already from day 2 and on, the insulin no significant differences between the groups at any time responses were more rapid and distinct and the peak occurred (Table 4). at 15–30 min in both groups (Fig. 3b–d). Total AUC for insu- lin was not different between the groups and only significantly decreased in the LSG group at 12 months compared to base- MOGTT line (0–180 min; Fig. 3e). However, the seemingly elevated insulin peak area at 2 days in LSG encouraged us to analyze In the LSG group, 3 out of 15 patients were able to ingest only insulin peak AUCs 0–60 min. This revealed a clearly signifi- part of the glucose dose 2 days after surgery because of nausea cant increase in the LSG, but not in the LRYGB group, both at (20 g in two patients and 15 g in one patient). All 2-day day 2 and at 3 weeks postoperatively (Fig. 4c, d). calculations were repeated with exclusion of these three pa- tients, but that did not change the outcomes in any significant way. Glucose and insulin levels during MOGTT in RYGB and Patient Self-Measured Glucose Levels Pre- SG from baseline to 12 months after surgery are shown in and Postoperatively Figs. 2 and 3. Glucose clearance was significantly improved in both groups at 3 weeks after surgery as calculated using Figure 5 shows patient self-measured FBG and 90 min PPBG AUC 0–180 min and continued to improve in both groups after an individual breakfast during the first 2 weeks before until 12 months after surgery (Fig. 2e). The preoperative compared to 2 weeks immediately after surgery. In line with Table 2 Total numbers of T2DM treatment OAD Insulin OAD + insulin All treatm No treatm patients and types of medications n (%) n (%) n (%) n (%) n (%) before and 12 months after surgery RYGB Before 9 (53) 1 (6) 7 (41) 17 (100) – After 6 (35) 1 (6) 0 (0) 7 (41) 10 (59) SG Before 11 (73) 0 (0) 4 (27) 15 (100) – After 5 (33) 0 (0) 1 (7) 6 (40) 9 (60) Total no. of patients on/off medications 12 months after surgery were compared by χ test OBES SURG (2018) 28:1461–1472 1465 Table 3 Diabetes medications in all subjects before and 12 months after surgery Subject number Diabetes treatment, baseline Diabetes treatment, 12 months Metformin (mg) OAD (mg) Insulin (IU) Metformin (mg) OAD (mg) Insulin (IU) RYGB 1 1500 0 2168 0 31500 0 41000 0 5 1000 Glimepiride (1000), liraglutide (1.8) 0 0 6 2000 Liraglutide (1.2) 40 0 0 0 81000 0 91000 0 10 2000 0 11 2000 28 0 0 14 1500 0 16 500 95 –– 19 3000 94 500 0 20 2550 Glibenklamide (1.75) 1000 0 21 1000 0 24 1000 wn 3000 0 26 2000 25 500 0 34 1500 30 1000 0 SG 12 1500 46 0 0 13 3000 Glimepiride (4) 0 0 17 2000 Glimepiride (4) 2000 Glimepiride (2) 18 3000 Glimepiride (2) 1000 0 22 1500 0 23 1000–1500 0 25 1500 Pioglitazone (30) 1000 0 27 3000 80 3000 28 28 1500 Glibenklamide (7) 2000 Glibenklamide (3.5) 29 1000 0 30 500 0 31 1500 0 32 2550 58–70 0 0 33 2000 80 1000 0 39 500 0 Liraglutide was administered by subcutaneous injections wn when needed the data from the MOGTTs, these self-reported glucose mea- Three weeks after surgery, GLP-1 levels, in response to the surements clearly showed significantly decreased FBG and MOGTT, were maintained in the LRYGB patients, whereas 90 min PPBG levels in both groups of patients with no differ- they had started to decline in the LSG patients and declined ences between the groups (Fig. 5). further at 12 months to levels not different compared with baseline (Fig. 6c, d). Although the total AUC at 12 months was not increased compared to baseline in LRYGB, it was still Glucagon-Like Peptide (GLP-)1 Levels after Surgery significantly higher in the LRYGB group compared to LSG group (Fig. 6e). Analysis of peak AUC (0–60 min; hatched The GLP-1 levels during MOGTT were substantially in- area in Fig. 6d) showed an increase in the GLP-1 peak after creased 2 days after both LRYGB and LSG with no differ- LRYGB also at 12 months compared to baseline, whereas ences in AUCs between the groups (Fig. 6a, b, e). there was no increase after LSG (Fig. 6f). 1466 OBES SURG (2018) 28:1461–1472 Fig. 1 a Fasting blood glucose (FBG) and b fasting plasma insulin (fP- intervals for AUCs. The plus sign shows the mean. *P <0.05, **P < Insulin) levels at baseline, 2 days, 3 weeks, and 12 months after LRYGB 0.01, and ***P < 0.001 for ANOVA with Dunnett’s post hoc test for or LSG surgery. The box plots show the median and 95% confidence comparisons within groups at the different times after surgery vs. baseline Gastric Inhibitory Peptide (GIP) Levels after Surgery in patients with obesity and T2DM. Therefore, we performed a comparative study between LSG and LRYGB, to examine GIPlevelsinresponsetoMOGTT weresignificantlyin- the early postoperative effects on glycemic control, supple- creased in both LSG and LRYGB patients at 2 days and mented by the effects after 1 year. 3 weeks after surgery compared to baseline (Fig. 7a–c). The most important finding of the present study in pa- They then started to decline and were not significantly in- tients with T2DM was that the early effect of SG on glucose creased at 12 months in either group compared to baseline control and insulin secretion was equal compared to that of (Fig. 7d, e). AUC GIP was higher in LRYGB compared with RYGB. Although based on a relatively limited number of LSG at baseline, but no differences were noted between patients, we found that RYGB elicited a statistically signif- groups postoperatively (Fig. 7e). icant increase in the GLP-1 response at 3 weeks. However, this did not translate into a greater improvement of glucose metabolism variables in the RYGB group at that moment Discussion compared to the LSG group. This is well in line with exper- imental data from animal studies, showing that even com- Sleeve gastrectomy (LSG) is currently one of the most com- plete absence of GLP-1 does not change the effect of LSG mon bariatric operations worldwide, although the long-term on weight decrease and glucose metabolism [20]. In relation effects on body weight and diabetes have not yet been char- to LRYGB, it has been speculated that decreased release of a acterized in detail. A number of studies focusing on long-term hitherto uncharacterized anti-incretin or Bdecretin^ factor effects are ongoing [16–19], but very few data on the very from the bypassed foregut, which would suppress insulin early weight-independent effects of LSG have been presented release, could be of importance [21]. If this factor is of Table 4 HOMA-IR and HOMA- RYGB SG Paired-samples t test Independent-samples t test B (%) at baseline and 2 days, 3 weeks, and 12 months after RYGB SG surgery Mean ± SD Mean ± SD P value P value P value HOMA-IR Baseline 9.2 ± 6.4 8.4 ± 6.2 –– 0.63 2 days 4.5 ± 2.4 5.4 ± 1.8 < 0.001 < 0.05 0.13 3 weeks 3.8 ± 2.0 4.0 ± 1.6 < 0.001 < 0.001 0.52 12 months 1.9 ± 1.2 2.3 ± 1.1 < 0.001 < 0.001 0.31 HOMA-B (%) Baseline 151 ± 132 130 ± 116 –– 0.63 2 days 87 ± 87 94 ± 46 <0.05 0.387 0.25 3 weeks 107 ± 81 93 ± 40 0.141 0.344 0.99 12 months 56 ± 42 87 ± 56 0.001 0.245 0.11 All statistical analyses were performed with logarithmically transformed values in order to obtain normal distri- bution. Paired-samples t test was performed comparing baseline values with values at 2 days, 3 weeks, and 12 months, respectively. Independent-samples t test was performed between RYGB and SG OBES SURG (2018) 28:1461–1472 1467 Fig. 2 Blood glucose levels (B- glucose) 0–180 min after a modified 30 g oral glucose tolerance test at a baseline, b 2days, c 3weeks, and d 12 months after LRYGB or LSG. Graphs (a)–(d) show means ± SEM. e The box plots show the median and 95% confidence intervals for AUCs for the corresponding times. The plus sign shows the mean. **P <0.01 and ***P <0.001 for ANOVA with Dunnett’s post hoc test for comparisons within groups at the different times after surgery vs. baseline importance after LSG as well, it would most probably be mentioned above, these differences did not translate into dif- released from the area along the major curvature of the ferences in clinically relevant diabetes measures or diabetes stomach, which is removed, rather than from the duodenum medication use between the groups at any time during the first since this is not bypassed in LSG. Moreover, this would also postoperative year. The fact that both groups lost more than fit with the rapid recurrence of diabetes in RYGB patients or 20% of their initial body weight after 1 year corresponds to the diabetic rats where food is reintroduced to the remnant stom- observed improvement in glucose metabolism. These im- ach via a gastrostomy cannula [22, 23]. On the other hand, provements can be equally important when the weight loss many other factors have been suggested to influence the has been achieved by non-dietary measures, as shown in the metabolic response after bariatric surgery, e.g., bile acids Look AHEAD study [28]. and changes of the microbiota [24]. Our study did not focus Postoperative vomiting and nausea (PONV) is more com- on the latter aspects, and as such, a contribution of these monly reported after LSG than after LRYGB. Accordingly, parameters cannot be excluded nor proven. Moreover, calo- three of the LSG patients were not able to ingest the entire rie restriction is known to be a potent insulin sensitizer [25]. 30 g glucose dose at the first 2-day MOGTT. This did, how- The improvement in glucose metabolism, observed in both ever, not influence the data presented in any significant way groups, could be influenced by the preoperative fasting and since the results were the same irrespective if these patients postoperatively decreased caloric intake. The authors assume were included or not. On post-op day 2, HOMA-IR was sig- caloric intake was similarly decreased within the first days nificantly reduced in both groups, whereas fP-insulin and and weeks after SG and RYGB despite the fact that the two HOMA-B (%) were significantly reduced only in the procedures are anatomically completely distinct. LRYGB patients. On the other hand, the peak AUC 0– In corroboration with previous studies [17, 18, 26, 27], the 60 min for insulin was increased only in the LSG patients at weight loss was statistically significantly lower after LSG this time. Although we cannot exclude that the lack of differ- compared to LRYGB 1 year after surgery. Despite this and ences between groups was due to a type II error, these findings might suggest that the anti-diabetes effects of these two despite the subtle differences in the insulin and GLP-1 curves, 1468 OBES SURG (2018) 28:1461–1472 Fig. 3 Plasma insulin levels 0– 180 min after a modified 30 g oral glucose tolerance test at a baseline, b 2days, c 3 weeks, and d 12 months after LRYGB or LSG. Graphs (a)–(d)show means ± SEM. e Box plots show the median and 95% confidence intervals for AUCs for the corresponding times. The plus sign shows the mean. *P <0.05 for ANOVA followed by Dunnett’s post hoc test for comparisons within groups at the different times after surgery vs. baseline operations are distinct, with a somewhat more pronounced The measurements at 1 year postoperatively were per- effect by LRYGB on insulin sensitivity, and by LSG on β- formed in order to evaluate the combined effect of weight- cell activity. dependent and non-weight-dependent mechanisms. There Fig. 4 Within-group plasma insulin levels 0–180 min after a modified 30 g oral glucose tolerance test at baseline, 2 days, 3 weeks, and 12 months after a LRYGB or b LSG. Graphs (a) and (b) show means ± SEM. Box plots show the median and 95% confidence intervals for AUCs 0– 60 min (gray hatched areas in a and b)for c LRYGB and d LSG. The plus sign shows the mean. AUCs *P < 0.05 and ***P < 0.001 for ANOVA followed by Dunnett’s post hoc test for comparisons within groups at the different times after surgery vs. baseline OBES SURG (2018) 28:1461–1472 1469 were no significant differences in glycemic control between LSG and LRYGB at 1 year, as assessed by HbA1c levels, MOGTT measurements, the patients self-reported FBG and PPBG, or the numbers of patients off anti-diabetes medica- tions. The exception being HOMA-B (%), that still was sig- nificantly decreased after LRYGB but not LSG. The effect of LSG, with removal of a major part of the stomach, could be related to the decreased reservoir capacity and the transfer of undigested food to the small intestine where the release of hindgut factors, e.g., GLP-1 and GIP, is stimulated and could exert beneficial effects on insulin and glucagon release. The levels of incretin hormones, in response to a somewhat higher oral glucose load, were previously shown to be relatively sim- ilar in non-diabetic RYGB and SG patients [11]. In the present Fig. 5 Patient self-reported morning FBG (left 4 box plots) and 90 min PPBG (right 4 box plots) measured during 14 days preoperatively (pre) study, however, the GLP-1 stimulatory effect of LSG was and 14 days postoperatively (post) after LRYGB or LSG, showing the transient and started to subside already 3 weeks after surgery. median and 95% confidence intervals. The plus sign shows the mean. The Whether this reflects a true difference in GLP-1 response after patients were not put on LED before surgery to avoid effects of fasting on LSG compared to LRYGB in patients with or without diabetes glucose. White bars represent LRYGB and hatched bars represent LSG. **P < 0.01 and ***P <0.001 for paired t test within groups before and is not entirely clear. An alternative explanation is that the after surgery differences in GLP-1 response are associated with the use of Fig. 6 Plasma GLP-1 levels 0– 180 min after a modified 30 g oral glucose tolerance test at a baseline, b 2days, c 3 weeks, and d 12 months after LRYGB or LSG. Graphs (a)–(d)show mean ± SEM. e Box plots showing median and 95% confidence intervals for AUCs for GLP-1 at corresponding times. The plus sign shows the mean. f Peak AUC for GLP-1 (0–60 min) after LRYGB and LSG. **P < 0.01 and ***P <0.001 for ANOVA followed by Dunnett’s post hoc test for comparisons within groups at the different times after surgery vs. baseline. # ## P <0.01 and P < 0.001 for unpaired t test between LRYGB and LSG. P < 0.05 paired- samples t test within group. N = 18 for LRYGB and 15 for LSG in all panels, except panel (d)where n = 11 for LSG 1470 OBES SURG (2018) 28:1461–1472 Fig. 7 Plasma GIP levels 0– 180 min after a modified 30 g oral glucose tolerance test at a baseline, b 2days, c 3 weeks, and d 12 months after LRYGB or LSG. Graphs (a)–(d)show means ± SEM. e Box plots showing median and 95% confidence intervals for AUCs for GIP at corresponding times. The plus sign shows the mean. *P < 0.05, **P < 0.01, and ***P < 0.001 for one-way ANOVA followed by Dunnett’spost hoc ## test. P < 0.001 for between- groups t test LRYGB vs. LSG. N = 18 for LRYGB and 15 for LSG in all panels, except panel (d)where n =11 for LSG a lower energy load in our study (30 g glucose vs. a liquid test Strengths of this study were the careful monitoring of glu- meal containing 15 g carbohydrates, 25 g protein, and 28 g cose metabolism at several times both very early and up to a fat). year after surgery by MOGTT, and the Breal-life^ self- Limitations of this study include the relatively small num- monitoring data from patients during 2 weeks before and bers of patients, which obviously is associated with a risk that 2 weeks after surgery on glucose levels at fasting and post- we were unable to statistically demonstrate some additional prandially after breakfast. true differences between the groups. Moreover, all patients In conclusion, in this study, LSG exerted early beneficial were not randomized. Anthropometric data were not different effects on glycemia that were nearly indistinguishable from in any aspect between the groups at baseline. To assess glu- those after LRYGB. GLP-1 secretion in response to an oral cose metabolism, ingestion of a low-dose glucose drink was glucose load was only transiently increased after LSG, in con- used. This choice was made to avoid vomiting and dumping, trast to LRYGB where GLP-1 peak levels were still increased despite the fact that this low-dose drink has not been exten- at 1 year postoperatively. The BMI loss after 1 year was lower sively validated. A similar load of glucose has, however, pre- after LSG than LRYGB. Elucidation of other mechanisms that viously been shown to induce a satisfactory response in intes- contribute to the positive glycemic effects of LSG may hold tinal hormones after bariatric surgery [29]. Moreover, using a the key to understanding how patients can be helped to main- glucose drink as opposed to a mixed meal test limits the inter- tain long-term glycemic control after bariatric surgery. pretability as human data indicate proteins are also able to elicit a dose-dependent incretin effect [30]. Detailed food di- aries, in particular during the first 3 weeks after surgery, were Conclusion not collected. Therefore, the authors cannot be certain that patients consumed the recommended post-op diet. Recent LRYGB and LSG induced similar effects on glycemic control, studies suggest that differences in glycemic control between both very early after surgery and up to 1 year after surgery, despite the groups may appear with longer follow-up time [19]. lower GLP-1 levels and inferior decrease of BMI after LSG. OBES SURG (2018) 28:1461–1472 1471 Acknowledgments We would like to thank My Engström, Niclas 8. Melissas J, Daskalakis M, Koukouraki S, et al. Sleeve gastrecto- Björnfot, Anette Bratt, and Hans-Georg Eckhardt for skillful technical my—a Bfood limiting^ operation. Obes Surg. 2008;18(10):1251–6. assistance. This study was started as a collaboration between European https://doi.org/10.1007/s11695-008-9634-4. endocrinologists and bariatric surgeons in the European Obesity 9. Melissas J, Koukouraki S, Askoxylakis J, et al. Sleeve gastrectomy: Academy 2, which was made possible by generous sponsorship from a restrictive procedure? Obes Surg. 2007;17(1):57–62. https://doi. Ethicon Endosurgery/Johnson & Johnson. The study was also funded org/10.1007/s11695-007-9006-5. by the Erling-Persson Family Foundation, the Erik & Lily Philipson 10. Grayson BE, Schneider KM, Woods SC, et al. Improved rodent Memorial Foundation, and the Western Region of Sweden ALF grant maternal metabolism but reduced intrauterine growth after vertical number 94251. sleeve gastrectomy. Sci Transl Med. 2013;5:199ra12. 11. Peterli R, Wolnerhanssen B, Peters T, et al. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Compliance with Ethical Standards roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial. Ann Surg. 2009;250(2):234–41. Conflict of Interest Dr. Wallenius reports grants from Western Region of https://doi.org/10.1097/SLA.0b013e3181ae32e3. Sweden, grants from Erik and Lily Philipson memorial foundation, dur- 12. Pournaras DJ, Nygren J, Hagstrom-Toft E, et al. Improved glucose ing the conduct of the study; personal fees from Johnson & Johnson, metabolism after gastric bypass: evolution of the paradigm. Surg outside the submitted work. Dr. Anders Thorell reports research grants Obes Relat Dis. 2016;12(8):1457–65. https://doi.org/10.1016/j. from the Erling Persson family foundation. Dr. Carel le Roux reports soard.2016.03.020. research grants from Science Foundation Ireland, and the Health 13. 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Obesity SurgerySpringer Journals

Published: Dec 20, 2017

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