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

Thirty-four subsequent patients with T2DM who fulfilled the inclusion criteria were asked to participate and were included from the waiting list for bariatric surgery at two sites in Sweden, the Sahlgrenska University Hospital, Gothenburg, and Ersta Hospital, Stockholm. The inclusion criteria were BMI 35–50 kg/m², age 18–60 years, and T2DM requiring any available diabetes medications, but not only dietary regimen. Exclusion criteria were inability to understand the Swedish language or to adhere to study instructions. At Sahlgrenska Hospital, all patients were randomized to either method (seven LRYGB, five LSG). At Ersta Hospital (12 LRYGB, 10 LSG), the patients were designated for either LRYGB or LSG depending on the patients’ preference and the surgeons’ judgment, e.g., severe reflux disease was considered a contraindication for LSG. There was no systematic bias for the choice of one or the other method. Patients were asked to daily record their fasting (FBG) and 90 min postprandial glucose levels (PPBG; after individual breakfast), as well as all use of diabetes medications during 2 weeks before and 2 weeks after surgery. Postoperative adjustments of diabetes medications were handled by the physician usually in charge of the patient’s diabetes treatment. Weight, waist circumference, and height were recorded with patients wearing only underwear after an overnight fast. The usual 2-week preoperative low-energy diet (LED) was omitted in order not to influence preoperative or early postoperative glycemic control [12]. Eighteen patients underwent LRYGB and 15 underwent LSG. One patient who was not operated on by the intended technique at Sahlgrenska was excluded. One patient was lost to follow-up after the 3-week follow-up. The total follow-up rate was 94% (see Supplementary Fig. 1 for flow chart of inclusion). Data for GLP-1 and GIP were lost for four patients in the LSG group at 12 months; therefore, data are shown for 11 LSG patients in Figs. 6d and 7d. All patients were of Caucasian origin. The study was registered at ClinicalTrials.​gov identifier NCT01984762.

This study was approved by the Regional Ethical Review Board of Gothenburg (study reference number 016-12), and the study was conducted according to the principles of the Helsinki declaration. All patients gave written informed consent.

MOGTT with 30 g of glucose (compared to standard OGTT 75 g) dissolved in 150 ml water was performed at four occasions: 3 weeks preoperatively and 2 days, 3 weeks, and 12 months postoperatively. The glucose dose was reduced in order to, as far as possible, avoid side effects such as vomiting and dumping in the postoperative phase. MOGTT was performed after a 12-h fast. Patients did not take any antidiabetic medications, and no long-, intermediate-, or fast-acting insulin was administered on the morning of the test. Glucose, insulin, glucagon-like peptide (GLP)-1, and gastric inhibitory peptide (GIP) levels were measured at 0, 15, 30, 60, 90, 120, 150, and 180 min after intake of the oral glucose dose. In case the glucose level declined to basal level at any time before 180 min, the blood sampling was terminated at that time.

All patients underwent a laparoscopic LRYGB or LSG by experienced bariatric surgeons. LRYGB was performed by a five-port technique with the use of a linear stapler for both the gastrojejunostomy and the jejuno-jejunostomy. A running suture was used for closure of the remaining defects as previously described [13]. The length of the Roux limb (alimentary limb) was typically 120 cm and the biliopancreatic limb 50 cm. For LSG, a linear stapler was used for resection of the stomach over a 35–36 F bougie from 3 to 5 cm proximal to the pylorus to 1–2 cm distal to the angle of His. Postoperative dietary recommendations included intake of fluids and semi-solid food for 2 weeks, and solid food thereafter. Patients were instructed to adhere to a diet rich in protein and with a calorie content of approximately 800–1000 kcal for the first six postoperative weeks.

At the Sahlgrenska University Hospital, blood glucose was measured using StatStrip according to the manufacturer’s instructions (Nova Biomedical, Waltham, MA, USA). At Ersta Hospital, blood glucose was measured using the YSI Model 2300 Stat Plus glucose analyzer according to the manufacturer’s instructions (Yellow Springs Instruments, OH, USA). Insulin was measured by an electrochemiluminescence immunoassay “ECLIA” using a Cobas e immunoassay analyzer according to the manufacturer’s instructions (Roche Diagnostics, Dublin, Ireland). The intra-assay variation of the insulin measurement was 1.1–1.4% (CV) and the inter-assay variation 3.5–3.7% (CV). The cross-reactivity with IGF-1 was 0.04%. GLP-1 and GIP were measured using ELISAs according to the manufacturer’s instructions (Merck Millipore, Solna, Sweden; Human total GIP ELISA, product number EZHGIP-54K, and Multi Species GLP-1 Total ELISA, product number EZGLP1T-36K). The intra-assay variation for GLP-1 was 1–2% (CV) and the inter-assay variation < 12% (CV). For GIP, the intra-assay variation was 3–8.8% (CV) and the inter-assay variation 1.8–6.1% (CV).

HOMA-IR, an index of insulin resistance, was calculated based on the morning fasting plasma insulin and blood glucose levels using the formula: HOMA-IR = (insulin (μIU/ml) × FBG (mmol/l))/ 22.5. HOMA-B (%) is a measure of pancreatic β-cell activity and was calculated using the formula: ((20 × insulin (μIU/ml))/(FBG (mmol/l)) – 3.5)% [14]. It should be noted that the assessment of the dynamics of beta cell functioning in the stability of a fasting state and using a single mathematical model such as HOMA-B is less reliable than the assessment of a relatively stable factor such as insulin resistance [15].

All statistics were performed using Prism 5 and 7 (version 5.0a and 7.0a). Logarithmic transformation was performed where indicated in order to obtain equal variances. Area under the curve for glucose, insulin, GLP-1, and GIP during the oral glucose tolerance tests was calculated using the trapezoidal rule. One-way ANOVA with Dunnett’s post hoc test was used for analyzing changes from baseline to the different postoperative times within groups. Paired and unpaired Student’s t test was used for single comparisons between baseline and postoperative values and between the groups, respectively. χ ² test was used to compare numbers of patients on/off diabetes medications 12 months after surgery. A P value of < 0.05 was considered statistically significant.

There were no differences in age, gender, weight, BMI, diabetes duration, or basal HbA1c between the LRYGB and LSG groups of patients (Table 1). The reduction in body weight and BMI at 12 months postoperatively was significantly greater after LRYGB compared to LSG, whereas the improvement of HbA1c did not differ between groups (Table 1). The number of patients needing diabetes medications and/or insulin treatment decreased after surgery and was not different between the LRYGB and the LSG group, neither at baseline nor postoperatively up to 12 months (Table 2). The diabetes medication and insulin doses in the individual patients in the respective group at baseline and 12 months postoperatively are shown in Table 3.

Fasting blood glucose (FBG) concentrations were not significantly changed in either group at 2 days after surgery, but were decreased in both groups at 3 weeks and 12 months after surgery (Fig. 1a). Fasting plasma insulin was decreased as early as on day 2 in both groups; however, only significantly in the LRYGB patients at this time (Fig. 1b). At 3 weeks and 12 months after surgery, fasting insulin was similarly decreased in both groups. HOMA-IR was significantly improved compared to baseline from day 2 to 12 months after surgery within both LRYGB and LSG groups, and did not differ between the groups at baseline, or at any time after surgery (Table 4). HOMA-B (%) improved both after SG and RYGB, but the difference reached significance only in RYGB compared to baseline at 2 days and 12 months, and there were no significant differences between the groups at any time (Table 4).

In the LSG group, 3 out of 15 patients were able to ingest only part of the glucose dose 2 days after surgery because of nausea (20 g in two patients and 15 g in one patient). All 2-day calculations were repeated with exclusion of these three patients, but that did not change the outcomes in any significant way. Glucose and insulin levels during MOGTT in RYGB and SG from baseline to 12 months after surgery are shown in Figs. 2 and 3. Glucose clearance was significantly improved in both groups at 3 weeks after surgery as calculated using AUC 0–180 min and continued to improve in both groups until 12 months after surgery (Fig. 2e). The preoperative insulin release in response to the glucose load was blunt and showed a prolonged peak from 15 to 90 min in both groups (Fig. 3a). After surgery, already from day 2 and on, the insulin responses were more rapid and distinct and the peak occurred at 15–30 min in both groups (Fig. 3b–d). Total AUC for insulin was not different between the groups and only significantly decreased in the LSG group at 12 months compared to baseline (0–180 min; Fig. 3e). However, the seemingly elevated insulin peak area at 2 days in LSG encouraged us to analyze insulin peak AUCs 0–60 min. This revealed a clearly significant increase in the LSG, but not in the LRYGB group, both at day 2 and at 3 weeks postoperatively (Fig. 4c, d).

Figure 5 shows patient self-measured FBG and 90 min PPBG after an individual breakfast during the first 2 weeks before compared to 2 weeks immediately after surgery. In line with the data from the MOGTTs, these self-reported glucose measurements clearly showed significantly decreased FBG and 90 min PPBG levels in both groups of patients with no differences between the groups (Fig. 5).

The GLP-1 levels during MOGTT were substantially increased 2 days after both LRYGB and LSG with no differences in AUCs between the groups (Fig. 6a, b, e).

Three weeks after surgery, GLP-1 levels, in response to the MOGTT, were maintained in the LRYGB patients, whereas they had started to decline in the LSG patients and declined 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 significantly higher in the LRYGB group compared to LSG group (Fig. 6e). Analysis of peak AUC (0–60 min; hatched area in Fig. 6d) showed an increase in the GLP-1 peak after LRYGB also at 12 months compared to baseline, whereas there was no increase after LSG (Fig. 6f).

GIP levels in response to MOGTT were significantly increased in both LSG and LRYGB patients at 2 days and 3 weeks after surgery compared to baseline (Fig. 7a–c). They then started to decline and were not significantly increased at 12 months in either group compared to baseline (Fig. 7d, e). AUC GIP was higher in LRYGB compared with LSG at baseline, but no differences were noted between groups postoperatively (Fig. 7e).