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Original article
Temporal changes in glucose homeostasis and incretin hormone response at 1 and 6 months after laparoscopic sleeve gastrectomy Akhila Mallipedhi, M.R.C.P.a,b,*, Sarah L. Prior, Ph.D.a, Jonathan Barry, M.Ch.c, Scott Caplin, F.R.C.S.c, John N. Baxter, M.D.c, Jeffrey W. Stephens, F.R.C.P.a,b,c a Diabetes Research Group, Institute of Life Sciences, Swansea University, Swansea, United Kingdom Department of Diabetes & Endocrinology, Morriston Hospital ABM University Health Board, Swansea, United Kingdom c Welsh Institute of Metabolic and Obesity Surgery, Morriston Hospital ABM University Health Board, Swansea, United Kingdom Received November 5, 2013; accepted February 24, 2014 b
Abstract
Background: Bariatric surgery is an effective treatment for morbid obesity. Current literature reports significant improvements in glucose homeostasis after malabsorptive surgery. There is limited evidence on the effects of laparoscopic sleeve gastrectomy (SG) on glucose-insulin homeostasis and postoperative incretin hormone response. The objective of this study was to examine the metabolic effects of SG on temporal changes in insulin and glucose homeostasis, incretin hormones and hepatic insulin clearance in patients with impaired glucose tolerance (IGT) and type 2 diabetes (T2 DM). Methods: A nonrandomized prospective study comprising 22 participants undergoing SG (body mass index [BMI] 50.1 kg/m2, glycated hemoglobin [HbA1c] 53 mmol/mol) and 15 participants undergoing biliopancreatic diversion (BPD) (BMI 62.1 kg/m2, HbA1c 58 mmol/mol). Serial measurements of glucose, insulin, C-peptide, glucagon like peptide-1 (GLP-1) and glucosedependent insulinotropic hormone (GIP) were performed during oral glucose tolerance testing preoperatively and 1 and 6 months postoperatively. Areas under the curve (AUC) were examined at 30, 60, and 120 minutes. Results: Within the SG group, significant improvements were observed respectively at 1 and 6 months in glucose control (HbA1c: 0.9%, 1.3%), measures of insulin sensitivity (fasting insulin: 4.8 mU/L, 8.5 mU/L; fasting C-peptide: 0.6 pmol/L, 1.1 pmol/L; Homeostasis Model Assessment [HOMA-IR]: 0.144, 0.174; HOMA %S: þ29.6, þ92.4), hepatic insulin clearance (þ0.07, þ0.13) and postprandial GLP-1 response (AUC0-30 pmol h L1: þ300, þ331, AUC0-60: þ300, þ294, AUC0-120: þ316, þ295). These results were comparable to the BPD group. Conclusions: SG is associated with significant early improvements in insulin sensitivity and incretin hormone response and results in significant improvements in IGT/T2 DM. (Surg Obes Relat Dis 2014;]:00–00.) r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Type 2 diabetes mellitus; Obesity; Sleeve gastrectomy; Biliopancreatic diversion
This study was supported by a project Research Grant from The BUPA Foundation (33 NOV06). * Correspondence: Dr. Akhila Mallipedhi, Diabetes Research Group, Institute of Life Sciences, Swansea University, Swansea SA2 8 PP, UK. E-mail: [email protected]
Bariatric surgery is an effective treatment for morbid obesity and is associated with resolution of impaired glucose tolerance (IGT) and type 2 diabetes (T2 DM) [1]. The literature reports resolution in glucose abnormalities after malabsorptive surgery such as biliopancreatic diversion
http://dx.doi.org/10.1016/j.soard.2014.02.038 1550-7289/r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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(BPD) and laparoscopic Roux-en-Y gastric bypass (RYGB) [1]. It is well documented that this improvement is related to an increase in postprandial release of glucagon like peptide-1 (GLP-1), improved insulin sensitivity, reduced calorie intake and associated weight loss [2–5]. The changes in GLP-1, insulin and glucose homeostasis are typically seen early after malabsorptive surgery (RYGB and BPD) before significant weight loss occurs [6]. With respect to restrictive surgical procedures such as laparoscopic gastric banding (LGB) and laparoscopic sleeve gastrectomy (SG), improvements in fasting plasma glucose and measures of insulin sensitivity typically occur with weight loss [7–9]. Recently, Tsoli et al. [10] described a significant increase in the GLP-1 response during an oral glucose tolerance test (OGTT) in 12 patients after a SG with comparable resolution of T2 DM in 12 participants undergoing a BPD [10]. Of interest in both groups of participants, improvements in postprandial GLP-1 were not observed until 3 months after surgery and improvements in insulin sensitivity were not observed until 12 months [10]. This study did not examine changes in the area under the curve (AUC) for C-peptide during a glucose load nor examine fasting insulin sensitivity. A recent study in 10 participants has also described improvements in postprandial GLP-1 and reductions in fasting insulin and the AUC for insulin as early as 6 weeks after SG and reductions in the AUC for glucose at 6 months postoperatively [8]. Because C-peptide is a direct measure of insulin production, this may provide a more accurate measure of β-cell insulin responsiveness to GLP-1 [11]. Total insulin concentrations are in part dependent on the body mass of an individual and the degree of insulin resistance within an individual [12]. Recent studies have described equally effective resolution of T2 DM in patients undergoing a SG and malabsorptive surgery (BPD or RYGB), [9,13,14] but these studies lack detailed examination of GLP-1, glucose, and insulin response to surgery. Little information is available on the effects of bariatric surgery on glucose-dependent insulinotropic hormone (GIP). GIPsecreting K-cells are predominantly located in the upper portions of the small intestine, namely, the duodenum and jejunum [15], and therefore investigation of GIP concentrations after both SG and malabsorptive surgery is warranted. Our aim was to specifically examine the postprandial temporal changes in insulin and glucose homeostasis, incretin hormones (GLP-1 and GIP), and hepatic insulin clearance preoperatively, and at 1 and 6 months after SG. We also examined this in a group of patients undergoing BPD.
Methods
both genders, age 20–40 years, body mass index (BMI) 4 40 kg/m2, and physically fit for surgery. Participants with pre-existing diabetes treated with diet, oral agents, GLP-1 analogues or insulin were included. Participants with impaired glucose regulation were those with either impaired fasting glycemia (5.6–6.9 mmol/L) or impaired glucose tolerance (2-hr glucose 7.8–11.0 mmol/L) [16]. Study design Participants were recruited prospectively and consecutively from the Bariatric Surgical clinic and were not blindly allocated to a surgical treatment option. As per local guidance, those with a BMI 4 50 kg/m2 were routinely offered a BPD, whereas those with a BMI below this are usually offered SG or laparoscopic gastric band (LGB). SG is a standard sleeve i.e., sleeve fashioned around a 32 F bougie taken from 5 cm proximal to the pylorus and up to the left crus. BPD involved a distal gastrectomy (as described by Scopinaro) and a 50-cm common channel. All participants were recruited preoperatively and followed-up postoperatively at 1 and 6 months where they underwent a standardized 75-g oral glucose tolerance test (OGTT) (122 mL of Polycal 61.9 g/100 mL of glucose, Nutricia Clinical Care, Trowbridge, UK). Previous studies have demonstrated that the level of glycemia reached 2 hours after 75 g of glucose is closely related to the level of glycemia after a standardized meal indicating an OGTT is a valid tool for revealing altered carbohydrate metabolism during a meal [17]. Insulin or oral hypoglycemic agents were omitted for 24 hours before the OGTT. There was no standardized meal prescribed for the night before and patients were asked to fast from the midnight before the test. Baseline clinical and biochemical information Baseline clinical measurements consisted of weight, height, BMI, waist circumference, and systolic and diastolic blood pressure. Baseline biochemical measurements (total cholesterol, low-density lipoprotein-cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], and triglycerides) were analyzed within the local hospital accredited laboratory. Glucose and lipids (Roche Modular P800 Analyzer) and insulin and C-peptide (Roche E170 Modular Analyzer) were also measured locally. During the OGTT, plasma and serum samples were collected for measurements of glucose, insulin, C-peptide, GLP-1, and GIP at time 0, 15, 30, 45, 60, and 120 minutes. All samples were collected on ice, centrifuged and separated within 1 hour of collection and subsequently stored at -80 oC until analysis.
Study participants
Measurements of insulin sensitivity
Approval for the study was obtained from the Local Research Ethics Committee. Participants were identified and recruited from patients undergoing a planned bariatric surgical procedure. Entry criteria at the outset included:
The Homeostasis Model Assessment (HOMA) was used to estimate steady state β-cell function (%B) and insulin sensitivity (%S). These were calculated using the Oxford University on-line calculator (http://www.dtu.ox.ac.uk/homacalculator,
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accessed 7 May 2013) [18]. HOMA-insulin resistance (IR) is the reciprocal of HOMA-%S. The HOMA-%B and HOMA-% S represent values of 100% in normal young adults when using currently available assays for insulin, specific insulin or C-peptide. The accuracy of these measures has been validated, and they have been shown to correlate with clamp-derived indices of insulin sensitivity and secretion [19]. They estimate steady state function. We have also examined nonsteady state function by analyzing the different AUC for insulin, glucose, C-peptide, GLP-1, and GIP at 30, 60 and 120 minutes. The fasting C-peptide to insulin molar ratio was calculated as an index of hepatic insulin clearance [20]. Measurement of total GLP-1 and total GIP Total GLP-1 was quantitatively measured using the Epitope Diagnostics Inc, Total GLP-1 ELISA Kit, which utilizes the 2-site sandwich technique with 2 selected GLP-1 antibodies to assess both the intact GLP-1 (7-36) amide and the primary (NH2-terminally truncated) metabolite, GLP-1 (9-36) amide. The intra- and interassay coefficients of variation were r4.7% and r9.5%, respectively. Total GIP was measured using the Millipore Human GIP (total) ELISA kit, which reacts fully with intact GIP (1-42) and the NH2-terminally truncated metabolite, GIP (3-42). The intra- and interassay coefficients of variation were r8.8% and r6.1%, respectively. Statistical methods Statistical analysis was performed using SPSS. Results for continuous variables are presented as mean and standard deviation and in graphical representation as mean and standard error. Continuous variables that did not have a normal distribution (triglyceride, fasting insulin, fasting C-peptide, HOMA-IR, HOMA-%B, HOMA-%S, hepatic insulin clearance, AUC insulin, AUC C-peptide) underwent log transformation to normalize the data for analysis and are described with the geometric mean and approximate standard deviation. For continuous variables, differences in means were compared between baseline and 1 or 6 months using a paired samples t test. Categorical data were analyzed using a Χ2 test. Paired t tests were used to compare mean differences at individual time points during the OGTT between baseline, and 1 and 6 months for glucose, insulin, C-peptide, GLP-1, and GIP. Changes in the AUC over 30 minutes (AUC0-30), 60 minutes (AUC0-60), and 120 minutes (AUC0-120) were analyzed during the OGTT at baseline, and 1 and 6 months for glucose, insulin, C-peptide, GLP-1, and GIP using the trapezoidal rule. In all cases, a P value of o .05 was considered statistically significant. Results Participant characteristics A total of 37 participants completed the study. Of these, 22 had a SG and 15 a BPD. There was no difference in age
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between the groups (mean age ¼ 48 ⫾ 7 and 50 ⫾ 8, P ¼ .31). In the SG group there were 15 females and 7 males, and in the BPD group there were 10 females and 5 males (P ¼ .6). 50% of the patients within the SG group had IGT compared to 20% within the BPD group. Within the SG group, the median duration of diabetes was 42 months (interquartile range: 21–66 months) compared to 54 months (26–112 months) in the BPD group (P ¼ .34). Weight, BMI, blood pressure, and lipids before and after surgery At baseline (Table 1a and 1b), as expected from the recruitment criteria, BMI and weight were higher in the BPD group compared to the SG group (BMI: P = .002; weight: P = .03). As shown in Table 1a, within the SG group, significant reductions were observed in weight at 1 month with a mean reduction of 31.1 kg at 6 months. In the BPD group (Table 1b) a significant reduction was observed for weight with a mean reduction of 37.5 kg seen at 6 months. These changes were associated with significant reductions in the waist circumference and BMI at 1 and 6 months in both groups. There was a significant reduction in the systolic blood pressure at 1 month after SG. No statistically significant changes were observed in systolic and diastolic blood pressure readings in the BPD group (Table 1a and 1b). There were no significant changes in total cholesterol, LDL-C or triglyceride concentrations after SG. In the BPD group, there was a significant reduction in total cholesterol and LDL-C concentrations at 1 month. Effects of bariatric surgery on glycemic control Significant changes were observed in fasting glucose, 2hour glucose, and glycated hemoglobin (HbA1c) in both groups at 1 month (Table 1a and 1b). As shown in Fig. 1, significant differences were observed in the proportion of patients with impaired glucose tolerance (IFG and IGT) and T2 DM at 1 and 6 months after both SG and BPD. After SG, within the IFG/IGT group, 54.5% had normal glucose concentrations and 45.5% had persisting IFG/IGT at 1 month. At 6 months, 100% of the patients demonstrated normal glucose concentrations. In patients with T2 DM, at 1 month- 10% of the patients had normal glucose concentrations, 60% had IFG/IGT and 30% DM. At 6 months 66.7% had normal tests, 30% IFG/IGT, and none with DM. After BPD, within the IFG/IGT group, 33% had normal glucose concentrations and 66.7% IFG/IGT at 1 month. At 6 months, 100% had reverted to normal glucose concentrations. In patients with T2 DM, at 1 month 20% had normal glucose concentrations, 40% IFG/IGT, and 40% DM. At 6 months 40% had normal tests, 40% IFG/IGT, and 20% DM. With respect to diabetes therapies, in the SG group (Table 2), the 3 participants treated with insulin preoperatively had discontinued it within 6 months.
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Table 1a Baseline and end of study clinical and biochemical measurements within the SG group Measurement Weight (kg) BMI (kg/m2) Waist (cm) Systolic BP (mm Hg) Diastolic BP (mm Hg) Cholesterol (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Triglyceride (mmol/L)‡ HbA1c (%) HbA1c (mmol/mol) Fasting glucose (mmol/L) 2-hr glucose (mmol/L)
Baseline 146.6 50.1 138 131 76 4.3 2.4 1.2 1.4 7.0 53 7.6 11.6
(29.6) (6.6) (18) (18) (11) (1.0) (.8) (.3) (.4) (1.7) (18.6) (3.6) (5.9)
P value*
1 mo 129.4 44.0 128 123 74 4.4 2.7 1.1 1.4 6.1 43 5.4 7.8
o.001 o.001 o.001 .04 .63 .58 .16 .02 .92 .005 .005 .02 .002
(26.9) (6.6) (17) (14) (9) (1.1) (1.0) (.3) (.2) (.8) (8.7) (.9) (3.4)
6 mo 115.5 39.6 118 128 73 4.7 2.8 1.3 1.1 5.7 39 5.0 5.4
(24.4) (6.2) (18) (20) (14) (1.2) (.9) (.3) (.2) (.8) (8.7) (1.0) (2.2)
P value† o.001 o.001 o.001 .12 .13 .09 .05 .10 .15 .002 .002 .08 o.001
SG ¼ sleeve gastrectomy; BMI ¼ body mass index; LDL-C ¼ low-density lipoprotein-cholesterol; HDL-C ¼ high-density lipoprotein-cholesterol; HbA1c ¼ glycated hemoglobin In the SG group there were 15 females and 7 males, and in the BPD group there were 10 females and 5 males (P ¼ .6). * P value comparing baseline with 1 mo. † P value comparing baseline with 6 mo. ‡ Log transformed for analysis. Geometric mean and approximate standard deviation shown for log-transformed data.
line with previous studies, we observed a significant reduction in fasting insulin level and an increase in hepatic insulin clearance (Table 3a) at 1 and 6 months, postoperatively. HOMA-%S was significantly increased (and HOMA-IR decreased) at 6 months. Fasting C-peptide was significantly decreased 6 months after surgery. Dynamic measures. As shown in Fig. 2a, there was a significant reduction in the mean plasma glucose values at 0, 60, and 120 minutes at 1 month and 0, 30, 45, 60, and 120 minutes at 6 months. There was a significant reduction in the mean AUC0-120 mins for glucose at 1 and 6 months after surgery compared to baseline (Table 3a). Postprandial C-peptide values (Fig. 2b) were significantly increased at 15, 30, 45, and 60 minutes at 1 month and 30, 45 and
Furthermore, 19 participants had discontinued all treatments within 6 months (87.5% off treatment). In the BPD group, no subject remained on insulin treatment 6 months postoperatively, and 10 (71.4%) participants had discontinued all treatments in 6 months. There was also a corresponding 50% reduction in the number of participants receiving oral therapies for T2 DM in both the groups. Effects of bariatric surgery on glucose-insulin homeostasis and incretin hormones SG group. Static measures. Within the SG group (Table 1a); mean HbA1c, fasting and 2-hour glucose values were significantly lower at 1 and 6 months after surgery. In
Table 1b Baseline and end of study clinical and biochemical measurements within the BPD group Measurement Weight (kg) BMI (kg/m2) Waist (cm) Systolic BP (mm Hg) Diastolic BP (mm Hg) Cholesterol (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Triglyceride (mmol/L)‡ HbA1c (%) HbA1c (mmol/mol) Fasting glucose (mmol/L) 2-hr glucose (mmol/L)
Baseline 172.4 62.1 154 136 81 4.5 2.3 1.3 1.8 7.5 58 8.2 12.9
(41.2) (14.3) (22) (17) (7) (.9) (.9) (.2) (.8) (1.5) (16.4) (4.1) (5.0)
1 mo 151.5 55.3 148 130 73 3.1 1.2 1.1 1.7 6.2 44 6.5 9.4
(28.2) (11.5) (19) (18) (9) (.6) (.5) (.3) (.2) (.7) (7.7) (2.1) (3.0)
P value* .001 o.001 o.001 .18 .009 o.001 o.001 o.001 .27 .005 .005 .08 .01
6 mo 134.9 49.7 131 131 77 3.3 1.5 1.0 1.6 5.9 41 6.2 9.4
(27.8) (10.2) (18) (10) (8) (.7) (.6) (.2) (.2) (1.4) (15.3) (3.7) (5.9)
P value† o.001 o.001 o.001 .48 .34 .08 .04 o.001 .12 .04 .04 .23 .12
BPD ¼ biliopancreatic diversion; BMI ¼ body mass index; LDL-C ¼ low-density lipoprotein-cholesterol; HDL-C ¼ high-density lipoprotein-cholesterol; HbA1c ¼ glycated hemoglobin * P value comparing baseline with 1 mo. † P value comparing baseline with 6 mo. ‡ Log transformed for analysis. Geometric mean and approximate standard deviation shown for log-transformed data.
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* **
*
5
**
*
* **
*
**
Fig. 1. (a). Proportion of participants with T2 DM and impaired glucose tolerance before and following sleeve gastrectomy. Significant differences were observed between the proportion of patients with T2 DM and impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG) at 1 and 6 months after SG. *P ¼ .02; **P o .01. (b). Proportion of participants with T2 DM and impaired glucose tolerance before and following biliopancreatic diversion (BPD). Significant differences were observed the proportion of patients with T2 DM and impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG) at 1 and 6 months after BPD.*P ¼ .02; **P ¼ .0002.
60 minutes at 6 months. There was a significant increase in AUC0-60 mins and AUC0-120 mins for C-peptide at 1 and 6 months postsurgery. The insulin AUC0-60 mins was significantly increased at both 1 and 6 months (Table 3a). Table 2 Changes in treatments at 1 and 6 months postsurgery Numbers (%) within groups
Time after surgery Baseline
No treatment Oral agents/ GLP-1 analogue Insulin and oral agents No treatment Oral agents/ GLP-1 analogue Insulin and oral agents
SG 12 (54.5%) 7 (31.8%) 3 (13.6%) BPD 3 (20.0%) 9 (60.0%) 3 (20.0%)
1 mo
6 mo
19 (86.4%) 2 (9.1%) 1 (4.5%)
19 (87.5%) 3 (12.5%) 0 (.0%)
9 (60.0%) 6 (40.0%) 0 (.0%)
10 (71.4%) 4 (28.6%) 0 (.0%)
SG ¼ sleeve gastrectomy; GLP-1 ¼ glucagon-like peptide-1; BPD ¼ biliopancreatic diversion
Incretin effect. Fasting GLP-1 concentrations (Fig. 2d) were not different at 0, 1, and 6 months. However, significant increases were observed at all postprandial sampling time points at 1 and 6 months compared to time 0 minutes. In line with this, there were significant increases in the AUC0-30 mins, AUC0-60 mins, and AUC0-120 mins for GLP-1 at 1 and 6 months postoperatively (Table 3a). No significant changes were observed in relation to GIP (Fig. 2e). BPD group. Static measures. Within the BPD group (Table 1b); HbA1c, fasting and 2-hour glucose values were lower at 1 and 6 months after surgery. There was a significant reduction in fasting insulin and an increase in hepatic insulin clearance (Table 3b) at 1 and 6 months postoperatively. Dynamic measures. As shown in Fig. 3a, there was a significant reduction in the mean plasma glucose values at 45 and 60 minutes at 1 and 6 months. There was a significant reduction in the mean AUC0-120 mins for glucose
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Table 3a Changes in insulin sensitivity and incretin hormones within the SG group Baseline Fasting insulin (mU/L)‡ Fasting C-peptide (pmol/L)‡ 2-hr insulin (mU/L)‡ HOMA-IR‡ HOMA-B%‡ HOMA-S%‡ Hepatic insulin clearance‡ AUC0-30 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1) AUC0-60 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1) AUC0-120 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1)
1 mo
P value*
6 mo
P value†
18.1 4.2 76.7 .394 23.7 351.3 .20
(4.8) (.6) (29.2) (.11) (7.4) (112.0) (.03)
13.3 3.6 79.1 .250 25.5 380.9 .27
(3.1) (.4) (29.7) (.07) (5.8) (97.8) (.06)
.009 .15 .24 .19 .93 .23 .02
9.6 3.1 27.9 .220 28.4 443.7 .33
(2.5) (.8) (20.7) (0.08) (6.1) (173.1) (.08)
.001 .01 .25 .04 .35 .03 o.001
4.5 17.3 2.7 1.3 131.5
(1.5) (5.6) (1.0) (1.1) (48.1)
4.1 20.8 3.2 5.2 152.3
(.6) (4.8) (.5) (2.2) (67.7)
.22 .14 .03 o.001 .08
3.8 25.8 2.7 5.6 142.8
(.8) (9.1) (.6) (3.8) (76.1)
.11 .07 .39 o.001 .57
10.8 50.2 6.8 3.2 313.7
(3.4) (17.2) (1.5) (2.8) (98.9)
9.5 65.6 8.9 12.8 339.3
(1.5) (14.0) (1.5) (5.1) (111.0)
.14 .01 .001 o.001 .16
8.8 73.1 7.7 12.6 334.7
(2.3) (28.9) (1.6) (7.9) (177.9)
.05 .03 .01 o.001 .65
23.4 142.1 16.9 5.6 620.9
(7.3) (45.8) (3.1) (5.1) (210.2)
19.1 167.4 21.5 23.3 638.2
(3.5) (46.3) (3.3) (10.9) (203.7)
.01 .06 o.001 o.001 .49
16.5 122.8 17.7 22.1 653.4
(4.7) (46.0) (3.7) (12.6) (372.3)
.003 .90 .04 o.001 .78
SG ¼ sleeve gastrectomy; AUC ¼ area under the curve; HOMA-IR ¼ homeostatic model assessment-insulin resistance; HOMA-%S ¼ homeostatic model assessment-insulin sensitivity; HOMA-%B ¼ Homeostatic model assessment β-cell function; GLP-1 ¼ glucagon-like peptide-1; GIP ¼ glucose-dependent insulinotropic hormone * P value comparing baseline with 1 mo. † P value comparing baseline with 6 mo. ‡ Log transformed for analysis. Geometric mean and approximate standard deviation for log-transformed data shown.
at 1 and 6 months after surgery compared to baseline (Table 3b). There was a significant (33%) increase in AUC0-120 mins for C-peptide at 1 and 6 months postsurgery. Incretin effect. Fasting GLP-1 concentrations (Fig. 3d) were not different at baseline, 1 and 6 months. However, significant increases were observed at all postprandial sampling time points at 1 and 6 months compared to time 0 minutes. In line with this, there were significant increases in the AUC0-30 mins, AUC0-60 mins, and AUC0-120 mins for GLP-1 at 1 and 6 months postoperatively (Table 3b). Significant reductions were observed in the AUC0-30 mins, AUC0-60, mins and AUC0-120 mins for GIP (Fig. 3e) at 1 and 6 months and furthermore, there were significant reductions observed at 15, 30, 45, and 60 minutes at 1 and 6 months compared to baseline. Discussion SG is recognized as a stand-alone bariatric procedure with a superior safety profile [21,22]. In line with previous studies, we observed significant resolution of IGT and T2 DM with SG. In this group, the 3 (100%) participants treated with insulin preoperatively had discontinued this within 6 months and 19 (87.5%) participants had discontinued all treatments within 6 months. A marked reduction
in fasting glucose, HbA1c and the AUC0-120 for glucose at 1 and 6 months postoperatively was observed, in addition to significant early improvements at 1 month in fasting insulin, hepatic insulin clearance and at 6 months in HOMA-IR (and HOMA-%S). Along with these changes, there was a marked postprandial increase in the AUC for GLP-1. In line with this GLP-1 response, a significant increase in the AUC for C-peptide was observed. These results therefore suggest that the improvement in glucose and insulin homeostasis is the result of improved hepatic insulin sensitivity, enhanced postprandial GLP-1 response and subsequent restoration of the early phase insulin release. The improvement in HOMA-IR observed at 6 months suggests a further improvement in insulin resistance facilitated by weight loss. With respect to the BPD group, we observed that no subject remained on insulin treatment 6 months postoperatively and 10 (71.4%) participants had discontinued all treatments in 6 months. In line with previous publications [2–5,20], we observed reductions in fasting glucose, HbA1c and the AUC0-120 for glucose at 1 and 6 months postoperatively and an early improvement in hepatic insulin clearance. Again, in line with previous studies, there was a marked significant postprandial increase in the AUC for GLP-1. We also observed a significant decrease in the
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Table 3b Changes in insulin sensitivity and incretin hormones within the BPD group Baseline Fasting insulin (mU/L)‡ Fasting C-peptide (pmol/L)‡ 2-hr insulin (mU/L)‡ HOMA-IRc HOMA-B%‡ HOMA-S‡ Hepatic insulin clearance‡ AUC0-30 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1) AUC0-60 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1) AUC0-120 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1)
P value*
1 mo
6 mo
P value† o.001 .89 .46 .14 .46 .13 .002
28.0 1.9 49.4 .444 23.27 217.7 .09
(3.7) (.5) (16.7) (.071) (1.43) (32.9) (.03)
16.8 2.6 43.8 .338 24.58 282.1 .15
(4.2) (1.3) (12.5) (.105) (7.53) (82.7) (.04)
.003 .85 .89 .35 .90 .36 .01
10.8 2.3 38.9 .278 20.56 346.8 .21
(3.5) (.5) (13.2) (.115) (6.63) (145.8) (.05)
4.4 17.0 1.52 3.3 192.7
(2.3) (4.4) (.3) (4.2) (93.5)
3.8 17.01 1.6 7.6 102.8
(1.0) (4.1) (.2) (7.2) (53.2)
.81 .95 .64 .02 .01
3.1 14.5 1.7 8.2 96.4
(.6) (3.8) (.3) (4.8) (37.9)
.05 .77 .26 .003 .006
11.0 45.6 2.6 7.4 472.8
(4.4) (15.5) (.8) (7.9) (214.3)
8.3 39.0 3.9 15.7 232.7
(2.4) (10.0) (.5) (10.2) (118.9)
.09 .68 .33 .02 .008
7.3 38.7 4.1 16.8 215.9
(1.6) (11.2) (.8) (7.7) (85.5)
.009 .74 .21 o.001 .005
24.8 97.0 6.3 11.8 842.9
(8.8) (34.4) (1.6) (14.2) (390.3)
17.6 77.5 9.9 29.1 460.0
(5.2) (19.0) (1.3) (17.4) (161.0)
.04 .97 .18 .003 .02
15.7 103.4 9.8 30.5 408.8
(3.1) (28.2) (1.8) (14.2) (162.6)
.02 .80 .09 o.001 .003
SG ¼ sleeve gastrectomy; AUC ¼ area under the curve; HOMA-IR ¼ homeostatic model assessment-insulin resistance; HOMA-%S ¼ homeostatic model assessment-insulin sensitivity; HOMA-%B ¼ Homeostatic model assessment β-cell function; GLP-1 ¼ glucagon-like peptide-1; GIP ¼ glucose-dependent insulinotropic hormone * P value comparing baseline with 1 mo. † P value comparing baseline with 6 mo. ‡ Log transformed for analysis. Geometric mean and approximate standard deviation for log-transformed data shown.
AUC0-60, AUC0-120 for GIP at 6 months, which is in line with a previous study [23]. While previous studies have reported these metabolic effects after BPD or RYGB, few studies have examined in detail the metabolic effects of SG in relation to glucose and insulin homeostasis. Our study is the first to examine the detailed postprandial temporal relationship of markers of glucose and insulin homeostasis in 22 patients. Previously, this has been described in a maximum of 12 patients [10]. Our results suggest that SG is effective in managing IGT and T2 DM in patients with morbid obesity. Within our present study, we observed significant improvements in IGT and T2 DM, which is in line with previous studies [14,24], which report comparable remission rates of T2 DM associated with BPD. These effects are superior to those observed with LGB [25]. The improved postprandial GLP-1 response accounts for part of the early improvement in glucose concentrations post-BPD. As previously discussed, GLP-1 stimulates insulin secretion, which promotes the peripheral uptake of glucose and suppresses glucagon secretion thereby reducing hepatic glucose production from glycogen. Furthermore, GLP-1 delays gastric emptying and induces satiety. This study adds to the growing evidence observed for SG. The
marked improvement in postprandial GLP-1 response after SG provides strong evidence that metabolic improvements are not exclusively related to the restrictive nature of this operation. Within our present study, we have not measured the serum concentrations of ghrelin. This hormone is produced mainly within the gastric fundus, an area that is resected during SG. Previous studies have shown a reduction in serum concentrations of ghrelin after SG [10], which may be associated with improved insulin sensitivity. Of interest, no changes in ghrelin have been described after BPD [10]. A weakness of our present study was that the patients were not blindly allocated to surgical treatment groups. The duration of diabetes was obtained from primary care medical records and this is therefore an estimate as diabetes may be present for some time before the diagnosis is made [26]. Furthermore there was no difference in the median duration of diabetes amongst those with T2 DM in the 2 groups. Another potential limitation of our study was that each of the groups consisted of patients with both IFG/IGT and T2 DM (50% IFG/IGT in the SG group and 20% IFG/ IGT in the BPD group). This limitation may have increased the risk of variability in hormone changes between the 2 groups.
671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725
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GLP-1 (pmol/L)
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700 600 Plasma GIP (pmol/L)
726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780
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8
500 400 Baseline
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Fig. 2. Changes in glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic hormone (GIP) during the 2-hour oral glucose tolerance test (OGTT) in the sleeve gastrectomy group. Mean and standard error is shown. *P o .05. (A) Glucose. At 1-month, glucose values were significantly reduced at times 0, 60, and 120 minutes. At 6 months, glucose values were significantly lower at times 0, 30, 45, 60, and 120 minutes. (B) C-peptide. At 1 month, C-peptide values were significantly increased at times 15, 30, 45, and 60 minutes. At 6 months, C-peptide values were significantly lower at 0 minutes and increased at times 30, 45, and 60 minutes. (C) Insulin. At 1 month, insulin was significantly lower at 0 minutes and increased at 45 minutes. At 6 months, insulin was significantly lower at time 0 and 120 minutes. (D) GLP-1. Fasting GLP-1 concentrations were not different at baseline, 1 and 6 months. However, significant differences were observed at all sampling time points during the OGTT at 1 and 6 months compared to baseline. (E) GIP. There were no significant differences at any of the time points between baseline and 1 and 6 months.
781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835
18
16
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12 10
*
*
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C-peptide (pmol/L)
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Baseline
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1 month
0
0 0
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* *
15 *
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*
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*
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Plasma GLP-1 (pmol/L)
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836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890
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Glucose Homeostasis after Bariatric Surgery / Surgery for Obesity and Related Diseases ] (2014) 00–00
500 400 Baseline
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*
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*
*
* *
*
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*
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Fig. 3. Changes in glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic hormone (GIP) during the 2-hour oral glucose tolerance test (OGTT) in the biliopancreatic diversion group. Mean and standard error is shown. *P o .05. (A) Glucose. At 1-month, glucose values were significantly reduced at times 45, 60, and of borderline significance at 120 minutes (P ¼ .07). At 6 months, glucose values were significantly lower at times 45 and 60 and of borderline significance at 120 minutes (P ¼ .08). (B) C-peptide. No significant increases were observed in C-peptide compared to baseline. (C) Insulin. The only significant difference was observed at time 0 minutes at 6 months. (D) GLP-1. Fasting GLP-1 concentrations were not different at baseline, 1 and 6 months. However, significant differences were observed at all sampling time points during the OGTT at 1 and 6 months compared to baseline. (E) GIP. Significant changes were observed at 6 months compared to baseline at 15, 30, 45, and 60 minutes.
891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945
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946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 Q5 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989
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Conclusion The present study contributes to the available literature supporting the role of SG for the treatment of T2 DM in association with morbid obesity. The rates of improvement in T2 DM and IGT are comparable to those associated with BPD. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. Acknowledgments Gareth Dunseath, M.Phil.; Richard M. Bracken, Ph.D.; Kathie Wareham, M.Sc.; Jane Griffiths, B.Sc.; Nia Eyre, B. Sc.; Morgan J, F.R.C.A., M.R.C.P.; Alam I, M.D., F.R.C. S.; Rice S, Ph.D., M.R.C.P.; Stephen C. Bain, M.D., F.R.C. P.; Steve D. Luzio, Ph.D. References [1] Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724–37. [2] Kashyap SR, Daud S, Kelly KR, et al. Acute effects of gastric bypass versus gastric restrictive surgery on beta-cell function and insulinotropic hormones in severely obese patients with type 2 diabetes. Int J Obes (Lond) 2010;34:462–71. [3] Rodieux F, Giusti V, D’Alessio DA, Suter M, Tappy L. Effects of gastric bypass and gastric banding on glucose kinetics and gut hormone release. Obesity (Silver Spring) 2008;16:298–305. [4] Falken Y, Hellstrom PM, Holst JJ, Naslund E. Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. J Clin Endocrinol Metab 2011;96:2227–35. [5] Dirksen C, Jorgensen NB, Bojsen-Moller KN, et al. Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass. Diabetologia 2012;55:1890–901. [6] Pories WJ, Swanson MS, MacDonald KG, et al. Who would have thought it? An operation proves to be the most effective therapy for adultonset diabetes mellitus. Ann Surg 1995;222:339–50. (discussion 50–2). [7] Alam I, Stephens JW, Fielding A, Lewis KE, Lewis MJ, Baxter JN. Temporal changes in glucose and insulin homeostasis after biliopancreatic diversion and laparoscopic adjustable gastric banding. Surg Obes Relat Dis 2012;8:752–63. [8] Papamargaritis D, le Roux CW, Sioka E, Koukoulis G, Tzovaras G, Zacharoulis D. Changes in gut hormone profile and glucose homeostasis after laparoscopic sleeve gastrectomy. Surg Obes Relat Dis 2013;9:192–201.
[9] Benaiges D, Flores Le-Roux JA, Pedro-Botet J, et al. Sleeve gastrectomy and Roux-en-Y gastric bypass are equally effective in correcting insulin resistance. Int J Surg 2013;11:309–13. [10] Tsoli M, Chronaiou A, Kehagias I, Kalfarentzos F, Alexandrides TK. Hormone changes and diabetes resolution after biliopancreatic diversion and laparoscopic sleeve gastrectomy: a comparative prospective study. Surg Obes Relat Dis 2013;9:667–77. [11] Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, Wajchenberg BL, Cummings DE. Effects of gastric bypass surgery in patients with type 2 diabetes and only mild obesity. Diabetes Care 2012;35:1420–8. [12] Carey DG, Jenkins AB, Campbell LV, Freund J, Chisholm DJ. Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 1996;45:633–8. [13] Leonetti F, Capoccia D, Coccia F, et al. Obesity, type 2 diabetes mellitus, and other comorbidities: a prospective cohort study of laparoscopic sleeve gastrectomy vs medical treatment. Arch Surg 2012;147:694–700. [14] Jimenez A, Casamitjana R, Flores L, et al. Long-term effects of sleeve gastrectomy and Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus in morbidly obese subjects. Ann Surg 2012;256:1023–9. [15] Meier JJ, Nauck MA. Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab Res Rev 2005;21:91–117. [16] Standards of medical care in diabetes. Diabetes Care 2013;36:S11–66. [17] Wolever TM, Chiasson JL, Csima A, et al. Variation of postprandial plasma glucose, palatability, and symptoms associated with a standardized mixed test meal versus 75 g oral glucose. Diabetes Care 1998;21:336–40. [18] Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 1998;21:2191–2. [19] Uwaifo GI, Fallon EM, Chin J, Elberg J, Parikh SJ, Yanovski JA. Indices of insulin action, disposal, and secretion derived from fasting samples and clamps in normal glucose-tolerant black and white children. Diabetes Care 2002;25:2081–7. [20] Bojsen-Moller KN, Dirksen C, Jorgensen NB, et al. Increased hepatic insulin clearance after Roux-en-Y Gastric Bypass. J Clin Endocrinol Metab 2013;98:E1066–71. (2013). [21] Deitel M, Crosby RD, Gagner M. The first International Consensus Summit for sleeve gastrectomy (SG), New York City, October 25–27, 2007. Obes Surg 2008;18:487–96. [22] Gumbs AA, Gagner M, Dakin G, Pomp A. Sleeve gastrectomy for morbid obesity. Obes Surg 2007;17:962–9. [23] Rao RS, Kini S. GIP and bariatric surgery. Obes Surg 2011;21: 244–52. [24] Sarkhosh K, Birch DW, Shi X, Gill RS, Karmali S. The impact of sleeve gastrectomy on hypertension: a systematic review. Obes Surg 2012;22:832–7. [25] Abbatini F, Rizzello M, Casella G, et al. Long-term effects of laparoscopic sleeve gastrectomy, gastric bypass, and adjustable gastric banding on type 2 diabetes. Surg Endosc 2010;24:1005–10. [26] Harris MI. Diabetes in America: epidemiology and scope of the problem. Diabetes Care 1998;21:C11–4.
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Surgery for Obesity and Related Diseases ] (2014) 00–00
Original article
Temporal changes in glucose homeostasis and incretin hormone response at 1 and 6 months after laparoscopic sleeve gastrectomy Akhila Mallipedhi, M.R.C.P.a,b,*, Sarah L. Prior, Ph.D.a, Jonathan Barry, M.Ch.c, Scott Caplin, F.R.C.S.c, John N. Baxter, M.D.c, Jeffrey W. Stephens, F.R.C.P.a,b,c a Diabetes Research Group, Institute of Life Sciences, Swansea University, Swansea, United Kingdom Department of Diabetes & Endocrinology, Morriston Hospital ABM University Health Board, Swansea, United Kingdom c Welsh Institute of Metabolic and Obesity Surgery, Morriston Hospital ABM University Health Board, Swansea, United Kingdom Received November 5, 2013; accepted February 24, 2014 b
Abstract
Background: Bariatric surgery is an effective treatment for morbid obesity. Current literature reports significant improvements in glucose homeostasis after malabsorptive surgery. There is limited evidence on the effects of laparoscopic sleeve gastrectomy (SG) on glucose-insulin homeostasis and postoperative incretin hormone response. The objective of this study was to examine the metabolic effects of SG on temporal changes in insulin and glucose homeostasis, incretin hormones and hepatic insulin clearance in patients with impaired glucose tolerance (IGT) and type 2 diabetes (T2 DM). Methods: A nonrandomized prospective study comprising 22 participants undergoing SG (body mass index [BMI] 50.1 kg/m2, glycated hemoglobin [HbA1c] 53 mmol/mol) and 15 participants undergoing biliopancreatic diversion (BPD) (BMI 62.1 kg/m2, HbA1c 58 mmol/mol). Serial measurements of glucose, insulin, C-peptide, glucagon like peptide-1 (GLP-1) and glucosedependent insulinotropic hormone (GIP) were performed during oral glucose tolerance testing preoperatively and 1 and 6 months postoperatively. Areas under the curve (AUC) were examined at 30, 60, and 120 minutes. Results: Within the SG group, significant improvements were observed respectively at 1 and 6 months in glucose control (HbA1c: 0.9%, 1.3%), measures of insulin sensitivity (fasting insulin: 4.8 mU/L, 8.5 mU/L; fasting C-peptide: 0.6 pmol/L, 1.1 pmol/L; Homeostasis Model Assessment [HOMA-IR]: 0.144, 0.174; HOMA %S: þ29.6, þ92.4), hepatic insulin clearance (þ0.07, þ0.13) and postprandial GLP-1 response (AUC0-30 pmol h L1: þ300, þ331, AUC0-60: þ300, þ294, AUC0-120: þ316, þ295). These results were comparable to the BPD group. Conclusions: SG is associated with significant early improvements in insulin sensitivity and incretin hormone response and results in significant improvements in IGT/T2 DM. (Surg Obes Relat Dis 2014;]:00–00.) r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Type 2 diabetes mellitus; Obesity; Sleeve gastrectomy; Biliopancreatic diversion
This study was supported by a project Research Grant from The BUPA Foundation (33 NOV06). * Correspondence: Dr. Akhila Mallipedhi, Diabetes Research Group, Institute of Life Sciences, Swansea University, Swansea SA2 8 PP, UK. E-mail: [email protected]
Bariatric surgery is an effective treatment for morbid obesity and is associated with resolution of impaired glucose tolerance (IGT) and type 2 diabetes (T2 DM) [1]. The literature reports resolution in glucose abnormalities after malabsorptive surgery such as biliopancreatic diversion
http://dx.doi.org/10.1016/j.soard.2014.02.038 1550-7289/r 2014 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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(BPD) and laparoscopic Roux-en-Y gastric bypass (RYGB) [1]. It is well documented that this improvement is related to an increase in postprandial release of glucagon like peptide-1 (GLP-1), improved insulin sensitivity, reduced calorie intake and associated weight loss [2–5]. The changes in GLP-1, insulin and glucose homeostasis are typically seen early after malabsorptive surgery (RYGB and BPD) before significant weight loss occurs [6]. With respect to restrictive surgical procedures such as laparoscopic gastric banding (LGB) and laparoscopic sleeve gastrectomy (SG), improvements in fasting plasma glucose and measures of insulin sensitivity typically occur with weight loss [7–9]. Recently, Tsoli et al. [10] described a significant increase in the GLP-1 response during an oral glucose tolerance test (OGTT) in 12 patients after a SG with comparable resolution of T2 DM in 12 participants undergoing a BPD [10]. Of interest in both groups of participants, improvements in postprandial GLP-1 were not observed until 3 months after surgery and improvements in insulin sensitivity were not observed until 12 months [10]. This study did not examine changes in the area under the curve (AUC) for C-peptide during a glucose load nor examine fasting insulin sensitivity. A recent study in 10 participants has also described improvements in postprandial GLP-1 and reductions in fasting insulin and the AUC for insulin as early as 6 weeks after SG and reductions in the AUC for glucose at 6 months postoperatively [8]. Because C-peptide is a direct measure of insulin production, this may provide a more accurate measure of β-cell insulin responsiveness to GLP-1 [11]. Total insulin concentrations are in part dependent on the body mass of an individual and the degree of insulin resistance within an individual [12]. Recent studies have described equally effective resolution of T2 DM in patients undergoing a SG and malabsorptive surgery (BPD or RYGB), [9,13,14] but these studies lack detailed examination of GLP-1, glucose, and insulin response to surgery. Little information is available on the effects of bariatric surgery on glucose-dependent insulinotropic hormone (GIP). GIPsecreting K-cells are predominantly located in the upper portions of the small intestine, namely, the duodenum and jejunum [15], and therefore investigation of GIP concentrations after both SG and malabsorptive surgery is warranted. Our aim was to specifically examine the postprandial temporal changes in insulin and glucose homeostasis, incretin hormones (GLP-1 and GIP), and hepatic insulin clearance preoperatively, and at 1 and 6 months after SG. We also examined this in a group of patients undergoing BPD.
Methods
both genders, age 20–40 years, body mass index (BMI) 4 40 kg/m2, and physically fit for surgery. Participants with pre-existing diabetes treated with diet, oral agents, GLP-1 analogues or insulin were included. Participants with impaired glucose regulation were those with either impaired fasting glycemia (5.6–6.9 mmol/L) or impaired glucose tolerance (2-hr glucose 7.8–11.0 mmol/L) [16]. Study design Participants were recruited prospectively and consecutively from the Bariatric Surgical clinic and were not blindly allocated to a surgical treatment option. As per local guidance, those with a BMI 4 50 kg/m2 were routinely offered a BPD, whereas those with a BMI below this are usually offered SG or laparoscopic gastric band (LGB). SG is a standard sleeve i.e., sleeve fashioned around a 32 F bougie taken from 5 cm proximal to the pylorus and up to the left crus. BPD involved a distal gastrectomy (as described by Scopinaro) and a 50-cm common channel. All participants were recruited preoperatively and followed-up postoperatively at 1 and 6 months where they underwent a standardized 75-g oral glucose tolerance test (OGTT) (122 mL of Polycal 61.9 g/100 mL of glucose, Nutricia Clinical Care, Trowbridge, UK). Previous studies have demonstrated that the level of glycemia reached 2 hours after 75 g of glucose is closely related to the level of glycemia after a standardized meal indicating an OGTT is a valid tool for revealing altered carbohydrate metabolism during a meal [17]. Insulin or oral hypoglycemic agents were omitted for 24 hours before the OGTT. There was no standardized meal prescribed for the night before and patients were asked to fast from the midnight before the test. Baseline clinical and biochemical information Baseline clinical measurements consisted of weight, height, BMI, waist circumference, and systolic and diastolic blood pressure. Baseline biochemical measurements (total cholesterol, low-density lipoprotein-cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], and triglycerides) were analyzed within the local hospital accredited laboratory. Glucose and lipids (Roche Modular P800 Analyzer) and insulin and C-peptide (Roche E170 Modular Analyzer) were also measured locally. During the OGTT, plasma and serum samples were collected for measurements of glucose, insulin, C-peptide, GLP-1, and GIP at time 0, 15, 30, 45, 60, and 120 minutes. All samples were collected on ice, centrifuged and separated within 1 hour of collection and subsequently stored at -80 oC until analysis.
Study participants
Measurements of insulin sensitivity
Approval for the study was obtained from the Local Research Ethics Committee. Participants were identified and recruited from patients undergoing a planned bariatric surgical procedure. Entry criteria at the outset included:
The Homeostasis Model Assessment (HOMA) was used to estimate steady state β-cell function (%B) and insulin sensitivity (%S). These were calculated using the Oxford University on-line calculator (http://www.dtu.ox.ac.uk/homacalculator,
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accessed 7 May 2013) [18]. HOMA-insulin resistance (IR) is the reciprocal of HOMA-%S. The HOMA-%B and HOMA-% S represent values of 100% in normal young adults when using currently available assays for insulin, specific insulin or C-peptide. The accuracy of these measures has been validated, and they have been shown to correlate with clamp-derived indices of insulin sensitivity and secretion [19]. They estimate steady state function. We have also examined nonsteady state function by analyzing the different AUC for insulin, glucose, C-peptide, GLP-1, and GIP at 30, 60 and 120 minutes. The fasting C-peptide to insulin molar ratio was calculated as an index of hepatic insulin clearance [20]. Measurement of total GLP-1 and total GIP Total GLP-1 was quantitatively measured using the Epitope Diagnostics Inc, Total GLP-1 ELISA Kit, which utilizes the 2-site sandwich technique with 2 selected GLP-1 antibodies to assess both the intact GLP-1 (7-36) amide and the primary (NH2-terminally truncated) metabolite, GLP-1 (9-36) amide. The intra- and interassay coefficients of variation were r4.7% and r9.5%, respectively. Total GIP was measured using the Millipore Human GIP (total) ELISA kit, which reacts fully with intact GIP (1-42) and the NH2-terminally truncated metabolite, GIP (3-42). The intra- and interassay coefficients of variation were r8.8% and r6.1%, respectively. Statistical methods Statistical analysis was performed using SPSS. Results for continuous variables are presented as mean and standard deviation and in graphical representation as mean and standard error. Continuous variables that did not have a normal distribution (triglyceride, fasting insulin, fasting C-peptide, HOMA-IR, HOMA-%B, HOMA-%S, hepatic insulin clearance, AUC insulin, AUC C-peptide) underwent log transformation to normalize the data for analysis and are described with the geometric mean and approximate standard deviation. For continuous variables, differences in means were compared between baseline and 1 or 6 months using a paired samples t test. Categorical data were analyzed using a Χ2 test. Paired t tests were used to compare mean differences at individual time points during the OGTT between baseline, and 1 and 6 months for glucose, insulin, C-peptide, GLP-1, and GIP. Changes in the AUC over 30 minutes (AUC0-30), 60 minutes (AUC0-60), and 120 minutes (AUC0-120) were analyzed during the OGTT at baseline, and 1 and 6 months for glucose, insulin, C-peptide, GLP-1, and GIP using the trapezoidal rule. In all cases, a P value of o .05 was considered statistically significant. Results Participant characteristics A total of 37 participants completed the study. Of these, 22 had a SG and 15 a BPD. There was no difference in age
3
between the groups (mean age ¼ 48 ⫾ 7 and 50 ⫾ 8, P ¼ .31). In the SG group there were 15 females and 7 males, and in the BPD group there were 10 females and 5 males (P ¼ .6). 50% of the patients within the SG group had IGT compared to 20% within the BPD group. Within the SG group, the median duration of diabetes was 42 months (interquartile range: 21–66 months) compared to 54 months (26–112 months) in the BPD group (P ¼ .34). Weight, BMI, blood pressure, and lipids before and after surgery At baseline (Table 1a and 1b), as expected from the recruitment criteria, BMI and weight were higher in the BPD group compared to the SG group (BMI: P = .002; weight: P = .03). As shown in Table 1a, within the SG group, significant reductions were observed in weight at 1 month with a mean reduction of 31.1 kg at 6 months. In the BPD group (Table 1b) a significant reduction was observed for weight with a mean reduction of 37.5 kg seen at 6 months. These changes were associated with significant reductions in the waist circumference and BMI at 1 and 6 months in both groups. There was a significant reduction in the systolic blood pressure at 1 month after SG. No statistically significant changes were observed in systolic and diastolic blood pressure readings in the BPD group (Table 1a and 1b). There were no significant changes in total cholesterol, LDL-C or triglyceride concentrations after SG. In the BPD group, there was a significant reduction in total cholesterol and LDL-C concentrations at 1 month. Effects of bariatric surgery on glycemic control Significant changes were observed in fasting glucose, 2hour glucose, and glycated hemoglobin (HbA1c) in both groups at 1 month (Table 1a and 1b). As shown in Fig. 1, significant differences were observed in the proportion of patients with impaired glucose tolerance (IFG and IGT) and T2 DM at 1 and 6 months after both SG and BPD. After SG, within the IFG/IGT group, 54.5% had normal glucose concentrations and 45.5% had persisting IFG/IGT at 1 month. At 6 months, 100% of the patients demonstrated normal glucose concentrations. In patients with T2 DM, at 1 month- 10% of the patients had normal glucose concentrations, 60% had IFG/IGT and 30% DM. At 6 months 66.7% had normal tests, 30% IFG/IGT, and none with DM. After BPD, within the IFG/IGT group, 33% had normal glucose concentrations and 66.7% IFG/IGT at 1 month. At 6 months, 100% had reverted to normal glucose concentrations. In patients with T2 DM, at 1 month 20% had normal glucose concentrations, 40% IFG/IGT, and 40% DM. At 6 months 40% had normal tests, 40% IFG/IGT, and 20% DM. With respect to diabetes therapies, in the SG group (Table 2), the 3 participants treated with insulin preoperatively had discontinued it within 6 months.
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Table 1a Baseline and end of study clinical and biochemical measurements within the SG group Measurement Weight (kg) BMI (kg/m2) Waist (cm) Systolic BP (mm Hg) Diastolic BP (mm Hg) Cholesterol (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Triglyceride (mmol/L)‡ HbA1c (%) HbA1c (mmol/mol) Fasting glucose (mmol/L) 2-hr glucose (mmol/L)
Baseline 146.6 50.1 138 131 76 4.3 2.4 1.2 1.4 7.0 53 7.6 11.6
(29.6) (6.6) (18) (18) (11) (1.0) (.8) (.3) (.4) (1.7) (18.6) (3.6) (5.9)
P value*
1 mo 129.4 44.0 128 123 74 4.4 2.7 1.1 1.4 6.1 43 5.4 7.8
o.001 o.001 o.001 .04 .63 .58 .16 .02 .92 .005 .005 .02 .002
(26.9) (6.6) (17) (14) (9) (1.1) (1.0) (.3) (.2) (.8) (8.7) (.9) (3.4)
6 mo 115.5 39.6 118 128 73 4.7 2.8 1.3 1.1 5.7 39 5.0 5.4
(24.4) (6.2) (18) (20) (14) (1.2) (.9) (.3) (.2) (.8) (8.7) (1.0) (2.2)
P value† o.001 o.001 o.001 .12 .13 .09 .05 .10 .15 .002 .002 .08 o.001
SG ¼ sleeve gastrectomy; BMI ¼ body mass index; LDL-C ¼ low-density lipoprotein-cholesterol; HDL-C ¼ high-density lipoprotein-cholesterol; HbA1c ¼ glycated hemoglobin In the SG group there were 15 females and 7 males, and in the BPD group there were 10 females and 5 males (P ¼ .6). * P value comparing baseline with 1 mo. † P value comparing baseline with 6 mo. ‡ Log transformed for analysis. Geometric mean and approximate standard deviation shown for log-transformed data.
line with previous studies, we observed a significant reduction in fasting insulin level and an increase in hepatic insulin clearance (Table 3a) at 1 and 6 months, postoperatively. HOMA-%S was significantly increased (and HOMA-IR decreased) at 6 months. Fasting C-peptide was significantly decreased 6 months after surgery. Dynamic measures. As shown in Fig. 2a, there was a significant reduction in the mean plasma glucose values at 0, 60, and 120 minutes at 1 month and 0, 30, 45, 60, and 120 minutes at 6 months. There was a significant reduction in the mean AUC0-120 mins for glucose at 1 and 6 months after surgery compared to baseline (Table 3a). Postprandial C-peptide values (Fig. 2b) were significantly increased at 15, 30, 45, and 60 minutes at 1 month and 30, 45 and
Furthermore, 19 participants had discontinued all treatments within 6 months (87.5% off treatment). In the BPD group, no subject remained on insulin treatment 6 months postoperatively, and 10 (71.4%) participants had discontinued all treatments in 6 months. There was also a corresponding 50% reduction in the number of participants receiving oral therapies for T2 DM in both the groups. Effects of bariatric surgery on glucose-insulin homeostasis and incretin hormones SG group. Static measures. Within the SG group (Table 1a); mean HbA1c, fasting and 2-hour glucose values were significantly lower at 1 and 6 months after surgery. In
Table 1b Baseline and end of study clinical and biochemical measurements within the BPD group Measurement Weight (kg) BMI (kg/m2) Waist (cm) Systolic BP (mm Hg) Diastolic BP (mm Hg) Cholesterol (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Triglyceride (mmol/L)‡ HbA1c (%) HbA1c (mmol/mol) Fasting glucose (mmol/L) 2-hr glucose (mmol/L)
Baseline 172.4 62.1 154 136 81 4.5 2.3 1.3 1.8 7.5 58 8.2 12.9
(41.2) (14.3) (22) (17) (7) (.9) (.9) (.2) (.8) (1.5) (16.4) (4.1) (5.0)
1 mo 151.5 55.3 148 130 73 3.1 1.2 1.1 1.7 6.2 44 6.5 9.4
(28.2) (11.5) (19) (18) (9) (.6) (.5) (.3) (.2) (.7) (7.7) (2.1) (3.0)
P value* .001 o.001 o.001 .18 .009 o.001 o.001 o.001 .27 .005 .005 .08 .01
6 mo 134.9 49.7 131 131 77 3.3 1.5 1.0 1.6 5.9 41 6.2 9.4
(27.8) (10.2) (18) (10) (8) (.7) (.6) (.2) (.2) (1.4) (15.3) (3.7) (5.9)
P value† o.001 o.001 o.001 .48 .34 .08 .04 o.001 .12 .04 .04 .23 .12
BPD ¼ biliopancreatic diversion; BMI ¼ body mass index; LDL-C ¼ low-density lipoprotein-cholesterol; HDL-C ¼ high-density lipoprotein-cholesterol; HbA1c ¼ glycated hemoglobin * P value comparing baseline with 1 mo. † P value comparing baseline with 6 mo. ‡ Log transformed for analysis. Geometric mean and approximate standard deviation shown for log-transformed data.
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* **
*
5
**
*
* **
*
**
Fig. 1. (a). Proportion of participants with T2 DM and impaired glucose tolerance before and following sleeve gastrectomy. Significant differences were observed between the proportion of patients with T2 DM and impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG) at 1 and 6 months after SG. *P ¼ .02; **P o .01. (b). Proportion of participants with T2 DM and impaired glucose tolerance before and following biliopancreatic diversion (BPD). Significant differences were observed the proportion of patients with T2 DM and impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG) at 1 and 6 months after BPD.*P ¼ .02; **P ¼ .0002.
60 minutes at 6 months. There was a significant increase in AUC0-60 mins and AUC0-120 mins for C-peptide at 1 and 6 months postsurgery. The insulin AUC0-60 mins was significantly increased at both 1 and 6 months (Table 3a). Table 2 Changes in treatments at 1 and 6 months postsurgery Numbers (%) within groups
Time after surgery Baseline
No treatment Oral agents/ GLP-1 analogue Insulin and oral agents No treatment Oral agents/ GLP-1 analogue Insulin and oral agents
SG 12 (54.5%) 7 (31.8%) 3 (13.6%) BPD 3 (20.0%) 9 (60.0%) 3 (20.0%)
1 mo
6 mo
19 (86.4%) 2 (9.1%) 1 (4.5%)
19 (87.5%) 3 (12.5%) 0 (.0%)
9 (60.0%) 6 (40.0%) 0 (.0%)
10 (71.4%) 4 (28.6%) 0 (.0%)
SG ¼ sleeve gastrectomy; GLP-1 ¼ glucagon-like peptide-1; BPD ¼ biliopancreatic diversion
Incretin effect. Fasting GLP-1 concentrations (Fig. 2d) were not different at 0, 1, and 6 months. However, significant increases were observed at all postprandial sampling time points at 1 and 6 months compared to time 0 minutes. In line with this, there were significant increases in the AUC0-30 mins, AUC0-60 mins, and AUC0-120 mins for GLP-1 at 1 and 6 months postoperatively (Table 3a). No significant changes were observed in relation to GIP (Fig. 2e). BPD group. Static measures. Within the BPD group (Table 1b); HbA1c, fasting and 2-hour glucose values were lower at 1 and 6 months after surgery. There was a significant reduction in fasting insulin and an increase in hepatic insulin clearance (Table 3b) at 1 and 6 months postoperatively. Dynamic measures. As shown in Fig. 3a, there was a significant reduction in the mean plasma glucose values at 45 and 60 minutes at 1 and 6 months. There was a significant reduction in the mean AUC0-120 mins for glucose
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Table 3a Changes in insulin sensitivity and incretin hormones within the SG group Baseline Fasting insulin (mU/L)‡ Fasting C-peptide (pmol/L)‡ 2-hr insulin (mU/L)‡ HOMA-IR‡ HOMA-B%‡ HOMA-S%‡ Hepatic insulin clearance‡ AUC0-30 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1) AUC0-60 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1) AUC0-120 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1)
1 mo
P value*
6 mo
P value†
18.1 4.2 76.7 .394 23.7 351.3 .20
(4.8) (.6) (29.2) (.11) (7.4) (112.0) (.03)
13.3 3.6 79.1 .250 25.5 380.9 .27
(3.1) (.4) (29.7) (.07) (5.8) (97.8) (.06)
.009 .15 .24 .19 .93 .23 .02
9.6 3.1 27.9 .220 28.4 443.7 .33
(2.5) (.8) (20.7) (0.08) (6.1) (173.1) (.08)
.001 .01 .25 .04 .35 .03 o.001
4.5 17.3 2.7 1.3 131.5
(1.5) (5.6) (1.0) (1.1) (48.1)
4.1 20.8 3.2 5.2 152.3
(.6) (4.8) (.5) (2.2) (67.7)
.22 .14 .03 o.001 .08
3.8 25.8 2.7 5.6 142.8
(.8) (9.1) (.6) (3.8) (76.1)
.11 .07 .39 o.001 .57
10.8 50.2 6.8 3.2 313.7
(3.4) (17.2) (1.5) (2.8) (98.9)
9.5 65.6 8.9 12.8 339.3
(1.5) (14.0) (1.5) (5.1) (111.0)
.14 .01 .001 o.001 .16
8.8 73.1 7.7 12.6 334.7
(2.3) (28.9) (1.6) (7.9) (177.9)
.05 .03 .01 o.001 .65
23.4 142.1 16.9 5.6 620.9
(7.3) (45.8) (3.1) (5.1) (210.2)
19.1 167.4 21.5 23.3 638.2
(3.5) (46.3) (3.3) (10.9) (203.7)
.01 .06 o.001 o.001 .49
16.5 122.8 17.7 22.1 653.4
(4.7) (46.0) (3.7) (12.6) (372.3)
.003 .90 .04 o.001 .78
SG ¼ sleeve gastrectomy; AUC ¼ area under the curve; HOMA-IR ¼ homeostatic model assessment-insulin resistance; HOMA-%S ¼ homeostatic model assessment-insulin sensitivity; HOMA-%B ¼ Homeostatic model assessment β-cell function; GLP-1 ¼ glucagon-like peptide-1; GIP ¼ glucose-dependent insulinotropic hormone * P value comparing baseline with 1 mo. † P value comparing baseline with 6 mo. ‡ Log transformed for analysis. Geometric mean and approximate standard deviation for log-transformed data shown.
at 1 and 6 months after surgery compared to baseline (Table 3b). There was a significant (33%) increase in AUC0-120 mins for C-peptide at 1 and 6 months postsurgery. Incretin effect. Fasting GLP-1 concentrations (Fig. 3d) were not different at baseline, 1 and 6 months. However, significant increases were observed at all postprandial sampling time points at 1 and 6 months compared to time 0 minutes. In line with this, there were significant increases in the AUC0-30 mins, AUC0-60 mins, and AUC0-120 mins for GLP-1 at 1 and 6 months postoperatively (Table 3b). Significant reductions were observed in the AUC0-30 mins, AUC0-60, mins and AUC0-120 mins for GIP (Fig. 3e) at 1 and 6 months and furthermore, there were significant reductions observed at 15, 30, 45, and 60 minutes at 1 and 6 months compared to baseline. Discussion SG is recognized as a stand-alone bariatric procedure with a superior safety profile [21,22]. In line with previous studies, we observed significant resolution of IGT and T2 DM with SG. In this group, the 3 (100%) participants treated with insulin preoperatively had discontinued this within 6 months and 19 (87.5%) participants had discontinued all treatments within 6 months. A marked reduction
in fasting glucose, HbA1c and the AUC0-120 for glucose at 1 and 6 months postoperatively was observed, in addition to significant early improvements at 1 month in fasting insulin, hepatic insulin clearance and at 6 months in HOMA-IR (and HOMA-%S). Along with these changes, there was a marked postprandial increase in the AUC for GLP-1. In line with this GLP-1 response, a significant increase in the AUC for C-peptide was observed. These results therefore suggest that the improvement in glucose and insulin homeostasis is the result of improved hepatic insulin sensitivity, enhanced postprandial GLP-1 response and subsequent restoration of the early phase insulin release. The improvement in HOMA-IR observed at 6 months suggests a further improvement in insulin resistance facilitated by weight loss. With respect to the BPD group, we observed that no subject remained on insulin treatment 6 months postoperatively and 10 (71.4%) participants had discontinued all treatments in 6 months. In line with previous publications [2–5,20], we observed reductions in fasting glucose, HbA1c and the AUC0-120 for glucose at 1 and 6 months postoperatively and an early improvement in hepatic insulin clearance. Again, in line with previous studies, there was a marked significant postprandial increase in the AUC for GLP-1. We also observed a significant decrease in the
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Table 3b Changes in insulin sensitivity and incretin hormones within the BPD group Baseline Fasting insulin (mU/L)‡ Fasting C-peptide (pmol/L)‡ 2-hr insulin (mU/L)‡ HOMA-IRc HOMA-B%‡ HOMA-S‡ Hepatic insulin clearance‡ AUC0-30 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1) AUC0-60 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1) AUC0-120 Glucose (mmol h L-1) Insulin (mU h L-1)‡ C-peptide (pmol h L-1)‡ GLP-1 (pmol h L-1) GIP (pmol h L-1)
P value*
1 mo
6 mo
P value† o.001 .89 .46 .14 .46 .13 .002
28.0 1.9 49.4 .444 23.27 217.7 .09
(3.7) (.5) (16.7) (.071) (1.43) (32.9) (.03)
16.8 2.6 43.8 .338 24.58 282.1 .15
(4.2) (1.3) (12.5) (.105) (7.53) (82.7) (.04)
.003 .85 .89 .35 .90 .36 .01
10.8 2.3 38.9 .278 20.56 346.8 .21
(3.5) (.5) (13.2) (.115) (6.63) (145.8) (.05)
4.4 17.0 1.52 3.3 192.7
(2.3) (4.4) (.3) (4.2) (93.5)
3.8 17.01 1.6 7.6 102.8
(1.0) (4.1) (.2) (7.2) (53.2)
.81 .95 .64 .02 .01
3.1 14.5 1.7 8.2 96.4
(.6) (3.8) (.3) (4.8) (37.9)
.05 .77 .26 .003 .006
11.0 45.6 2.6 7.4 472.8
(4.4) (15.5) (.8) (7.9) (214.3)
8.3 39.0 3.9 15.7 232.7
(2.4) (10.0) (.5) (10.2) (118.9)
.09 .68 .33 .02 .008
7.3 38.7 4.1 16.8 215.9
(1.6) (11.2) (.8) (7.7) (85.5)
.009 .74 .21 o.001 .005
24.8 97.0 6.3 11.8 842.9
(8.8) (34.4) (1.6) (14.2) (390.3)
17.6 77.5 9.9 29.1 460.0
(5.2) (19.0) (1.3) (17.4) (161.0)
.04 .97 .18 .003 .02
15.7 103.4 9.8 30.5 408.8
(3.1) (28.2) (1.8) (14.2) (162.6)
.02 .80 .09 o.001 .003
SG ¼ sleeve gastrectomy; AUC ¼ area under the curve; HOMA-IR ¼ homeostatic model assessment-insulin resistance; HOMA-%S ¼ homeostatic model assessment-insulin sensitivity; HOMA-%B ¼ Homeostatic model assessment β-cell function; GLP-1 ¼ glucagon-like peptide-1; GIP ¼ glucose-dependent insulinotropic hormone * P value comparing baseline with 1 mo. † P value comparing baseline with 6 mo. ‡ Log transformed for analysis. Geometric mean and approximate standard deviation for log-transformed data shown.
AUC0-60, AUC0-120 for GIP at 6 months, which is in line with a previous study [23]. While previous studies have reported these metabolic effects after BPD or RYGB, few studies have examined in detail the metabolic effects of SG in relation to glucose and insulin homeostasis. Our study is the first to examine the detailed postprandial temporal relationship of markers of glucose and insulin homeostasis in 22 patients. Previously, this has been described in a maximum of 12 patients [10]. Our results suggest that SG is effective in managing IGT and T2 DM in patients with morbid obesity. Within our present study, we observed significant improvements in IGT and T2 DM, which is in line with previous studies [14,24], which report comparable remission rates of T2 DM associated with BPD. These effects are superior to those observed with LGB [25]. The improved postprandial GLP-1 response accounts for part of the early improvement in glucose concentrations post-BPD. As previously discussed, GLP-1 stimulates insulin secretion, which promotes the peripheral uptake of glucose and suppresses glucagon secretion thereby reducing hepatic glucose production from glycogen. Furthermore, GLP-1 delays gastric emptying and induces satiety. This study adds to the growing evidence observed for SG. The
marked improvement in postprandial GLP-1 response after SG provides strong evidence that metabolic improvements are not exclusively related to the restrictive nature of this operation. Within our present study, we have not measured the serum concentrations of ghrelin. This hormone is produced mainly within the gastric fundus, an area that is resected during SG. Previous studies have shown a reduction in serum concentrations of ghrelin after SG [10], which may be associated with improved insulin sensitivity. Of interest, no changes in ghrelin have been described after BPD [10]. A weakness of our present study was that the patients were not blindly allocated to surgical treatment groups. The duration of diabetes was obtained from primary care medical records and this is therefore an estimate as diabetes may be present for some time before the diagnosis is made [26]. Furthermore there was no difference in the median duration of diabetes amongst those with T2 DM in the 2 groups. Another potential limitation of our study was that each of the groups consisted of patients with both IFG/IGT and T2 DM (50% IFG/IGT in the SG group and 20% IFG/ IGT in the BPD group). This limitation may have increased the risk of variability in hormone changes between the 2 groups.
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18
16
16
14
14
12
*
10
* *
8 6 4
*
*
Baseline 1 month
*
* *
6 months
*
C-peptide (pmol/L)
18
* * * *
12 10
* 1 month
*
6
2
0
6 months
*
0 0
15
30
45
60
120
0
15
30
Time (mins)
45
60
120
Time (mins)
25
300
20
200 150
Baseline 1 month
*
100
6 months
GLP-1 (pmol/L)
250
*
15
* *
*
* *
Baseline
**
1 month 6 months
*
10
*
5
50 0
Baseline
*
8
4
2
Insulin (mU/L)
*
* * *
0 0
15
30
45
60
0
120
15
Time (mins)
30 45 Time (mins)
60
120
700 600 Plasma GIP (pmol/L)
726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780
Plasma glucose (mmol/L)
8
500 400 Baseline
300
1 month
6 months
200 100 0 0
15
30
45
60
120
Time (mins)
Fig. 2. Changes in glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic hormone (GIP) during the 2-hour oral glucose tolerance test (OGTT) in the sleeve gastrectomy group. Mean and standard error is shown. *P o .05. (A) Glucose. At 1-month, glucose values were significantly reduced at times 0, 60, and 120 minutes. At 6 months, glucose values were significantly lower at times 0, 30, 45, 60, and 120 minutes. (B) C-peptide. At 1 month, C-peptide values were significantly increased at times 15, 30, 45, and 60 minutes. At 6 months, C-peptide values were significantly lower at 0 minutes and increased at times 30, 45, and 60 minutes. (C) Insulin. At 1 month, insulin was significantly lower at 0 minutes and increased at 45 minutes. At 6 months, insulin was significantly lower at time 0 and 120 minutes. (D) GLP-1. Fasting GLP-1 concentrations were not different at baseline, 1 and 6 months. However, significant differences were observed at all sampling time points during the OGTT at 1 and 6 months compared to baseline. (E) GIP. There were no significant differences at any of the time points between baseline and 1 and 6 months.
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18
16
16
14
14
12 10
*
*
8
*
*
Baseline 1 month 6 months
6
C-peptide (pmol/L)
18
9
12 10 8
Baseline
6
6 months
4
4
2
2
1 month
0
0 0
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0
120
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Time (mins)
300
25
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Baseline 1 month 6 months
100
* *
15 *
10
* * *
*
Baseline 1 month
*
6 months
5
*
0
*
*
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*
20
Plasma GLP-1 (pmol/L)
Insulin (mU/L)
0 15
30
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60
0
120
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60
120
Time (mins)
Time (mins)
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600 Plasma GIP (pmol/L)
836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890
Plasma glucose (mmol/L)
Glucose Homeostasis after Bariatric Surgery / Surgery for Obesity and Related Diseases ] (2014) 00–00
500 400 Baseline
300
*
200
*
*
* *
*
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*
6 months
*
100 0 0
15
30
45
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Time (mins)
Fig. 3. Changes in glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic hormone (GIP) during the 2-hour oral glucose tolerance test (OGTT) in the biliopancreatic diversion group. Mean and standard error is shown. *P o .05. (A) Glucose. At 1-month, glucose values were significantly reduced at times 45, 60, and of borderline significance at 120 minutes (P ¼ .07). At 6 months, glucose values were significantly lower at times 45 and 60 and of borderline significance at 120 minutes (P ¼ .08). (B) C-peptide. No significant increases were observed in C-peptide compared to baseline. (C) Insulin. The only significant difference was observed at time 0 minutes at 6 months. (D) GLP-1. Fasting GLP-1 concentrations were not different at baseline, 1 and 6 months. However, significant differences were observed at all sampling time points during the OGTT at 1 and 6 months compared to baseline. (E) GIP. Significant changes were observed at 6 months compared to baseline at 15, 30, 45, and 60 minutes.
891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945
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A. Mallipedhi et al. / Surgery for Obesity and Related Diseases ] (2014) 00–00
Conclusion The present study contributes to the available literature supporting the role of SG for the treatment of T2 DM in association with morbid obesity. The rates of improvement in T2 DM and IGT are comparable to those associated with BPD. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. Acknowledgments Gareth Dunseath, M.Phil.; Richard M. Bracken, Ph.D.; Kathie Wareham, M.Sc.; Jane Griffiths, B.Sc.; Nia Eyre, B. Sc.; Morgan J, F.R.C.A., M.R.C.P.; Alam I, M.D., F.R.C. S.; Rice S, Ph.D., M.R.C.P.; Stephen C. Bain, M.D., F.R.C. P.; Steve D. Luzio, Ph.D. References [1] Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724–37. [2] Kashyap SR, Daud S, Kelly KR, et al. Acute effects of gastric bypass versus gastric restrictive surgery on beta-cell function and insulinotropic hormones in severely obese patients with type 2 diabetes. Int J Obes (Lond) 2010;34:462–71. [3] Rodieux F, Giusti V, D’Alessio DA, Suter M, Tappy L. Effects of gastric bypass and gastric banding on glucose kinetics and gut hormone release. Obesity (Silver Spring) 2008;16:298–305. [4] Falken Y, Hellstrom PM, Holst JJ, Naslund E. Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides. J Clin Endocrinol Metab 2011;96:2227–35. [5] Dirksen C, Jorgensen NB, Bojsen-Moller KN, et al. Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass. Diabetologia 2012;55:1890–901. [6] Pories WJ, Swanson MS, MacDonald KG, et al. Who would have thought it? An operation proves to be the most effective therapy for adultonset diabetes mellitus. Ann Surg 1995;222:339–50. (discussion 50–2). [7] Alam I, Stephens JW, Fielding A, Lewis KE, Lewis MJ, Baxter JN. Temporal changes in glucose and insulin homeostasis after biliopancreatic diversion and laparoscopic adjustable gastric banding. Surg Obes Relat Dis 2012;8:752–63. [8] Papamargaritis D, le Roux CW, Sioka E, Koukoulis G, Tzovaras G, Zacharoulis D. Changes in gut hormone profile and glucose homeostasis after laparoscopic sleeve gastrectomy. Surg Obes Relat Dis 2013;9:192–201.
[9] Benaiges D, Flores Le-Roux JA, Pedro-Botet J, et al. Sleeve gastrectomy and Roux-en-Y gastric bypass are equally effective in correcting insulin resistance. Int J Surg 2013;11:309–13. [10] Tsoli M, Chronaiou A, Kehagias I, Kalfarentzos F, Alexandrides TK. Hormone changes and diabetes resolution after biliopancreatic diversion and laparoscopic sleeve gastrectomy: a comparative prospective study. Surg Obes Relat Dis 2013;9:667–77. [11] Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, Wajchenberg BL, Cummings DE. Effects of gastric bypass surgery in patients with type 2 diabetes and only mild obesity. Diabetes Care 2012;35:1420–8. [12] Carey DG, Jenkins AB, Campbell LV, Freund J, Chisholm DJ. Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 1996;45:633–8. [13] Leonetti F, Capoccia D, Coccia F, et al. Obesity, type 2 diabetes mellitus, and other comorbidities: a prospective cohort study of laparoscopic sleeve gastrectomy vs medical treatment. Arch Surg 2012;147:694–700. [14] Jimenez A, Casamitjana R, Flores L, et al. Long-term effects of sleeve gastrectomy and Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus in morbidly obese subjects. Ann Surg 2012;256:1023–9. [15] Meier JJ, Nauck MA. Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab Res Rev 2005;21:91–117. [16] Standards of medical care in diabetes. Diabetes Care 2013;36:S11–66. [17] Wolever TM, Chiasson JL, Csima A, et al. Variation of postprandial plasma glucose, palatability, and symptoms associated with a standardized mixed test meal versus 75 g oral glucose. Diabetes Care 1998;21:336–40. [18] Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 1998;21:2191–2. [19] Uwaifo GI, Fallon EM, Chin J, Elberg J, Parikh SJ, Yanovski JA. Indices of insulin action, disposal, and secretion derived from fasting samples and clamps in normal glucose-tolerant black and white children. Diabetes Care 2002;25:2081–7. [20] Bojsen-Moller KN, Dirksen C, Jorgensen NB, et al. Increased hepatic insulin clearance after Roux-en-Y Gastric Bypass. J Clin Endocrinol Metab 2013;98:E1066–71. (2013). [21] Deitel M, Crosby RD, Gagner M. The first International Consensus Summit for sleeve gastrectomy (SG), New York City, October 25–27, 2007. Obes Surg 2008;18:487–96. [22] Gumbs AA, Gagner M, Dakin G, Pomp A. Sleeve gastrectomy for morbid obesity. Obes Surg 2007;17:962–9. [23] Rao RS, Kini S. GIP and bariatric surgery. Obes Surg 2011;21: 244–52. [24] Sarkhosh K, Birch DW, Shi X, Gill RS, Karmali S. The impact of sleeve gastrectomy on hypertension: a systematic review. Obes Surg 2012;22:832–7. [25] Abbatini F, Rizzello M, Casella G, et al. Long-term effects of laparoscopic sleeve gastrectomy, gastric bypass, and adjustable gastric banding on type 2 diabetes. Surg Endosc 2010;24:1005–10. [26] Harris MI. Diabetes in America: epidemiology and scope of the problem. Diabetes Care 1998;21:C11–4.
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