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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2008 Apr 22;93(7):2479–2485. doi: 10.1210/jc.2007-2851

Effect of Weight Loss by Gastric Bypass Surgery Versus Hypocaloric Diet on Glucose and Incretin Levels in Patients with Type 2 Diabetes

Blandine Laferrère 1, Julio Teixeira 1, James McGinty 1, Hao Tran 1, Joseph R Egger 1, Antonia Colarusso 1, Betty Kovack 1, Baani Bawa 1, Ninan Koshy 1, Hongchan Lee 1, Kimberly Yapp 1, Blanca Olivan 1
PMCID: PMC2453054  PMID: 18430778

Abstract

Context: Gastric bypass surgery (GBP) results in rapid weight loss, improvement of type 2 diabetes (T2DM), and increase in incretins levels. Diet-induced weight loss also improves T2DM and may increase incretin levels.

Objective: Our objective was to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, after equivalent weight loss.

Design and Methods: Obese women with T2DM studied before and 1 month after GBP (n = 9), or after a diet-induced equivalent weight loss (n = 10), were included in the study. Patients from both groups were matched for age, body weight, body mass index, diabetes duration and control, and amount of weight loss.

Setting: This outpatient study was conducted at the General Clinical Research Center.

Main Outcome Measures: Glucose, insulin, proinsulin, glucagon, gastric inhibitory peptide (GIP), and glucagon-like peptide (GLP)-1 levels were measured after 50-g oral glucose. The incretin effect was measured as the difference in insulin levels in response to oral and to an isoglycemic iv glucose load.

Results: At baseline, none of the outcome variables (fasting and stimulated values) were different between the GBP and diet groups. Total GLP-1 levels after oral glucose markedly increased six times (peak:17 ± 6 to 112 ± 54 pmol/liter; P < 0.001), and the incretin effect increased five times (9.4 ± 27.5 to 44.8 ± 12.7%; P < 0.001) after GBP, but not after diet. Postprandial glucose levels (P = 0.001) decreased more after GBP.

Conclusions: These data suggest that early after GBP, the greater GLP-1 and GIP release and improvement of incretin effect are related not to weight loss but rather to the surgical procedure. This could be responsible for better diabetes outcome after GBP.

A comparative study of matched weight loss by gastric bypass surgery or diet in morbid obese patients with type 2 diabetes suggests that the mechanisms of diabetes resolution after gastric bypass surgery, in concert with weight loss, may be the marked increases in incretin glucagon-like peptide 1 and gastric inhibitory peptide levels and their effects on insulin secretion.

Together with the epidemic of obesity (1), the number of weight loss surgeries has surged in the last decade (2). Roux-en-Y gastric bypass surgery (GBP) results in significant and prolonged weight loss with resolution of type 2 diabetes (T2DM) in 80% of cases (3). The mechanism by which T2DM improves rapidly after GBP, often before significant weight loss, has not yet been elucidated. The hormonal changes described after GBP suggest a possible endocrine effect of this surgery. We (4) and others (5,6,7,8,9,10) have shown that the meal- or glucose-stimulated incretin levels, which are blunted in T2DM, increase after GBP. In parallel with the increased levels of glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP), the incretin effect on insulin secretion, impaired in patients with T2DM, markedly increased to levels similar to that of matched controls without T2DM, 1 month after GBP (4).

The two main incretins, GIP and GLP-1 (11), are secreted by the endocrine cells of the intestinal mucosa (12) in response to food and are responsible for 50–60% of insulin secretion after meals (12,13). The incretin effect is impaired in patients with T2DM (14). GLP-1 levels are blunted (15), but the effect of administered GLP-1 on insulin secretion persists (16). GIP levels are usually normal in patients with T2DM, but the effect of administered GIP on insulin secretion is blunted (17), although can be restored under normal glycemic conditions (18). GIP and GLP-1 are rapidly degraded by the enzyme dipeptidyl peptidase-IV (DPPIV) (19). GLP-1 and GIP analogs and DPPIV inhibitors are in use or currently being developed as antidiabetic agents (20).

The markedly increased incretin levels and effect observed after GBP could be one of the key mediators of the antidiabetic effects of the surgery. However, weight loss occurs very rapidly after GBP, and it is unclear whether the early changes in incretin levels and effect are a result of the surgery or could be attributed to weight loss per se. The blunted postprandial response of GLP-1 observed in severely obese individuals (21) has improved after diet-induced weight loss (22). Other studies suggest that it is not the weight loss, but the surgical procedure, that is responsible for the improvement of glucose tolerance. Ileal transposition, which increases GLP-1 levels, results in improved glucose control (23) independently of weight loss in rodent models (24) as well as in humans (25).

The goal of this study was to determine whether the magnitude of the change of the incretin levels and effect is greater after GBP compared with a low caloric diet, under conditions of short-term equivalent weight loss, in morbidly obese patients with T2DM. Specifically, we measured the changes in GLP-1 and GIP levels after oral glucose stimulation, and their incretin effect on insulin, in obese patients with T2DM before and 1 month after GBP, or after an equivalent diet-induced weight loss. A second goal was to determine whether an equivalent weight loss, achieved by GBP or by diet, would result in the same improvement of blood glucose levels in patients with T2DM.

Subjects and Methods

Subjects

Obese patients with body mass index (BMI) above or equal to 35 kg/m2, eligible candidates for GBP, younger than 60 yr of age, of both genders and all ethnic groups, with T2DM diagnosed for less than 5 yr, not on insulin, thiazolidinedione, exenatide, or DPPIV inhibitors, with an glycosylated hemoglobin (HbA1c) less than 8%, were invited to participate in the study. All participants signed an informed consent, approved by our institution, before enrolling in the study. One group of patients was studied before and 1 month after GBP (surgical group). A second group of patients, fulfilling the same recruitment criteria, was studied before and after a 10-kg diet-induced weight loss (diet group). In addition, patients in the diet group were matched for age, weight, BMI, T2DM duration and control (HbA1c) to patients from the surgical group.

Diet-induced weight loss and diabetes treatment

The diet consisted of a meal replacement plan of 1000 kcal/d. A 1-wk supply of meal replacement products (Robard Corp., Mt. Laurel, NJ), including high-protein shakes, bars, fruit drinks, and soups, was given to each patient during an individual weekly visit at the General Clinical Research Center. Fresh fruits and vegetables were allowed. Body weight was measured weekly and the diet adjusted when necessary. If no weight loss, or if weight gain occurred at two consecutive weekly visits, the patients were excluded from the study. Patients were kept on the 1000-kcal diet and in negative energy balance (active weight loss) while retested for incretin levels and effect after a 10-kg weight loss. Although there was no time limit, the expectation was that patients would lose 10 kg in 4–8 wk. During the weight loss, patients were asked to monitor blood glucose levels by finger stick and keep logs. Diabetes medications were adjusted by a nurse educator or a diabetologist to avoid hypoglycemia and to fulfill the American Diabetes Association standard of treatment, based on fasting and postprandial glucose levels. In most cases, patients on sulfonylureas had their medication decreased or discontinued to avoid hypoglycemia.

Roux-en-Y gastric bypass (GBP) protocol

All patients underwent a laparoscopic GBP. In brief, the jejunum was divided 30 cm from the ligament of Treitz and anastomosed to a 30-ml proximal gastric pouch. The jejunum was reanastomosed 150-cm distal to the gastrojejunostomy. All mesenteric defects were closed. The post-GBP diet recommendations included a daily intake of 600–800 kcal, 70 g protein, and 1.8 liter fluid. This was achieved, on an individual basis, with multiple small meals and snacks with various commercial protein supplements. The diet after GBP was monitored by food records but not directly supervised. The diet in the few days preceding the testing in surgical or diet patients before weight loss was not controlled for.

Incretin effect: insulin secretion after oral and isoglycemic iv glucose load (IsoG IVGT)

Subjects were studied for the oral glucose tolerance test (OGTT) and IsoG IVGT in the morning after a 12-h overnight fast, on 2 different days, separated by less than 5 d.

Three-hour OGTT

All patients underwent first a 3-h OGTT with 50 g glucose (noncarbonated, in a total volume of 200 ml). After iv insertion, at 0800 h, subjects received orally 50 g glucose. Blood samples, collected on chilled EDTA tubes with added aprotinin (500 kallikrein inhibitory U/ml blood) and DPPIV inhibitor (LINCO Research, Inc., St. Charles, MO) (10 μl/ml blood), were centrifuged at 4 C before storage at −70 C.

IsoG IVGT

The goal of the IsoG IVGT was to expose the pancreas to blood glucose levels matched to the ones obtained during the OGTT in the same subject. Glucose (sterile 20% dextrose solution in water) was infused iv over 3 h using a Gemini pump (Gemini, Inc., St. Louis, MI). A sample of blood was collected every 5 min, using a contralateral antecubital iv catheter, then transferred in a microcentrifuge tube without any additive and centrifuged at bedside for immediate measure of glucose levels. The glucose infusion rate was adjusted to match the glucose concentrations obtained for the same patient during the OGTT at each time point for 3 h. For insulin levels, blood samples were collected every 15 min for the first 90 min, then every 30 min until 180′. During the OGTT and IsoG IVGT, the arm used for blood sampling was kept warm with a heating pad.

Incretin effect

The difference in β-cell responses (insulin total area under the curve or INS AUC (0–180′) to the oral and isoglycemic iv glucose stimuli represents the action of the incretin factor expressed as the percentage of the physiological response to oral glucose, which is taken as the denominator (100%) (26). The formula is:

graphic file with name M1.gif

Assays

Total GLP-1, an indicator of GLP secretion, was measured by RIA (LINCO Research) after plasma ethanol extraction. The intraassay and interassay coefficients of variation (CVs) were 3–6.5% and 4.7–8.8%, respectively. This assay cross-reacts 100% with GLP-17–36, GLP-19–36, and GLP-17–37 but does not cross-react with glucagon (0.2%), GLP-2 (<0.01%), or exendin (<0.01%). Active GLP-1, an indicator of GLP potential action, was measured by ELISA (LINCO Research). The intraassay and interassay CVs were 3–7% and 7–8%, respectively. The assay cross-reacts 100% with GLP-17–36 and GLP-17–37 but does not cross-react with GLP-19–36, glucagon, or GLP-2. Total GIP was measured by ELISA. The assay cross-reacts 100% with GIP 1–42 and GIP 3–42 but does not cross-react with GLP-1, GLP-2, oxyntomodulin, or glucagon. The intraassay and interassay CVs were 3.0–8.8% and 1.8–6.1%, respectively. Plasma insulin, C peptide, proinsulin, and glucagon concentrations were measured by RIA (LINCO Research) with an intraassay CV of 3–8% and interassay CV of 5.5–9%. The glucagon assay cross-reacts 100% with glucagon but cross-reacts less than 0.1% with oxyntomodulin. Glucose concentration was measured at the bedside by the glucose oxidase method (Beckman glucose analyzer; Beckman Coulter, Inc., Fullerton, CA). All hormonal and metabolites assays were performed at the Hormone and Metabolite Core Laboratory of the New York Obesity Research Center.

Statistical analysis

Outcome variables were plasma glucose and plasma insulin, C peptide, glucagon, proinsulin, GLP-1, and GIP concentrations. Total AUCs 0–180′ for outcome variables were calculated using the trapezoidal method. ANOVA with repeated measures was used to detect glucose and hormonal changes over time during the OGTT within each condition, and for comparison before and after GBP and before and after diet, or between diet and surgical groups with T2DM. Paired t tests were used to compare data between before and after GBP or diet. Data are expressed as the mean ± sd, except in the figures where sems are used. Statistical significance was set at P < 0.05. Statistical analyses were performed with SPSS 14.0 (SPSS, Inc., Chicago, IL).

Results

Subject characteristics

Subject characteristics are shown in Table 1. Obese women with T2DM and normal liver enzymes, thyroid function tests, and blood pressure were studied before and 1 month after GBP (n = 9), and before and after an equivalent diet-induced weight loss (n = 10). Of the 12 women recruited in the diet group, two did not complete the weight loss due to pregnancy or breast cancer, and data from 10 diet completers are presented. Diabetes medications, sulfonylureas and/or metformin, were discontinued 3 d before being studied at baseline in all patients and were adjusted during the diet-induced weight loss to avoid hypoglycemia. Patients from the diet and surgical group were matched for age, body weight, BMI, diabetes duration and control (HbA1c) (Table 1). Before weight loss, neither fasting glucose (P = 0.874), proinsulin (P = 0.797), insulin (P = 0.629), C peptide (P = 0.589), glucagon (P = 0.363), GLP-1 (P = 0.832) and GIP (P = 0.414) and incretin effect (P = 0.245), nor stimulated variables during the OGTT were significantly different between the diet and GBP groups.

Table 1.

Subject characteristics before and after weight loss, by either diet or GBP

Before diet After diet Before GBP After GBP P value
Age (yr) 46.80 ± 7.24 44.56 ± 9.65
Weight (kg) 110.9 ± 10.2 101.1 ± 9.5a 113.2 ± 15.5 103.2 ± 16.6a 0.816
BMI (kg/m2) 43.3 ± 3.6 39.6 ± 3.5a 43.3 ± 6.2 39.5 ± 6.5a 0.939
T2DM duration (months) 22.2 ± 17.7 31.4 ± 26.4
HbA1c (%) 6.68 ± 0.88 6.51 ± 0.78
Fasting glucose (mmol/liter) 7.84 ± 1.09 6.34 ± 1.00a 7.95 ± 1.74 6.42 ± 0.80b 0.957
120′ glucose (mmol/liter) 10.17 ± 2.40 9.62 ± 2.34 11.12 ± 1.64 7.22 ± 1.62a 0.001
Peak glucose (mmol/liter) 12.83 ± 1.36 11.45 ± 3.04 14.24 ± 3.23 12.02 ± 1.38 0.514
AUC glucose (mmol/liter−1·min−1) 10.29 ± 1.54 9.13 ± 2.09b 11.15 ± 1.80 8.51 ± 1.22a 0.014
Fasting insulin (pmol/liter) 192 ± 108 110 ± 50a 172 ± 69 127 ± 51b 0.195
Peak insulin (pmol/liter) 545 ± 357 575 ± 522 492 ± 288 769 ± 335b 0.286
AUC insulin (pmol/liter−1·min−1) 363 ± 237 350 ± 268a 349 ± 188 341 ± 138 0.974
Fasting C peptide (pmol/liter) 4.09 ± 2.27 3.47 ± 2.35 4.04 ± 1.71 3.71 ± 1.01 0.656
AUC C-peptide (pmol/liter−1·min−1) 2.20 ± 1.01 2.19 ± 1.26 2.12 ± 0.77 2.48 ± 0.62 0.304
Fasting glucagon (ng/liter) 71.6 ± 10.6 58.5 ± 16.0b 65.9 ± 15.0 67.0 ± 21.8 0.002
AUC glucagon (ng/liter−1·min−1) 58.1 ± 14.5 49.2 ± 12.4b 58.4 ± 10.8 77.3 ± 17.5b 0.002
Peak glucagon (ng/liter) 84.7 ± 24.2 68.5 ± 19.7b 81.1 ± 14.8 96.9 ± 21.5b 0.002
Fasting proinsulin (pmol/liter) 34.6 ± 26.1 16.3 ± 9.6b 31.8 ± 17.0 19.2 ± 22.5a 0.876
Proinsulin/insulin 0.18 ± 0.11 0.16 ± 0.11 0.19 ± 0.07 0.16 ± 0.19a 0.082
Fasting total GLP-1 (pmol/liter) 6.18 ± 2.87 6.34 ± 4.36 6.52 ± 4.06 6.69 ± 3.28 0.998
Peak total GLP-1 (pmol/liter) 18.20 ± 16.33 9.80 ± 5.83 17.49 ± 6.02 112.5 ± 54.3a 0.001
AUC total GLP-1 (pmol/liter−1·min−1) 8.20 ± 7.29 4.94 ± 1.96 7.55 ± 2.80 31.82 ± 8.10a 0.000
Fasting active GLP-1 (pmol/liter) 6.04 ± 3.55 4.28 ± 0.90 7.91 ± 3.77 8.45 ± 4.41 0.216
Peak active GLP-1 (pmol/liter) 10.85 ± 9.73 5.27 ± 1.74 11.21 ± 3.94 24.13 ± 19.31 0.038
AUC active GLP-1 (pmol/liter−1·min−1) 6.43 ± 3.69 4.25 ± 0.96 7.38 ± 2.98 10.88 ± 4.94 0.029
Fasting GIP (ng/liter) 34.18 ± 11.41 33.84 ± 33.11 39.27 ± 15.05 40.54 ± 29.87 0.901
Peak GIP (ng/liter) 175 ± 60 208 ± 115 204 ± 56 316 ± 124a 0.090
AUC GIP (ng/liter−1·min−1) 40.96 ± 12.71 54.00 ± 31.85 48.67 ± 11.35 51.56 ± 18.54 0.399
HOMA-IR 7.96 ± 4.17 4.04 ± 1.91a 8.11 ± 3.61 5.16 ± 2.88b 0.476
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Data are expressed as mean ± sd. Fasting, peak, 120 min, and AUC (total AUC, 180′) values are obtained during the OGTT. The reported P value represents the difference between the changes occurring with either weight loss intervention. HOMA-IR, homeostasis model of assessment of insulin resistance. 

a

P < 0.001, effect of weight loss within each group (diet, n = 10; or GBP, n = 9). 

b

P < 0.05 effect of weight loss within each group (diet, n = 10; or GBP, n = 9). 

Side effects

Although 50 g glucose drink was used rather than 75 g to minimize the risk of dumping syndrome after GBP, four patients experienced stomach cramping and discomfort, nausea, sweating, flushing, and palpitations 5–20 min into the OGTT. No severe adverse effects were observed. There was no adverse effect from the diet.

Effect of weight loss

All patients in the surgical group discontinued their diabetes medications the day of the surgery. In the diet group, diabetes medications were either discontinued (n = 2), or the dosage was decreased, with patients taking only low doses of metformin (n = 8) at the completion of the weight loss. The duration of weight loss was shorter for the GBP group (32.3 ± 13.1 d) compared with the diet group (55.0 ± 9.9 d; P = 0.001). Body weight, BMI, fasting glucose, insulin, C peptide, proinsulin, proinsulin to insulin ratio, and homeostasis model of assessment of insulin resistance decreased significantly and equally in the surgical and diet groups (Table 1). Fasting incretins did not change with either weight loss treatment.

Glucose AUC and glucose levels at 120′ were significantly lower after GBP compared with diet (P = 0.014 and P = 0.001, respectively) (Table 1). Although the changes of insulin with weight loss (fasting, AUC, peak response) were not different between GBP and diet, the pattern of secretion of insulin changed considerably after GBP (P = 0.001), with recovery of the early phase with a peak at 30 min and a return to baseline after 180 min (Fig. 1).

Figure 1.

Figure 1

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Glucose, insulin, C peptide, glucagon, total and active GLP-1 and GIP levels during the OGTT in patients before (diamond) and after (square) GBP, and before (triangle) and after (circle) diet. Data are mean ± sem. *, P < 0.05 between groups after weight loss by GBP or diet.

Stimulated levels of incretins increased significantly after surgery by a factor of six (peak GLP-1: 17 ± 6 to 112 ± 54 pmol/liter; P < 0.001), 2.1 (peak GLP-1 active; P = 0.038), and 1.5 (peak GIP; P = 0.006). (Table 1 and Fig. 1). On the contrary, after diet, GLP-1 levels (total and active) tended to decrease (P, Not significant), and GIP did not change significantly. There was no change in GLP-1 or GIP levels during the IsoG IVGT (data not shown). A significant linear relationship was found between total GLP-1 release and insulin release during the OGTT, only in patients after GBP (r = 0.762; P = 0.028).

The glucose concentrations were well matched between the IsoG IVGT and OGTT in the surgical and diet groups before and after the weight loss intervention (Table 2). The insulin response was not greater after oral than iv glucose before GBP or before diet, with a resulting blunted incretin effect. The incretin effect increased significantly by a factor of 3.8 after GBP (+35.4 ± 22.7%; P = 0.009), but only minimally after diet (+7.15 ± 18.13%; P = 0.244).

Table 2.

Mean glucose, insulin, and C peptide levels, AUC for glucose and insulin during the OGTT and Iso IVGT, before and after weight loss by either diet (n = 10) or GBP (n = 9)

Before GBP After GBP Before diet After diet
Oral IV Oral IV Oral IV Oral IV
GAUC (mmol/liter·min) 11.2 ± 1.8 11.4 ± 1.8 8.5 ± 1.2 9.8 ± 1.2a 10.3 ± 1.5 10.1 ± 1.6 9.1 ± 2.1 8.9 ± 2.3
Glucose (mmol/liter) 10.7 ± 1.9 10.9 ± 1.8 8.5 ± 1.0 9.4 ± 0.9 9.8 ± 1.2 9.6 ± 1.3 8.4 ± 1.8 8.3 ± 1.9
IAUC (pmol/liter·min) 349 ± 188 296 ± 154 340 ± 145 183 ± 75a 363 ± 237 250 ± 131 350 ± 268 220 ± 165
Insulin (pmol/liter) 315 ± 152 261 ± 127 347 ± 138 170 ± 62a 330 ± 210 218 ± 113 302 ± 191 195 ± 130
C peptide (pmol/liter) 1.95 ± 0.7 1.97 ± 0.57 2.31 ± 0.54 1.58 ± 0.4a 1.98 ± 0.92 1.62 ± 0.81 1.89 ± 1.05 1.55 ± 0.95
Incretin effect (%) 9.42 ± 27.46 44.84 ± 12.73b 27.44 ± 14.909 34.59 ± 15.15
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Data are expressed as mean ± sd. The incretin effect was calculated by comparing the insulin response to oral and matched iv glucose load. GAUC, Glucose area under the curve 0−180; IAUC, insulin area under the curve 0−180. 

a

Between oral and iv glucose challenges within each group (P < 0.05). 

b

Between before and after weight loss by either GBP or diet (P = 0.002). 

Glucagon levels were mildly suppressed during the OGTT from 90–180 min (P < 0.001), with no difference between the GBP and diet groups before intervention (P = 0.351). After diet, glucagon levels remained similarly suppressed during the OGTT. However, after GBP, there was a paradoxical increase of glucagon levels during the OGTT from 15–120 min (P = 0.001) (Fig. 1).

Discussion

The magnitude of the effect of GBP on T2DM resolution has thus far baffled scientists and clinicians. Many studies (5,6,8,10,20,27,28,29,30), including ours (4), have shown an increase of incretin levels after GBP. It is unclear whether the caloric restriction and/or rapid weight loss contributes to the change of the incretins levels because diet-induced weight loss has also been associated with an increase, although of lesser magnitude, of GLP-1 levels (22). In this study we compared the effect of an equivalent weight loss by GBP or by diet in two groups of matched morbidly obese patients with T2DM. The intensive diet intervention with meal replacements and weekly outpatient visits resulted in a weight loss equivalent to that lost by patients 1 month after the GBP. Although the well-matched surgical and diet groups lost the same amount of weight, their changes in incretin levels were strikingly different. As shown previously (4), GLP-1 response to oral glucose markedly increased 1 month after GBP. GLP-1 levels tended to decrease after diet intervention, although this decrease was not significant. This is contrary to the results by Verdich et al. (22), who showed an increase of GLP-1 levels, although of smaller magnitude, during a mixed meal after weight reduction in men. These differences between studies could be due to gender differences, the absence of T2DM, a greater weight loss (18.8 kg), and/or the use of a solid mixed meal as a stimulus in the study by Verdich et al. (22). Our data on increase GIP levels after GBP are consistent with data after jejunoileal bypass (JIB) (31) but contrary to another study showing a decrease of GIP levels in patients without T2DM 6 months after GBP (30). The time of testing after surgery, which varied between studies, could be an important variable because we have shown that the increase of GIP levels is transient and does not persist 6–12 months after GBP (32). In parallel with the increase in incretin levels, the incretin effect markedly increased after GBP, but not after diet. These results need to be interpreted with caution because the sample size was small with large individual variation.

The data from this study suggest that the effect of GBP on the incretins is likely not weight loss related. However, the mechanism by which the incretins increase after GBP remains unclear. Whether it is the rapid and direct stimulation of the L cells of the distal ileum, referred to as the hindgut mechanism, or the bypass of the duodenum (the foregut hypothesis) is still unclear. Elegant studies in rodents support the foregut hypothesis. In these studies in Goto-Kakizaki type 2 diabetic rats, the improvement of glucose tolerance after surgical exclusion of the duodenum, but not after gastrojejunostomy, is independent of calorie restriction or weight loss (33). The hindgut hypothesis is based on the results of experimental ileal transposition, a surgical procedure that improves diabetes in rodents (23) independently of weight loss (24). The foregut/hindgut hypothesis has not been tested in humans. Recent data demonstrate that ileal transposition with sleeve gastrectomy can improve diabetes, even after minimal weight loss, in patient with BMI less than 35 kg/m2 (34). Our experiment was designed to address the effect of weight loss on incretins and did not allow us to separate the effect of duodenal bypass vs. rapid stimulation of the distal gut on incretin stimulation after GBP. Gastric emptying (GE) and intestinal transit time have increased after GBP (27,35), but not after diet (22). The release of GIP and GLP-1 is related to the rate of carbohydrate entry into the small intestine (36). Faster small intestinal glucose delivery increases plasma GIP and GLP-1 levels (37). The rapid delivery of nutrient after GBP could represent a mechanism by which incretins are markedly released after the surgery. We did not measure GE or intestinal transit time in our study. Therefore, we cannot exclude the possibility that, in the diet group, the glucose solution was absorbed entirely in the duodenum and did not reach the lower part of the ileum to exert its stimulating effect directly on the L cells to release GLP-1. However, recent data showed that the enteroendocrine K and L cells, which secrete GIP and GLP-1, respectively, are distributed all along the gut (38). Therefore, it is unlikely that the L cells would have had no contact with the glucose solution in the diet group.

We cannot exclude that gut adaptation played a role in the increased incretin response after GBP because hyperplasia of intestinal endocrine cells have been described 3 months after JIB (39). We have shown persistent increased GLP-1 levels 1 yr after GBP (32), and others have shown increased incretin levels 20 yr after JIB (31). Adaptative changes in gut motility have also been shown after a period of energy restriction and weight loss (40). We cannot exclude a role of calorie restriction per se, independently of weight loss, in the improvement of incretins after GBP. The daily calorie intake of patients after GBP was 600–800 kcal (data not shown) compared with 1000 kcal in the diet group. Although the calorie restriction was not matched between the two groups from day to day, the overall calorie deficit and weight loss were identical.

Diet-induced (41,42,43,44,45,46) or surgical weight loss (3,47) improves T2DM control. In this study the effect of an equivalent weight loss on diabetes control was greater after GBP than after diet. Patients in the surgical group had a better clinical outcome and did not require diabetes medications after the weight loss. In addition, postprandial glucose levels were lower after GBP compared with diet. In the fed state, GE (36,37), glucose absorption (48), and the release of incretins (12) are key determinants of postprandial glucose levels. In patients with T2DM, many components of the gut physiology are impaired, such as GE (40,49), and incretin release and effect (14), resulting in postprandial hyperglycemia, a predictor of cardiovascular complications and mortality (50). Our data show that a diet-equivalent weight loss does not lower postprandial glucose levels to the same extent as GBP in patients with T2DM. This may indicate that the marked increase of incretins associated with GBP, and not with the diet, could be responsible for the better postprandial glucose control. The administration of the synthetic exendin-4, a compound that binds to the GLP-1 receptor and exerts similar effects as the native GLP-1 (51), or of vildagliptin, an inhibitor of DPPIV, the enzyme that rapidly inactivates the endogenous incretins (52,53), has been shown to reduce postprandial glucose levels and improve diabetes control.

Patients with T2DM have typically hyperglucagonemia (54), which contributes to the postprandial hyperglycemia. It is puzzling to see that the decrease of postprandial glucose levels after GBP is associated with a paradoxical increase of glucagon levels during the OGTT. The increase in glucagon is seen despite a marked increase in GLP-1, a gut hormone that inhibits glucagon release (55). This increase of glucagon levels was previously shown after GBP (56) and ileal transposition in dogs (56). The source of this increase in glucagon is unclear. Although the commercial assay used in this study is specific for pancreatic glucagon, cross-reactivity with enteroglucagon or oxyntomodulin cannot be entirely excluded. Our study group was small and limited to women. Future studies will need to address gender differences in incretin levels and effect after bariatric surgery.

In summary, our data suggest that it is the surgical procedure per se, rather than weight loss, that stimulates incretin release and effect after GBP. The rapid and marked increase of GLP-1 levels after GBP plays an important role in insulin secretion, and could be a key determinant in the decrease of postprandial glycemia and the resolution of T2DM after GBP.

Acknowledgments

We thank our volunteer participants, Ping Zhou and Yim Dam for their technical help, and Mousumi Bose for editing this manuscript.

Footnotes

This work was supported by grants from the American Diabetes Association CR-7-05 CR-18, NIH R01-DK67561, GCRC 1 UL1 RR024156-02, ORC DK-26687, DERC DK-63068-05, Merck Investigator Initiated Studies Program.

Disclosure Statement: B.L. received grant support through the Merck Investigator Initiated Studies Program in 2007. J.T., J.M., H.T., J.R.E., A.C., B.K., B.B., N.K., H.L., K.Y., and B.O. have nothing to declare.

First Published Online April 22, 2008

Abbreviations: AUC, Area under the curve; BMI, body mass index; CV, coefficient of variation; DPPIV, dipeptidyl peptidase-IV; GBP, Gastric bypass surgery; GE, gastric emptying; GIP, gastric inhibitory peptide; GLP, glucagon-like peptide; HbA1c, glycosylated hemoglobin; IsoG, isoglycemic; IVGT, iv glucose test; JIB, jejunoileal bypass; OGTT, oral glucose tolerance test; T2DM, type 2 diabetes.

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