Original article
Changes in insulin sensitivity and secretion after sleeve gastrectomy G. Casella1 , E. Soricelli1 , L. Castagneto-Gissey1 , A. Redler1 , N. Basso1 and G. Mingrone2,3,4 1 Surgical
Sciences Department, Medical School ‘Sapienza’ University, and 2 Department of Internal Medicine, Catholic University of Rome, Rome, Italy, of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College, London, UK, and 4 Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Dresden, Germany Correspondence to: Professor G. Mingrone, Catholic University, Largo A. Gemelli 8, Rome, Italy (e-mail: [email protected]) 3 Department
Background: Sleeve gastrectomy is indicated for the treatment of obesity and related co-morbidity
including diabetes. The dynamic changes in insulin secretion and sensitivity after sleeve gastrectomy are unknown. Methods: Whole-body insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp technique, and insulin secretion by C-peptide deconvolution after an oral glucose tolerance test (OGTT), before and 3, 6 and 12 months after sleeve gastrectomy in morbidly obese subjects. The time course of glucagon-like peptide (GLP) 1, as a marker of insulin secretion following OGTT, was also assessed. Results: Ten patients were included in the study. Median (range) baseline insulin sensitivity (M-value) increased from 84⋅0 (20⋅2–131⋅4) mmol per kg per min at baseline to 122⋅8 (99⋅0–179⋅3) mmol per kg per min at 12 months after surgery (P = 0⋅015). Fasting insulin sensitivity, measured by homeostatic model assessment of insulin resistance, which represents a surrogate index of hepatic insulin resistance, decreased from 3⋅3 (1⋅9–5⋅5) to 0⋅7 (0⋅5–1⋅1) mg/dl⋅𝛍units/ml (P < 0⋅001). Total insulin secretion, measured as incremental area under the curve (AUC), after OGTT decreased from 360⋅4 (347⋅9–548⋅0) to 190⋅1 (10⋅1–252⋅0) mmol/l⋅180 min at 12 months (P = 0⋅011). The AUC for GLP-1 increased from 258⋅5 (97⋅5–552⋅6) to 5531⋅8 (4143⋅0–7540⋅9) pmol/l⋅180 min at 12 months after sleeve gastrectomy (P < 0⋅001). In multiple regression analysis, 51 per cent of the M-value variability was explained by GLP-1 secretion. Conclusion: Sleeve gastrectomy improved insulin sensitivity and reduced insulin secretion within 6 months after surgery. Although there was a correlation between insulin sensitivity and bodyweight, the major driver of the improvement in insulin sensitivity was GLP-1 secretion. Paper accepted 23 September 2015 Published online 9 November 2015 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.10039
Introduction
Sleeve gastrectomy (SG) has become used widely for the surgical treatment of obesity and related co-morbidity including diabetes1 – 3 . Schauer and colleagues1 showed that diabetes remission, defined by a glycated haemoglobin level below 6 per cent, was achieved in 24 per cent of patients who underwent SG compared with 5 per cent of those who received medical treatment. However, its mechanism of action has not yet been elucidated. Roux-en-Y gastric bypass (RYGB) is known to improve glycaemic control mainly by increasing insulin secretion and stimulation of glucagon-like peptide (GLP) 1 secretion4,5 . Although the effect of RYGB on whole-body insulin sensitivity is relatively small compared with that © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
of biliopancreatic diversion (20 per cent increase from baseline after RYGB versus almost 100 per cent increase after biliopancreatic diversion)6 – 8 , its major action seems to be exerted on hepatic insulin sensitivity9 – 12 . Abbatini and co-workers3 reported that insulin sensitivity was restored in subjects with type 2 diabetes 1 year after SG or RYGB. In contrast, Kashyap et al.13 did not find any improvement 2 years after SG, but they used a surrogate marker of whole-body insulin sensitivity. Recently, Bradley and colleagues12 reported that the degree of improvement in hepatic and peripheral insulin resistance was similar following SG or RYGB. Few studies have investigated insulin secretion after SG. Using the intravenous glucose tolerance test, it was demonstrated that the first phase of insulin secretion was restored BJS 2016; 103: 242–248
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fully a few days after SG14 . Bradley and co-workers12 showed that the total insulin secretion rate after a mixed meal was decreased whereas β-cell function was greatly improved after SG or RYGB accompanied by loss of 20 per cent bodyweight. However, the dynamic changes in insulin sensitivity and secretion over time following SG are unknown. Therefore, insulin sensitivity was investigated by the euglycaemic hyperinsulinaemic clamp (EHC) method, and insulin secretion by C-peptide deconvolution after an oral glucose tolerance test (OGTT) before, and 3, 6 and 12 months after SG. Methods
Participants scheduled for SG were recruited from the Department of Internal Medicine at the obesity outpatient clinic, Catholic University of Rome, Italy. Inclusion criteria for the study were: age 30–65 years; and body mass index over 40 kg/m2 or at least 35 kg/m2 in the presence of complications such as arthritis with walking difficulty, sleep apnoea or obesity-induced physical problems interfering with lifestyle. Exclusion criteria were: presence of diabetes mellitus, coronary heart disease and/or interventions for such disease in the previous 6 months (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty), liver cirrhosis or end-stage renal failure; participation in any other concurrent clinical trial; other life-threatening, non-cardiac disease; pregnancy; or inability to give informed consent. The study protocol was approved by the Institutional Review Board and conducted according to the principles of the Helsinki Declaration, with all subjects providing written consent. All tests were carried out from 30 to 7 days before surgery, and at 3, 6 and 12 months after SG.
Anthropometry On the day of each test, bodyweight was measured and rounded to the nearest 0⋅1 kg by a beam scale. Height was assessed and rounded to the nearest 0⋅5 cm using a stadiometer (Holatin, Crosswell, UK). Body composition was assessed by dual-energy X-ray absorptiometry (DEXA) using a Lunar Prodigy system (GE Healthcare, Fort Edward, New York, USA). DEXA permits measurement of fat-free mass and fat mass.
Sleeve gastrectomy SG was performed according to the technique described by Gagner and colleagues15 with a few modifications2 . Division of the vascular supply of the gastric greater curvature © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
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started at 6 cm from the pylorus and proceeded upwards until the angle of His. The SG was created using a linear stapler, which was applied alongside a 48-Fr calibrating bougie. The resection line was made avoiding the critical area by resecting the fundus 1⋅5 cm from the angle of His. The residual gastric remnant capacity was 60–80 ml.
Homeostasis model assessment Hepatic insulin resistance was measured by means of the homeostatic model assessment of insulin resistance (HOMA-IR), which was computed as fasting plasma glucose (mmol/l) times fasting serum insulin (munits/litre) divided by 22⋅5, as described previously16 . Because fasting plasma levels of glucose and insulin are used to calculate HOMA-IR, and the fasting glucose level is regulated entirely by the liver, HOMA-IR is considered worldwide as a measure of hepatic insulin resistance.
Euglycaemic–hyperinsulinaemic clamp Peripheral insulin sensitivity was evaluated by a 3-h EHC procedure. This technique is currently the standard for insulin sensitivity measurement. After inserting an intravenous cannula into the dorsal vein of the hand for sampling arterialized venous blood, and another in the antecubital fossa of the contralateral arm for infusions, the patient rested in the supine position for at least 1 h. Arterialized blood was obtained by inserting the hand into a heating pad (60∘ C). Insulin was administered using decreasing boluses given in 10 min, followed by a continuous infusion rate of 40 munits per m2 per min (6 pmol per kg bodyweight per min)17 . To maintain plasma glucose levels in a normal range (fasting levels), 20 per cent glucose was infused and blood glucose levels were measured every 5 min. Once a steady state had been reached, usually 2–3 h after starting the clamp, the glucose infusion rate represented the insulin-mediated glucose uptake by the body (M-value in μmol per kg fat-free mass per min). Whole-body peripheral glucose utilization was calculated during the last 40 min of the steady-state insulin infusion.
Insulin secretion The basal insulin secretion rate was computed after an overnight fast, and after the OGTT, using the C-peptide deconvolution model18 . For every mole of insulin secreted by the pancreas, the pancreas also secretes 1 mole of connecting peptide (C-peptide) that is not extracted appreciably by the liver, and instead breaks down insulin. Using the deconvolution function it is possible to compute insulin www.bjs.co.uk
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G. Casella, E. Soricelli, L. Castagneto-Gissey, A. Redler, N. Basso and G. Mingrone
Anthropometric data, insulin sensitivity and secretion, and glucagon peptide 1 secretion before, and 3, 6 and 12 months after sleeve gastrectomy in ten patients
Table 1
After sleeve gastrectomy Baseline Weight (kg) BMI (kg/m2 ) Fasting glucose (mmol/l) Fasting plasma insulin (pmol/l) HOMA-IR (mg/dl⋅μunits/ml) M-value (mmol per kg fat-free mass per min) Plasma insulin at steady state (pmol/l) Fasting insulin secretion (pmol per m2 per min) Total insulin secretion (mmol/l⋅180 min) Total GLP-1 secretion (pmol/l⋅180 min)
116⋅3 (99⋅0–136⋅7) 41⋅6 (38⋅1–45⋅2) 5⋅1 (4⋅1–6⋅0) 103⋅1 (50⋅2–155⋅0) 3⋅3 (1⋅9–5⋅5) 84⋅0 (20⋅2–131⋅4) 499⋅1 (434⋅0–562⋅3) 423⋅8 (52⋅0–748⋅7) 360⋅4 (347⋅9–548⋅0) 258⋅5 (97⋅5–552⋅6)
3 months 98⋅6 (88⋅1–12⋅6) 36⋅4 (33⋅0–41⋅5) 4⋅8 (4⋅2–5⋅3) 59⋅0 (35⋅1–78⋅0) 2⋅0 (0⋅9–2⋅5)† 110⋅7 (61⋅2–178⋅2) 468⋅0 (404⋅5–538⋅1) 542⋅9 (73⋅8–594⋅3) 192⋅0 (56⋅6–348⋅6) 7002⋅9 (3953⋅0–8992⋅5)‡
6 months 89⋅2 (82⋅0–107⋅0)† 32⋅8 (29⋅2–53⋅3)‡ 4⋅5 (3⋅8–4⋅9) 50⋅0 (24⋅4–62⋅1)† 1⋅6 (0⋅7– 2⋅1)‡ 120⋅0 (91⋅4–181⋅1)* 441⋅5 (381⋅0–481⋅8) 346⋅8 (38⋅5–602⋅4) 178⋅6 (10⋅5–251⋅2) 5589⋅2 (4552⋅4–7040⋅0)‡
12 months 81⋅0 (64⋅0–89⋅8)‡ 28⋅7 (25⋅3–30⋅5)‡ 4⋅4 (3⋅9–4⋅8) 25⋅5 (5⋅8–64⋅2)‡ 0⋅7 (0⋅5–1⋅1)‡ 122⋅8 (99⋅0–179⋅3)* 405⋅0 (356⋅1–497⋅2) 393⋅0 (80⋅0–516⋅5) 190⋅1 (10⋅1–252⋅0)* 5531⋅8 (4143⋅0–7540⋅9)‡
Values are median (range). Fasting insulin sensitivity as homeostatic model assessment of insulin resistance (HOMA-IR) was computed as fasting plasma glucose × fasting serum insulin divided by 22⋅5. BMI, body mass index; GLP, glucagon-like peptide 1. *P < 0⋅050, †P < 0⋅010, ‡P < 0⋅001 versus baseline (2-way repeated-measures ANOVA).
secretion from the circulating levels of C-peptide. The total insulin secretion is the area under the curve (AUC) of the insulin secretion rate after the oral glucose load.
Assays For GLP-1 analysis, venous blood was collected in ice-chilled EDTA dipotassium-treated tubes containing 400 × 106 units aprotinin per litre of blood. For all blood samples, the plasma was separated immediately by centrifugation at 4∘ C and stored at −80∘ C pending assay. Plasma glucose was measured by the glucose oxidase method (Beckman, Fullerton, California, USA). Plasma insulin was assayed using a microparticle enzyme immunoassay (Abbott, Pasadena, California, USA) with a sensitivity of 1 μunit/ml and an intra-assay coefficient of variation (CV) of 6⋅6 per cent. Total GLP-1 was measured by radioimmunoassay (Linco Research, St Charles, Missouri, USA); intra-assay and interassay CVs were 9–14 and 11–20 per cent respectively. This assay has 100 per cent specificity for GLP-1(7–36), GLP-1(9–36) and GLP-1(7–37), and does not cross-react with glucagon (0⋅2 per cent), GLP-2 (less than 0⋅01 per cent) or exendin (less than 0⋅01 per cent).
Statistical analysis All data are expressed as median (range) unless specified otherwise. Data were examined for normal distribution according to Shapiro–Wilks criteria. Two-way repeated-measures ANOVA with Tukey’s post hoc test was used to analyse the effects of SG on study outcome measures. The AUC for insulin secretion and GLP-1 concentrations was calculated by the trapezoidal rule. Correlation analyses were performed using the Spearman © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
correlation coefficient. Multiple regression analysis was carried out to identify the determinants of insulin sensitivity. Probability plots were constructed to look for normality of the residuals and lack of heteroscedasticity (uneven distribution of random disturbance, suggesting non-linearity). Residuals were also assessed by use of the Durbin–Watson statistic. Casewise diagnostics did not reveal any obvious outliers. SPSS® version 13.0 (IBM, Armonk, New York, USA) was used for statistical analysis. Results
Ten patients participated in the study, four men and six women with a median age of 35 (range 19–49) years.
Insulin secretion One year after SG, the patients had lost 30 per cent of their initial median weight (Table 1). Fasting insulin levels dropped from 103⋅1 (50⋅2–155⋅0) pmol/l at baseline to 25⋅5 (5⋅8–64⋅2) pmol/l 1 year after SG (P < 0⋅001). The fasting insulin secretion rate decreased from 423⋅8 (52⋅0–748⋅7) to 393⋅0 (80⋅0–516⋅5) pmol per m2 per min. The maximum decrease was achieved by 6 months after surgery and the rate then remained stable up to 12 months. Before surgery, plasma glucose concentrations peaked at 50–60 min after the oral glucose load and then decreased slowly; after surgery the peak came earlier at 30–50 min after oral glucose loading, and glucose levels then declined rapidly to hypoglycaemic values of around 3⋅3–3⋅7 mmol/l at 120 min (Fig. 1). Later on hypoglycaemic symptoms developed in three of ten patients. Although plasma insulin levels were higher before surgery, after SG the peak value was reached more than 70 min earlier (Fig. 2). www.bjs.co.uk
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Mean plasma glucose concentration in the oral glucose tolerance test carried out before, and 3, 6 and 12 months after sleeve gastrectomy. The dotted line indicates the lowest glucose level (3⋅3 mmol/l). The glycaemic peak occurred at 60 min after glucose loading before surgery compared with 30–50 min after sleeve gastrectomy
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Insulin secretion rate time course before, and 3, 6 and 12 months after sleeve gastrectomy. The curves are fittings of the insulin secretion rate measured by the minimal mode
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Plasma insulin concentration time course before, and 3, 6 and 12 months after sleeve gastrectomy. The peak occurred between 90 and 120 min before sleeve gastrectomy, and at 30–60 min after surgery. Values are mean(s.d.)
Fig. 2
Total insulin secretion after the OGTT had decreased by 47 per cent by the end of the study (Fig. 3 and Table 1), and its reduction followed the same trend as fasting insulin secretion.
Insulin sensitivity The fasting insulin sensitivity measured by HOMA-IR, which represents an index of hepatic insulin resistance, decreased from 3⋅3 (1⋅9–5⋅5) mg/dl⋅μunits/ml at © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
Plasma glucagon-like peptide (GLP) 1 concentration time course before, and 3, 6 and 12 months after sleeve gastrectomy. Values are mean(s.d.)
Fig. 4
baseline to 0⋅7 (0⋅5–1⋅1) mg/dl⋅μunits/ml at 12 months after surgery (P < 0⋅001). Insulin sensitivity (M-value) measured by the hyperinsulinaemic clamp method increased from 84⋅0 (20⋅2–131⋅4) to 122⋅8 (99⋅0–179⋅3) mmol per kg fat-free mass per min (P = 0⋅015) at 12 months after SG, but it had already reached a plateau at 6 months (Table 1). A similar trend was observed for GLP-1 secretion (Fig. 4), which increased rapidly by 3 months after SG, declined slightly by 6 months and stabilized thereafter (Table 1). The AUC for GLP-1 after the OGTT increased from 258⋅5 (97⋅5–526⋅6) pmol/l⋅180 min at baseline to 5531⋅8 (4143⋅0–7540⋅9) pmol/l⋅180 min at 1 year (P < 0⋅001) (Table 1). www.bjs.co.uk
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The insulin sensitivity M-value at 1 year, measured using the euglycaemic clamp, correlated well with the total GLP-1 secretion above baseline (R = 0⋅71, P < 0⋅001) and with bodyweight (R = −0⋅70, P = 0⋅001). However, in a stepwise regression model with M-value as the dependent variable, and GLP-1 AUC and bodyweight as independent variables, weight was no longer significant, whereas 51 per cent (P < 0⋅001) of the M-value variability was explained by GLP-1 secretion (GLP-1 standardized coefficient β = 0⋅71, P < 0⋅001; weight standardized β = −0⋅34, P = 0⋅303). Discussion
In this study, insulin sensitivity improved markedly after SG and this was associated with increased serum GLP-1 levels. In addition, hypoglycaemia with levels of 3⋅3–3⋅7 mmol/l was elicited by simple carbohydrate ingestion, and probably occurred as a result of rapid delivery of glucose from the stomach into the small intestine, stimulating a quick insulin response. In previous studies, insulin sensitivity after SG was found to be either increased12,14 or unmodified19 . The variability in these results could be due to differences in demographics of the study population, study design or methods used to assess insulin sensitivity. The current standard for assessment of insulin sensitivity is the EHC method, which was used in the present study. Insulin sensitivity increased progressively for up to 6 months after SG and remained stable thereafter. The metabolic results at 3 months after surgery may be affected by the low-calorie diet of liquid and soft foods that is usually prescribed for the first 2 months following SG, after which regular food is introduced gradually. The net improvement in insulin sensitivity correlated highly with both GLP-1 and bodyweight. However, in a linear multiple regression model bodyweight lost its influence on insulin sensitivity, whereas GLP-1 remained the only predictor, explaining about 51 per cent of the sensitivity to insulin. In an experimental study20 , administration of the GLP-1 receptor antagonist exendin (9–39) prevented improvements in glucose and insulin responses after a meal in obese rats that underwent RYGB or SG. In humans, Jiménez and colleagues21 found that blocking the action of GLP-1 by exendin (9–39) infusion in type 2 diabetic subjects, who had remission of diabetes after SG, led to decreased insulin secretion but only a limited deterioration in glucose tolerance after surgery. This suggests that GLP-1 is not the only factor responsible for the improvement in glucose homeostasis after SG. However, in that study insulin sensitivity was evaluated using the AUC of the glycaemic response to a meal rather than with © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
the euglycaemic clamp method. Although GLP-1 may play a role in the observed improvement in insulin sensitivity after SG, in the present study it explained only half of the M-value variability. Further studies are needed to clarify the mechanisms involved, including the contribution of factors other than GLP-1. It has been shown that chronic subcutaneous administration of GLP-1 increases insulin sensitivity in insulinresistant C57Bl/6 J mice fed a high-fat diet22 . In addition, there is evidence that GLP-1 and its analogues improve insulin resistance in obese animal models23 and in patients with type 2 diabetes mellitus24 . Recently, Green and co-workers25 showed that GLP-1 receptor protein is expressed in human myocytes and that, under euglycaemic conditions, GLP-1 promotes glucose uptake by increased membrane expression of glucose transporter 4 and enhances glycogen synthesis. Therefore, it is likely that the remarkable increase in GLP-1 secretion observed after SG does account for the net improvement in insulin sensitivity observed in the present study. SG is associated with rapid gastric emptying and accelerated small bowel transit of semisolids in animals26 and humans27 . The accelerated intestinal transit, which seems to be partially independent of the faster gastric emptying27 , might be responsible for the rapid increase in insulin secretion and consequently explain the hypoglycaemic episodes observed. Interestingly, it has been reported that, although some patients reported hypoglycaemic symptoms and others did not, their gastric caloric emptying rate was similar28 . Hypoglycaemia has been described in one-third to one-half of patients underging SG29 . In the present study, only three of ten patients had symptoms of hypoglycaemia, but all subjects exhibited plasma glucose levels as low as 2⋅94 mmol/l (53 mg/dl). The American Diabetes Association30 established a plasma glucose concentration of 70 mg/dl or less as the criterion for the definition of hypoglycaemia; this glucose level represents the glycaemic threshold for glucagon activation31 and it reduces sympathoadrenal responses to subsequent hypoglycaemia32 . The high incidence of hypoglycaemia in the present study is similar to that found after RYGB using a continuous glucose monitoring system. Kefurt and colleagues33 reported that 75 per cent of patients had hypoglycaemic episodes with glucose levels lower than 3⋅05 mmol/l (55 mg/dl) after RYGB. A similar proportion (72 per cent) was reported by Roslin and colleagues34 . The present finding highlights the need to advise consumption of frequent and small meals after SG, and to avoid simple carbohydrates. It is important to note that the insulinotropic action of GLP-1 is negligible in patients with a plasma glucose www.bjs.co.uk
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concentration below 4⋅3 mmol/l35 . Therefore, it has been hypothesized that the hypoglycaemic episodes observed after SG are due to the rapid delivery of glucose into the duodenum, which stimulates a brisk insulin response, rather than being mediated by GLP-1 hypersecretion. In healthy subjects an intragastric pressure above 2 mmHg is able to open the pylorus, permitting gastric content to flow into the duodenum36 . Nutrient delivery and absorption in the small intestine is increased after SG. The pressure in the gastric sleeve during saline infusion has been reported to be 43 mmHg, compared with 34 mmHg before surgery37 . Thus, the higher intrasleeve pressure may be related to the increased gastric emptying reported after SG27 . Recently, Seeley and co-workers38 stressed the link between bile acids and improvement in glucose disposal after bariatric surgery. The effects of both RYGB and SG on glucose disposal are greatly reduced in knockout nuclear bile acid receptor (FXR) rodents. These findings may result from the changes in gut microbiota following bariatric surgery. In fact, gut microbiota reduces the bile acid pool size and composition. It is important in the future to analyse bile acid and microbiota changes after SG, and their interactions with glucose metabolism, in humans. This study has some limitations. The sample size is small and the oral glucose load is not a proper physiological stimulus, although it gives a more prompt and predictable glucose absorption than using a mixed meal. Second, hepatic insulin sensitivity was assessed by means of a surrogate index, the HOMA-IR, instead of being measured directly with 6,6-deuterated glucose infusion. Finally, follow-up was only 1 year. It would have been of interest to study these patients 2–3 years after surgery, given that bodyweight often increases 1–2 years after SG. This could have provided more interesting information on the mechanisms by which insulin sensitivity is increased by SG, which some authors consider the best current bariatric surgery option39 . Disclosure
The authors declare no conflict of interest. References 1 Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD et al.; STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes – 3-year outcomes. N Engl J Med 2014; 370: 2002–2013. 2 Abbatini F, Rizzello M, Casella G, Alessandri G, Capoccia D, Leonetti F et al. Long-term effects of laparoscopic sleeve gastrectomy, gastric bypass, and adjustable gastric banding on type 2 diabetes. Surg Endosc 2010; 24: 1005–1010.
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3 Abbatini F, Capoccia D, Casella G, Soricelli E, Leonetti F, Basso N. Long-term remission of type 2 diabetes in morbidly obese patients after sleeve gastrectomy. Surg Obes Relat Dis 2013; 9: 498–502. 4 Laferrère B, Teixeira J, McGinty J, Tran H, Egger JR, Colarusso A et al. Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes. J Clin Endocrinol Metab 2008; 93: 2479–2485. 5 Van der Schueren BJ, Homel P, Alam M, Agenor K, Wang G, Reilly D et al. Magnitude and variability of the glucagon-like peptide-1 response in patients with type 2 diabetes up to 2 years following gastric bypass surgery. Diabetes Care 2012; 35: 42–46. 6 Salinari S, Bertuzzi A, Guidone C, Previti E, Rubino F, Mingrone G. Insulin sensitivity and secretion changes after gastric bypass in normotolerant and diabetic obese subjects. Ann Surg 2013; 257: 462–468. 7 Guidone C, Manco M, Valera-Mora E, Iaconelli A, Gniuli D, Mari A et al. Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Diabetes 2006; 55: 2025–2031. 8 Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G. First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery. Diabetes Care 2009; 32: 375–380. 9 Jørgensen NB, Jacobsen SH, Dirksen C, Bojsen-Møller KN, Naver L, Hvolris L et al. Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance. Am J Physiol Endocrinol Metab 2012; 303: E122–E131. 10 Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med 2012; 366: 1567–1576. 11 Rubino F. Bariatric surgery: effects on glucose homeostasis. Curr Opin Clin Nutr Metab Care 2006; 9: 497–507. 12 Bradley D, Magkos F, Eagon JC, Varela JE, Gastaldelli A, Okunade AL et al. Matched weight loss induced by sleeve gastrectomy or gastric bypass similarly improves metabolic function in obese subjects. Obesity (Silver Spring) 2014; 22: 2026–2031. 13 Kashyap SR, Bhatt DL, Wolski K, Watanabe RM, Abdul-Ghani M, Abood B et al. Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment. Diabetes Care 2013; 36: 2175–2182. 14 Basso N, Capoccia D, Rizzello M, Abbatini F, Mariani P, Maglio C et al. First-phase insulin secretion, insulin sensitivity, ghrelin, GLP-1, and PYY changes 72 h after sleeve gastrectomy in obese diabetic patients: the gastric hypothesis. Surg Endosc 2011; 25: 3540–3550. 15 Gagner M, Gumbs AA, Milone L, Yung E, Goldenberg L, Pomp A. Laparoscopic sleeve gastrectomy for the
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super-super-obese (body mass index > 60 kg/m2 ). Surg Today 2008; 38: 399–403. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214–E223. Polonsky KS, Given BD, Hirsch L, Shapiro ET, Tillil H, Beebe C et al. Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Invest 1988; 81: 435–441. Garrido-Sanchez L, Murri M, Rivas-Becerra J, Ocaña-Wilhelmi L, Cohen RV, Garcia-Fuentes E et al. Bypass of the duodenum improves insulin resistance much more rapidly than sleeve gastrectomy. Surg Obes Relat Dis 2012; 8: 145–150. Chambers AP, Jessen L, Ryan KK, Sisley S, Wilson-Pérez HE, Stefater MA et al. Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology 2011; 141: 950–958. Jiménez A, Mari A, Casamitjana R, Lacy A, Ferrannini E, Vidal J. GLP-1 and glucose tolerance after sleeve gastrectomy in morbidly obese subjects with type 2 diabetes. Diabetes 2014; 63: 3372–3377. Parlevliet ET, de Leeuw van Weenen JE, Romijn JA, Pijl H. GLP-1 treatment reduces endogenous insulin resistance via activation of central GLP-1 receptors in mice fed a high-fat diet. Am J Physiol Endocrinol Metab 2010; 299: E318–E324. Young AA, Gedulin BR, Bhavsar S, Bodkin N, Jodka C, Hansen B et al. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes 1999; 48: 1026–1034. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359: 824–830. Green CJ, Henriksen TI, Pedersen BK, Solomon TP. Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia. PLoS One 2012; 7: e44284. Chambers AP, Smith EP, Begg DP, Grayson BE, Sisley S, Greer T et al. Regulation of gastric emptying rate and its role in nutrient-induced GLP-1 secretion in rats after vertical sleeve gastrectomy. Am J Physiol Endocrinol Metab 2014; 306: E424–E432. Melissas J, Leventi A, Klinaki I, Perisinakis K, Koukouraki S, de Bree E et al. Alterations of global gastrointestinal
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motility after sleeve gastrectomy: a prospective study. Ann Surg 2013; 258: 976–982. Burgerhart JS, van Rutte PW, Edelbroek MA, Wyndaele DN, Smulders JF, van de Meeberg PC et al. Association between postprandial symptoms and gastric emptying after sleeve gastrectomy. Obes Surg 2014; 25: 209–214. Papamargaritis D, Koukoulis G, Sioka E, Zachari E, Bargiota A, Zacharoulis D et al. Dumping symptoms and incidence of hypoglycaemia after provocation test at 6 and 12 months after laparoscopic sleeve gastrectomy. Obes Surg 2012; 22: 1600–1606. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005; 28: 1245–1249. Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol Endocrinol Metab 1991; 260: E67–E74. Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2004; 350: 2272–2279. Kefurt R, Langer FB, Schindler K, Shakeri-Leidenmühler S, Ludvik B, Prager G. Hypoglycemia after Roux-en-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test. Surg Obes Relat Dis 2015; 11: 564–569. Roslin M, Damani T, Oren J, Andrews R, Yatco E, Shah P. Abnormal glucose tolerance testing following gastric bypass demonstrates reactive hypoglycemia. Surg Endosc 2011; 25: 1926–1932. Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 2002; 87: 1239–1246. Tougas G, Anvari M, Dent J, Somers S, Richards D, Stevenson GW. Relation of pyloric motility to pyloric opening and closure in healthy subjects. Gut 1992; 33: 466–471. Yehoshua RT, Eidelman LA, Stein M, Fichman S, Mazor A, Chen J et al. Laparoscopic sleeve gastrectomy – volume and pressure assessment. Obes Surg 2008; 18: 1083–1088. Seeley RJ, Chambers AP, Sandoval DA. The role of gut adaptation in the potent effects of multiple bariatric surgeries on obesity and diabetes. Cell Metab 2015; 21: 369–378. Cohen R. Sleeve gastrectomy: the ideal option for metabolic surgery? Nat Rev Endocrinol 2013; 9: 623.
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BJS 2016; 103: 242–248
Changes in insulin sensitivity and secretion after sleeve gastrectomy G. Casella1 , E. Soricelli1 , L. Castagneto-Gissey1 , A. Redler1 , N. Basso1 and G. Mingrone2,3,4 1 Surgical
Sciences Department, Medical School ‘Sapienza’ University, and 2 Department of Internal Medicine, Catholic University of Rome, Rome, Italy, of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College, London, UK, and 4 Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Dresden, Germany Correspondence to: Professor G. Mingrone, Catholic University, Largo A. Gemelli 8, Rome, Italy (e-mail: [email protected]) 3 Department
Background: Sleeve gastrectomy is indicated for the treatment of obesity and related co-morbidity
including diabetes. The dynamic changes in insulin secretion and sensitivity after sleeve gastrectomy are unknown. Methods: Whole-body insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp technique, and insulin secretion by C-peptide deconvolution after an oral glucose tolerance test (OGTT), before and 3, 6 and 12 months after sleeve gastrectomy in morbidly obese subjects. The time course of glucagon-like peptide (GLP) 1, as a marker of insulin secretion following OGTT, was also assessed. Results: Ten patients were included in the study. Median (range) baseline insulin sensitivity (M-value) increased from 84⋅0 (20⋅2–131⋅4) mmol per kg per min at baseline to 122⋅8 (99⋅0–179⋅3) mmol per kg per min at 12 months after surgery (P = 0⋅015). Fasting insulin sensitivity, measured by homeostatic model assessment of insulin resistance, which represents a surrogate index of hepatic insulin resistance, decreased from 3⋅3 (1⋅9–5⋅5) to 0⋅7 (0⋅5–1⋅1) mg/dl⋅𝛍units/ml (P < 0⋅001). Total insulin secretion, measured as incremental area under the curve (AUC), after OGTT decreased from 360⋅4 (347⋅9–548⋅0) to 190⋅1 (10⋅1–252⋅0) mmol/l⋅180 min at 12 months (P = 0⋅011). The AUC for GLP-1 increased from 258⋅5 (97⋅5–552⋅6) to 5531⋅8 (4143⋅0–7540⋅9) pmol/l⋅180 min at 12 months after sleeve gastrectomy (P < 0⋅001). In multiple regression analysis, 51 per cent of the M-value variability was explained by GLP-1 secretion. Conclusion: Sleeve gastrectomy improved insulin sensitivity and reduced insulin secretion within 6 months after surgery. Although there was a correlation between insulin sensitivity and bodyweight, the major driver of the improvement in insulin sensitivity was GLP-1 secretion. Paper accepted 23 September 2015 Published online 9 November 2015 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.10039
Introduction
Sleeve gastrectomy (SG) has become used widely for the surgical treatment of obesity and related co-morbidity including diabetes1 – 3 . Schauer and colleagues1 showed that diabetes remission, defined by a glycated haemoglobin level below 6 per cent, was achieved in 24 per cent of patients who underwent SG compared with 5 per cent of those who received medical treatment. However, its mechanism of action has not yet been elucidated. Roux-en-Y gastric bypass (RYGB) is known to improve glycaemic control mainly by increasing insulin secretion and stimulation of glucagon-like peptide (GLP) 1 secretion4,5 . Although the effect of RYGB on whole-body insulin sensitivity is relatively small compared with that © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
of biliopancreatic diversion (20 per cent increase from baseline after RYGB versus almost 100 per cent increase after biliopancreatic diversion)6 – 8 , its major action seems to be exerted on hepatic insulin sensitivity9 – 12 . Abbatini and co-workers3 reported that insulin sensitivity was restored in subjects with type 2 diabetes 1 year after SG or RYGB. In contrast, Kashyap et al.13 did not find any improvement 2 years after SG, but they used a surrogate marker of whole-body insulin sensitivity. Recently, Bradley and colleagues12 reported that the degree of improvement in hepatic and peripheral insulin resistance was similar following SG or RYGB. Few studies have investigated insulin secretion after SG. Using the intravenous glucose tolerance test, it was demonstrated that the first phase of insulin secretion was restored BJS 2016; 103: 242–248
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fully a few days after SG14 . Bradley and co-workers12 showed that the total insulin secretion rate after a mixed meal was decreased whereas β-cell function was greatly improved after SG or RYGB accompanied by loss of 20 per cent bodyweight. However, the dynamic changes in insulin sensitivity and secretion over time following SG are unknown. Therefore, insulin sensitivity was investigated by the euglycaemic hyperinsulinaemic clamp (EHC) method, and insulin secretion by C-peptide deconvolution after an oral glucose tolerance test (OGTT) before, and 3, 6 and 12 months after SG. Methods
Participants scheduled for SG were recruited from the Department of Internal Medicine at the obesity outpatient clinic, Catholic University of Rome, Italy. Inclusion criteria for the study were: age 30–65 years; and body mass index over 40 kg/m2 or at least 35 kg/m2 in the presence of complications such as arthritis with walking difficulty, sleep apnoea or obesity-induced physical problems interfering with lifestyle. Exclusion criteria were: presence of diabetes mellitus, coronary heart disease and/or interventions for such disease in the previous 6 months (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty), liver cirrhosis or end-stage renal failure; participation in any other concurrent clinical trial; other life-threatening, non-cardiac disease; pregnancy; or inability to give informed consent. The study protocol was approved by the Institutional Review Board and conducted according to the principles of the Helsinki Declaration, with all subjects providing written consent. All tests were carried out from 30 to 7 days before surgery, and at 3, 6 and 12 months after SG.
Anthropometry On the day of each test, bodyweight was measured and rounded to the nearest 0⋅1 kg by a beam scale. Height was assessed and rounded to the nearest 0⋅5 cm using a stadiometer (Holatin, Crosswell, UK). Body composition was assessed by dual-energy X-ray absorptiometry (DEXA) using a Lunar Prodigy system (GE Healthcare, Fort Edward, New York, USA). DEXA permits measurement of fat-free mass and fat mass.
Sleeve gastrectomy SG was performed according to the technique described by Gagner and colleagues15 with a few modifications2 . Division of the vascular supply of the gastric greater curvature © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
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started at 6 cm from the pylorus and proceeded upwards until the angle of His. The SG was created using a linear stapler, which was applied alongside a 48-Fr calibrating bougie. The resection line was made avoiding the critical area by resecting the fundus 1⋅5 cm from the angle of His. The residual gastric remnant capacity was 60–80 ml.
Homeostasis model assessment Hepatic insulin resistance was measured by means of the homeostatic model assessment of insulin resistance (HOMA-IR), which was computed as fasting plasma glucose (mmol/l) times fasting serum insulin (munits/litre) divided by 22⋅5, as described previously16 . Because fasting plasma levels of glucose and insulin are used to calculate HOMA-IR, and the fasting glucose level is regulated entirely by the liver, HOMA-IR is considered worldwide as a measure of hepatic insulin resistance.
Euglycaemic–hyperinsulinaemic clamp Peripheral insulin sensitivity was evaluated by a 3-h EHC procedure. This technique is currently the standard for insulin sensitivity measurement. After inserting an intravenous cannula into the dorsal vein of the hand for sampling arterialized venous blood, and another in the antecubital fossa of the contralateral arm for infusions, the patient rested in the supine position for at least 1 h. Arterialized blood was obtained by inserting the hand into a heating pad (60∘ C). Insulin was administered using decreasing boluses given in 10 min, followed by a continuous infusion rate of 40 munits per m2 per min (6 pmol per kg bodyweight per min)17 . To maintain plasma glucose levels in a normal range (fasting levels), 20 per cent glucose was infused and blood glucose levels were measured every 5 min. Once a steady state had been reached, usually 2–3 h after starting the clamp, the glucose infusion rate represented the insulin-mediated glucose uptake by the body (M-value in μmol per kg fat-free mass per min). Whole-body peripheral glucose utilization was calculated during the last 40 min of the steady-state insulin infusion.
Insulin secretion The basal insulin secretion rate was computed after an overnight fast, and after the OGTT, using the C-peptide deconvolution model18 . For every mole of insulin secreted by the pancreas, the pancreas also secretes 1 mole of connecting peptide (C-peptide) that is not extracted appreciably by the liver, and instead breaks down insulin. Using the deconvolution function it is possible to compute insulin www.bjs.co.uk
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Anthropometric data, insulin sensitivity and secretion, and glucagon peptide 1 secretion before, and 3, 6 and 12 months after sleeve gastrectomy in ten patients
Table 1
After sleeve gastrectomy Baseline Weight (kg) BMI (kg/m2 ) Fasting glucose (mmol/l) Fasting plasma insulin (pmol/l) HOMA-IR (mg/dl⋅μunits/ml) M-value (mmol per kg fat-free mass per min) Plasma insulin at steady state (pmol/l) Fasting insulin secretion (pmol per m2 per min) Total insulin secretion (mmol/l⋅180 min) Total GLP-1 secretion (pmol/l⋅180 min)
116⋅3 (99⋅0–136⋅7) 41⋅6 (38⋅1–45⋅2) 5⋅1 (4⋅1–6⋅0) 103⋅1 (50⋅2–155⋅0) 3⋅3 (1⋅9–5⋅5) 84⋅0 (20⋅2–131⋅4) 499⋅1 (434⋅0–562⋅3) 423⋅8 (52⋅0–748⋅7) 360⋅4 (347⋅9–548⋅0) 258⋅5 (97⋅5–552⋅6)
3 months 98⋅6 (88⋅1–12⋅6) 36⋅4 (33⋅0–41⋅5) 4⋅8 (4⋅2–5⋅3) 59⋅0 (35⋅1–78⋅0) 2⋅0 (0⋅9–2⋅5)† 110⋅7 (61⋅2–178⋅2) 468⋅0 (404⋅5–538⋅1) 542⋅9 (73⋅8–594⋅3) 192⋅0 (56⋅6–348⋅6) 7002⋅9 (3953⋅0–8992⋅5)‡
6 months 89⋅2 (82⋅0–107⋅0)† 32⋅8 (29⋅2–53⋅3)‡ 4⋅5 (3⋅8–4⋅9) 50⋅0 (24⋅4–62⋅1)† 1⋅6 (0⋅7– 2⋅1)‡ 120⋅0 (91⋅4–181⋅1)* 441⋅5 (381⋅0–481⋅8) 346⋅8 (38⋅5–602⋅4) 178⋅6 (10⋅5–251⋅2) 5589⋅2 (4552⋅4–7040⋅0)‡
12 months 81⋅0 (64⋅0–89⋅8)‡ 28⋅7 (25⋅3–30⋅5)‡ 4⋅4 (3⋅9–4⋅8) 25⋅5 (5⋅8–64⋅2)‡ 0⋅7 (0⋅5–1⋅1)‡ 122⋅8 (99⋅0–179⋅3)* 405⋅0 (356⋅1–497⋅2) 393⋅0 (80⋅0–516⋅5) 190⋅1 (10⋅1–252⋅0)* 5531⋅8 (4143⋅0–7540⋅9)‡
Values are median (range). Fasting insulin sensitivity as homeostatic model assessment of insulin resistance (HOMA-IR) was computed as fasting plasma glucose × fasting serum insulin divided by 22⋅5. BMI, body mass index; GLP, glucagon-like peptide 1. *P < 0⋅050, †P < 0⋅010, ‡P < 0⋅001 versus baseline (2-way repeated-measures ANOVA).
secretion from the circulating levels of C-peptide. The total insulin secretion is the area under the curve (AUC) of the insulin secretion rate after the oral glucose load.
Assays For GLP-1 analysis, venous blood was collected in ice-chilled EDTA dipotassium-treated tubes containing 400 × 106 units aprotinin per litre of blood. For all blood samples, the plasma was separated immediately by centrifugation at 4∘ C and stored at −80∘ C pending assay. Plasma glucose was measured by the glucose oxidase method (Beckman, Fullerton, California, USA). Plasma insulin was assayed using a microparticle enzyme immunoassay (Abbott, Pasadena, California, USA) with a sensitivity of 1 μunit/ml and an intra-assay coefficient of variation (CV) of 6⋅6 per cent. Total GLP-1 was measured by radioimmunoassay (Linco Research, St Charles, Missouri, USA); intra-assay and interassay CVs were 9–14 and 11–20 per cent respectively. This assay has 100 per cent specificity for GLP-1(7–36), GLP-1(9–36) and GLP-1(7–37), and does not cross-react with glucagon (0⋅2 per cent), GLP-2 (less than 0⋅01 per cent) or exendin (less than 0⋅01 per cent).
Statistical analysis All data are expressed as median (range) unless specified otherwise. Data were examined for normal distribution according to Shapiro–Wilks criteria. Two-way repeated-measures ANOVA with Tukey’s post hoc test was used to analyse the effects of SG on study outcome measures. The AUC for insulin secretion and GLP-1 concentrations was calculated by the trapezoidal rule. Correlation analyses were performed using the Spearman © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
correlation coefficient. Multiple regression analysis was carried out to identify the determinants of insulin sensitivity. Probability plots were constructed to look for normality of the residuals and lack of heteroscedasticity (uneven distribution of random disturbance, suggesting non-linearity). Residuals were also assessed by use of the Durbin–Watson statistic. Casewise diagnostics did not reveal any obvious outliers. SPSS® version 13.0 (IBM, Armonk, New York, USA) was used for statistical analysis. Results
Ten patients participated in the study, four men and six women with a median age of 35 (range 19–49) years.
Insulin secretion One year after SG, the patients had lost 30 per cent of their initial median weight (Table 1). Fasting insulin levels dropped from 103⋅1 (50⋅2–155⋅0) pmol/l at baseline to 25⋅5 (5⋅8–64⋅2) pmol/l 1 year after SG (P < 0⋅001). The fasting insulin secretion rate decreased from 423⋅8 (52⋅0–748⋅7) to 393⋅0 (80⋅0–516⋅5) pmol per m2 per min. The maximum decrease was achieved by 6 months after surgery and the rate then remained stable up to 12 months. Before surgery, plasma glucose concentrations peaked at 50–60 min after the oral glucose load and then decreased slowly; after surgery the peak came earlier at 30–50 min after oral glucose loading, and glucose levels then declined rapidly to hypoglycaemic values of around 3⋅3–3⋅7 mmol/l at 120 min (Fig. 1). Later on hypoglycaemic symptoms developed in three of ten patients. Although plasma insulin levels were higher before surgery, after SG the peak value was reached more than 70 min earlier (Fig. 2). www.bjs.co.uk
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Mean plasma glucose concentration in the oral glucose tolerance test carried out before, and 3, 6 and 12 months after sleeve gastrectomy. The dotted line indicates the lowest glucose level (3⋅3 mmol/l). The glycaemic peak occurred at 60 min after glucose loading before surgery compared with 30–50 min after sleeve gastrectomy
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Insulin secretion rate time course before, and 3, 6 and 12 months after sleeve gastrectomy. The curves are fittings of the insulin secretion rate measured by the minimal mode
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Plasma insulin concentration time course before, and 3, 6 and 12 months after sleeve gastrectomy. The peak occurred between 90 and 120 min before sleeve gastrectomy, and at 30–60 min after surgery. Values are mean(s.d.)
Fig. 2
Total insulin secretion after the OGTT had decreased by 47 per cent by the end of the study (Fig. 3 and Table 1), and its reduction followed the same trend as fasting insulin secretion.
Insulin sensitivity The fasting insulin sensitivity measured by HOMA-IR, which represents an index of hepatic insulin resistance, decreased from 3⋅3 (1⋅9–5⋅5) mg/dl⋅μunits/ml at © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
Plasma glucagon-like peptide (GLP) 1 concentration time course before, and 3, 6 and 12 months after sleeve gastrectomy. Values are mean(s.d.)
Fig. 4
baseline to 0⋅7 (0⋅5–1⋅1) mg/dl⋅μunits/ml at 12 months after surgery (P < 0⋅001). Insulin sensitivity (M-value) measured by the hyperinsulinaemic clamp method increased from 84⋅0 (20⋅2–131⋅4) to 122⋅8 (99⋅0–179⋅3) mmol per kg fat-free mass per min (P = 0⋅015) at 12 months after SG, but it had already reached a plateau at 6 months (Table 1). A similar trend was observed for GLP-1 secretion (Fig. 4), which increased rapidly by 3 months after SG, declined slightly by 6 months and stabilized thereafter (Table 1). The AUC for GLP-1 after the OGTT increased from 258⋅5 (97⋅5–526⋅6) pmol/l⋅180 min at baseline to 5531⋅8 (4143⋅0–7540⋅9) pmol/l⋅180 min at 1 year (P < 0⋅001) (Table 1). www.bjs.co.uk
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The insulin sensitivity M-value at 1 year, measured using the euglycaemic clamp, correlated well with the total GLP-1 secretion above baseline (R = 0⋅71, P < 0⋅001) and with bodyweight (R = −0⋅70, P = 0⋅001). However, in a stepwise regression model with M-value as the dependent variable, and GLP-1 AUC and bodyweight as independent variables, weight was no longer significant, whereas 51 per cent (P < 0⋅001) of the M-value variability was explained by GLP-1 secretion (GLP-1 standardized coefficient β = 0⋅71, P < 0⋅001; weight standardized β = −0⋅34, P = 0⋅303). Discussion
In this study, insulin sensitivity improved markedly after SG and this was associated with increased serum GLP-1 levels. In addition, hypoglycaemia with levels of 3⋅3–3⋅7 mmol/l was elicited by simple carbohydrate ingestion, and probably occurred as a result of rapid delivery of glucose from the stomach into the small intestine, stimulating a quick insulin response. In previous studies, insulin sensitivity after SG was found to be either increased12,14 or unmodified19 . The variability in these results could be due to differences in demographics of the study population, study design or methods used to assess insulin sensitivity. The current standard for assessment of insulin sensitivity is the EHC method, which was used in the present study. Insulin sensitivity increased progressively for up to 6 months after SG and remained stable thereafter. The metabolic results at 3 months after surgery may be affected by the low-calorie diet of liquid and soft foods that is usually prescribed for the first 2 months following SG, after which regular food is introduced gradually. The net improvement in insulin sensitivity correlated highly with both GLP-1 and bodyweight. However, in a linear multiple regression model bodyweight lost its influence on insulin sensitivity, whereas GLP-1 remained the only predictor, explaining about 51 per cent of the sensitivity to insulin. In an experimental study20 , administration of the GLP-1 receptor antagonist exendin (9–39) prevented improvements in glucose and insulin responses after a meal in obese rats that underwent RYGB or SG. In humans, Jiménez and colleagues21 found that blocking the action of GLP-1 by exendin (9–39) infusion in type 2 diabetic subjects, who had remission of diabetes after SG, led to decreased insulin secretion but only a limited deterioration in glucose tolerance after surgery. This suggests that GLP-1 is not the only factor responsible for the improvement in glucose homeostasis after SG. However, in that study insulin sensitivity was evaluated using the AUC of the glycaemic response to a meal rather than with © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd
the euglycaemic clamp method. Although GLP-1 may play a role in the observed improvement in insulin sensitivity after SG, in the present study it explained only half of the M-value variability. Further studies are needed to clarify the mechanisms involved, including the contribution of factors other than GLP-1. It has been shown that chronic subcutaneous administration of GLP-1 increases insulin sensitivity in insulinresistant C57Bl/6 J mice fed a high-fat diet22 . In addition, there is evidence that GLP-1 and its analogues improve insulin resistance in obese animal models23 and in patients with type 2 diabetes mellitus24 . Recently, Green and co-workers25 showed that GLP-1 receptor protein is expressed in human myocytes and that, under euglycaemic conditions, GLP-1 promotes glucose uptake by increased membrane expression of glucose transporter 4 and enhances glycogen synthesis. Therefore, it is likely that the remarkable increase in GLP-1 secretion observed after SG does account for the net improvement in insulin sensitivity observed in the present study. SG is associated with rapid gastric emptying and accelerated small bowel transit of semisolids in animals26 and humans27 . The accelerated intestinal transit, which seems to be partially independent of the faster gastric emptying27 , might be responsible for the rapid increase in insulin secretion and consequently explain the hypoglycaemic episodes observed. Interestingly, it has been reported that, although some patients reported hypoglycaemic symptoms and others did not, their gastric caloric emptying rate was similar28 . Hypoglycaemia has been described in one-third to one-half of patients underging SG29 . In the present study, only three of ten patients had symptoms of hypoglycaemia, but all subjects exhibited plasma glucose levels as low as 2⋅94 mmol/l (53 mg/dl). The American Diabetes Association30 established a plasma glucose concentration of 70 mg/dl or less as the criterion for the definition of hypoglycaemia; this glucose level represents the glycaemic threshold for glucagon activation31 and it reduces sympathoadrenal responses to subsequent hypoglycaemia32 . The high incidence of hypoglycaemia in the present study is similar to that found after RYGB using a continuous glucose monitoring system. Kefurt and colleagues33 reported that 75 per cent of patients had hypoglycaemic episodes with glucose levels lower than 3⋅05 mmol/l (55 mg/dl) after RYGB. A similar proportion (72 per cent) was reported by Roslin and colleagues34 . The present finding highlights the need to advise consumption of frequent and small meals after SG, and to avoid simple carbohydrates. It is important to note that the insulinotropic action of GLP-1 is negligible in patients with a plasma glucose www.bjs.co.uk
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concentration below 4⋅3 mmol/l35 . Therefore, it has been hypothesized that the hypoglycaemic episodes observed after SG are due to the rapid delivery of glucose into the duodenum, which stimulates a brisk insulin response, rather than being mediated by GLP-1 hypersecretion. In healthy subjects an intragastric pressure above 2 mmHg is able to open the pylorus, permitting gastric content to flow into the duodenum36 . Nutrient delivery and absorption in the small intestine is increased after SG. The pressure in the gastric sleeve during saline infusion has been reported to be 43 mmHg, compared with 34 mmHg before surgery37 . Thus, the higher intrasleeve pressure may be related to the increased gastric emptying reported after SG27 . Recently, Seeley and co-workers38 stressed the link between bile acids and improvement in glucose disposal after bariatric surgery. The effects of both RYGB and SG on glucose disposal are greatly reduced in knockout nuclear bile acid receptor (FXR) rodents. These findings may result from the changes in gut microbiota following bariatric surgery. In fact, gut microbiota reduces the bile acid pool size and composition. It is important in the future to analyse bile acid and microbiota changes after SG, and their interactions with glucose metabolism, in humans. This study has some limitations. The sample size is small and the oral glucose load is not a proper physiological stimulus, although it gives a more prompt and predictable glucose absorption than using a mixed meal. Second, hepatic insulin sensitivity was assessed by means of a surrogate index, the HOMA-IR, instead of being measured directly with 6,6-deuterated glucose infusion. Finally, follow-up was only 1 year. It would have been of interest to study these patients 2–3 years after surgery, given that bodyweight often increases 1–2 years after SG. This could have provided more interesting information on the mechanisms by which insulin sensitivity is increased by SG, which some authors consider the best current bariatric surgery option39 . Disclosure
The authors declare no conflict of interest. References 1 Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD et al.; STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes – 3-year outcomes. N Engl J Med 2014; 370: 2002–2013. 2 Abbatini F, Rizzello M, Casella G, Alessandri G, Capoccia D, Leonetti F et al. Long-term effects of laparoscopic sleeve gastrectomy, gastric bypass, and adjustable gastric banding on type 2 diabetes. Surg Endosc 2010; 24: 1005–1010.
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