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Effect of Frey's procedure on islet cell function in patients with chronic calcific pancreatitis
Accepted Manuscript
Effect of Frey’s procedure on islet cell function in patients with chronic calcific pancreatitis Ritesh Kumar , Jaya Prakash Sahoo , Biju Pottakat , Sadishkumar Kamalanathan , Pazhanivel Mohan , Vikram Kate , Sitanshu Sekhar Kar , Jayakumar Selviambigapathy PII: DOI: Reference:
S1499-3872(18)30133-4 10.1016/j.hbpd.2018.06.001 HBPD 56
To appear in:
Hepatobiliary & Pancreatic Diseases International
Received date: Accepted date:
24 November 2017 4 June 2018
Please cite this article as: Ritesh Kumar , Jaya Prakash Sahoo , Biju Pottakat , Sadishkumar Kamalanathan , Pazhanivel Mohan , Vikram Kate , Sitanshu Sekhar Kar , Jayakumar Selviambigapathy , Effect of Frey’s procedure on islet cell function in patients with chronic calcific pancreatitis, Hepatobiliary & Pancreatic Diseases International (2018), doi: 10.1016/j.hbpd.2018.06.001
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Article Type: Original Article/Pancreas Article Title: Effect of Frey’s procedure on islet cell function in patients with chronic calcific pancreatitis
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Running Title: Frey’s procedure and islet cell function Authors: Ritesh Kumar1, Jaya Prakash Sahoo1, Biju Pottakat2, Sadishkumar Kamalanathan1, Pazhanivel Mohan3, Vikram Kate4, Sitanshu Sekhar Kar5, Jayakumar Selviambigapathy1
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(Kumar R, Sahoo JP, Pottakat B, Kamalanathan S, Mohan P, Kate V, Kar SS, Selviambigapathy J)
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Received 24 November 2017
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Author Affiliations:
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Accepted 4 June 2018
1. Department of Endocrinology & Metabolism, Jawaharlal Institute of Postgraduate
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Medical Education and Research (JIPMER), Pondicherry 605006, India
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2. Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India
3. Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India 4. Department of Surgery, Jawaharlal Institute of Postgraduate Medical Education and
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Research (JIPMER), Pondicherry 605006, India 5. Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India
Nagar, Pondicherry 605009, India (Email: [email protected])
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Corresponding Author: Dr. Jaya Prakash Sahoo, MD, DM, House No-28, Lane -B, VVP
Contributors: SJP, PB, KS and SJ designed the study and revised it critically for important
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intellectual content. KR acquired the data and drafted the work. MP, KV and KSS analyzed the data and revised it critically for important intellectual content. All authors approved the final version of the manuscript. SJP is the guarantor.
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Funding: This study was supported by Intramural research grant from Jawaharlal Institute of
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Postgraduate Medical Education and Research (JIPMER) (JIP/Res/Intra-DM-M.Ch/02/2014). Ethical approval: The study protocol was approved by the Institute Ethics Committee and
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written informed consent was obtained from all participants before enrolment in the study. The
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study was conducted based on the principles outlined in the Declaration of Helsinki. Competing interest: No benefits in any form have been received or will be received from a
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commercial party related directly or indirectly to the subject of this article.
Abstract Background: As Frey's procedure involves both drainage and resection of the pancreas in subjects with chronic calcific pancreatitis (CCP). The procedure may affect the pancreatic 2 / 20
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endocrine function after surgery. The present study was to evaluate the effect of Frey's procedure on both beta and alpha cell function in CCP patients. Methods: Thirty CCP patients who underwent Frey’s procedure were included. According to the
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glycemic status, patients were divided into the diabetes mellitus (DM), prediabetes, and normal glucose tolerance (NGT) groups. Islet cell function was assessed before and 3 months after surgery.
Results: At baseline, there was a significant difference in beta cell function among the three
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groups [NGT group 1.71 (1.64-2.07) vs prediabetes group1.50 (0.83-1.61) vs DM group 0.33 (0.12-0.55), P < 0.0001], but the insulin resistance was not different among them. Post glucose hyperglucagonemia representing alpha-cell dysfunction during oral glucose tolerance test was present in all of them, but showed no significant difference [NGT group 0.15 (0.06-0.31) vs
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prediabetes group 0.32 (0.05-0.70) vs DM group 0.07 (0.02-0.18), P = 0.20]. Frey's procedure
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did not change beta cell function and insulin resistance. However, alpha-cell dysfunction deteriorated after surgery [0.10 (0.03-0.27) vs 0.33 (0.09-0.68), P =0.004].
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Conclusions: Although Frey’s procedure does not affect the beta cell function and insulin
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resistance in CCP patients, the alpha-cell dysfunction deteriorates after surgery. Key words: Beta-cell; diabetes mellitus; glucagon; insulin secretion sensitivity index; Matsuda
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index
Introduction Chronic calcific pancreatitis (CCP) is a progressive inflammatory disease leading to 3 / 20
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destruction, fibrosis, and calcification of parenchyma [1]. There is dilatation of the main pancreatic duct due to multiple intraductal calculi and strictures. Chronic abdominal pain is the most common presentation, which deteriorates the quality of life and causes addiction to narcotic analgesics. Irreversible damage of pancreas ultimately leads to endocrine as well as exocrine
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insufficiency [1]. Another important cause of morbidity is diabetes mellitus (DM) which is brittle and insulin-dependent [1].
Chronic intractable abdominal pain is the most common indication for surgery in CCP
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patients. Increased intra-ductal pressure due to pancreatic duct obstruction and presence of an inflammatory mass in the head of the pancreas are two major contributors for pain in these subjects [1]. Different types of pancreatic surgery are available for the relief of abdomen pain. In drainage procedures, the whole pancreatic duct is decompressed and the major portion of
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pancreatic tissue is preserved. Pain relief is seen in most of the patients on short-term follow-up but these procedures fail to provide long-term relief in pain [1]. Frey's procedure includes both
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pancreatic drainage (longitudinal pancreatico-jejunostomy) and resection (coring of the head of
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the pancreas) [2]. Long-term pain relief is excellent in Frey’s procedure in comparison to simple drainage procedures.
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As Frey’s procedure involves both drainage and resection of the pancreas, it may affect pancreatic function after surgery. Various studies have observed the change in pancreatic
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exocrine function and glycaemic status following Frey’s procedure [3-11]. But only a few studies examined the effect of Frey’s procedure on islet cell function [10, 11]. The beta cell function was studied by measuring only fasting C-peptide and insulin but the alpha cell function was not evaluated. Therefore, we designed this study to evaluate the effect of Frey’s procedure on both beta and alpha cell function.
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Methods The study was conducted in Endocrinology, Surgical Gastroenterology and Medical
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Gastroenterology Departments of a tertiary care institute from February 2015 to November 2016. The study protocol was approved by the Institute Ethics Committee and written informed consent was obtained from all participants before enrolment in the study. The study was conducted based on the principles outlined in the Declaration of Helsinki.
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The patients aged between 18 to 65 years and diagnosed with CCP were included. Fortynine CCP patients were evaluated during this study period. Eleven patients were excluded: two patients had hypercalcemia, one pancreatic adenocarcinoma, one aged >65 years old, and seven
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having no indication for surgery. Additionally, eight patients did not turn up for evaluation after surgery (5 patients lost to follow-up and 3 died). Finally, 30 patients were included in the study.
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According to the glycemic status, patients were divided into the diabetes mellitus (DM, n =18), prediabetes (n =7), and normal glucose tolerance (NGT, n =5) groups. Basic demographic
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evaluation.
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characteristics were collected for all subjects. All patients underwent a detailed clinical
The diagnosis of CCP was based on clinical features (abdominal pain, diarrhea with/without
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DM) and imaging characteristics (calcifications in the pancreas or pancreatic duct on abdomen X-ray/ultrasonography/computed tomography scan). The decision for Frey's procedure was taken by the surgical gastroenterologist and it was based on persistence intractable pain in abdomen, dilated main pancreatic duct and the presence of an inflammatory mass in the head of the pancreas.
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DM was diagnosed on the basis of a 75-g oral glucose tolerance test (OGTT) and/or glycosylated hemoglobin (HbA1c) [12]. All the DM patients were on the basal-bolus regimen of insulin i.e. regular and neutral protamine Hagedorn (NPH) insulin. The last dose of regular and NPH insulin was given between 6:00 to 7:00 pm of the previous night. Morning insulin was
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withheld before OGTT. We measured the fasting, 60 and 120 minutes plasma glucose, insulin, and glucagon after giving 75 g of oral glucose. The plasma glucose, HbA1c, amylase, and erythrocyte sedimentation rate (ESR) were measured immediately in the fasting blood sample. For glucagon assay, venous blood was collected in pre-chilled ethylene diamine tetra-acetic acid
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tube, centrifuged immediately and plasma was stored at -80 0C until further analysis. For insulin assay, serum was separated and stored at -80 0C until further analysis. The area under the curve (AUC) was calculated by the linear trapezoidal method for glucagon, insulin, and glucose.
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Insulin secretion –sensitivity index -2 (ISSI-2) was used to measure the beta cell function. It was calculated as the product of (AUCinsulin/ AUCglucose) and Matsuda index. It is a validated OGTT-
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derived measure of beta cell function that is analogous to the disposition index obtained from the intravenous glucose tolerance test [13]. Alpha cell function was measured by AUCglucagon and
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[(glucagon120 –glucagon0)/ (glucose120 –glucose0)] [14, 15]. The homeostatic model assessment 2-
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insulin resistance (HOMA2-IR) & Matsuda index were calculated for hepatic insulin resistance and whole body insulin sensitivity, respectively [16,17]. Baseline investigations were done
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within one week before surgery and all the tests were repeated 3 months after the Frey’s procedure.
Plasma glucagon was measured by Quantikine enzyme-linked immunosorbent assay
(ELISA) glucagon kit (R&D Systems). Each sample was run in the same assay. The assay has <12% cross-reactivity with oxyntomodulin and no significant cross-reactivity with gastric
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inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP2), or glicentin related polypeptide. The assay has a minimum detection limit of 2.12 pg/mL. The inter-assay coefficient of variation was 5.8%-8.7% and the intra-assay coefficient of variation was 2.7%-3.6%. Serum insulin was estimated by chemiluminescence method using ADVIA
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Centaur XP Immunoassay system (Siemens Healthcare Global, New York, USA). The plasma glucose was measured by glucose oxidase method and the HbA1c was measured by Bio-Rad D10 system using a high performance liquid chromatography method.
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Statistical analysis
Statistical analysis was performed using Statistical Package for Social Sciences (SPSS, version 19.0). Kolmogorov-Smirnov test was used to verify data distribution. Continuous variables were expressed as mean ± standard deviation or median (interquartile range)
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respectively. Categorical variables were presented as the percentage. Kruskal-Wallis test was
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used to analyze the differences between the DM, prediabetes and NGT groups at baseline. MannWhitney U test was used to analyze the baseline differences between the two groups. Paired t test
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and Wilcoxon sign rank test were used to compare before and after surgery for parametric and
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nonparametric data, respectively. The P value < 0.05 was considered statistically significant.
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Results
Thirty CCP patients who underwent Frey’s procedure were included in the study. The mean
age of patients was 36.03±11.95 years and two-third of the study population was male. Sixteen patients (53%) of our subjects were alcoholic and 13 patients (43%) were smokers. The abdomen pain was present in all subjects and the median duration of abdomen pain was 3 years. The 7 / 20
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patients with exocrine insufficiency were on pancreatic enzyme replacement. The mean body mass index (BMI) of patients was 19.03±3.17 kg/m2. DM was detected only after the diagnosis of CCP. The family history of DM was present in
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4 CCP patients. However, none of the DM patients was overweight or obese. At baseline, the beta cell function (as measured by ISSI-2) was the highest in the NGT group followed by the prediabetes and DM groups [NGT group 1.71 (1.64-2.07), prediabetes group 1.50 (0.83-1.61), and DM group 0.33 (0.12-0.55), P <0.0001] (Table 1). Insulin resistance, measured by HOMA2-
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IR, was not different in all the 3 groups [NGT group 1.32 (0.84-1.67), prediabetes group 1.16 (0.69-2.5), and DM group 0.92 (0.67-1.33), P=0.39]. Similarly, there was no difference in wholebody insulin sensitivity measured by Matsuda index in all the 3 groups [NGT group 4.26 (3.1910.01), prediabetes group 4.40 (2.23-9.45), and DM group 5.7 (3.43-11.51), P=0.69]. Sixty and
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120 minutes plasma glucose were significantly elevated in comparison to fasting plasma glucose in all the 3 groups (Table 2). Post-OGTT 60 and 120 minutes plasma glucagon were also
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significantly elevated instead of suppression as compared to fasting state, suggesting the
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presence of alpha-cell dysfunction before surgery. The alpha cell function (measured by glucagon120–glucagon0)/ (glucose120 –glucose0) was not different among the 3 groups [NGT
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group 0.15 (0.06-0.31), prediabetes group 0.32 (0.05-0.70), and DM group 0.07 (0.02-0.18), P
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=0.20] (Table 1).
There was no difference in beta cell function [0.59 (0.27-1.62) vs 0.46 (0.17-1.01), P =
0.46] and glycaemic status before and 3 months after surgery in the whole study cohort (Table 3). Similarly, the beta cell function did not change in the NGT group [1.71 (1.64-2.07) vs 1.60 (0.87-1.98), P = 0.22], prediabetes group [1.50 (0.83-1.61) vs 1.11 (0.96-1.88), P = 0.73] and DM group [0.33 (0.12-0.55) vs 0.32 (0.17-0.46), P = 0.68]. HOMA2-IR and Matsuda index were 8 / 20
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also not affected by surgery. But plasma glucagon at 0, 60 and 120 minutes was significantly increased after surgery in comparison to baseline (Fig. 1). Similarly, AUCglucagon has also increased post-surgery compared to pre-surgery (89.74±48.03 vs 156.18±71.01), P<0.0001). Thus, alpha-cell dysfunction deteriorated after surgery compared to before surgery [0.10 (0.03-
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0.27) vs 0.33 (0.09-0.68), P =0.004]. The glucose profile has worsened in two patients from prediabetes to diabetes state after surgery and one of them had a family history of DM. Serum amylase [69.50 (35.5-107) vs 34 (23-68) IU/L, P =0.03] and ESR (35.23±19.63 vs 24.7±11.05
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mm/h, P =0.003) were also significantly decreased after surgery in comparison to before surgery.
Discussion
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Loss of beta cell function in chronic pancreatitis (CP) is due to fibrosis and atrophy of islet cells because of chronic inflammation [18]. The beta cell function was significantly lower in the
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DM group in comparison to both the prediabetes and NGT groups in our study. This difference
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in beta cell function was responsible for their glycemic status as there were no differences in insulin sensitivity, insulin resistance and alpha-cell dysfunction. In Mehrotra et al’s study [19],
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CCP subjects with DM had lower beta cell reserve compared to CCP-NGT patients, but there was no difference in insulin sensitivity. In a study by Cavallini et al [20], DM subjects had lower
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beta cell function compared to prediabetes and NGT patients, but CP patients with DM had more insulin resistance compared to CP subjects with NGT. Inconsistent results regarding the insulin sensitivity and insulin resistance may be possible due to heterogeneous study population, different etiology of CP, variable duration of disease, and the different method of measurement of insulin indices used in different studies.
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The plasma glucagon is normally suppressed in healthy subjects during OGTT [14]. However, in our study both 60 and 120 minutes plasma glucagon levels were significantly increased in comparison to fasting glucagon in all the three groups of CCP subjects before surgery, suggesting alpha-cell dysfunction presenting in CCP patients irrespective of their
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glycemic status. Other studies also reported similar findings in CP patients [21-23]. Lundberg et al. [21] found that both fasting as well as stimulated glucagon level were elevated after a mixed meal in nondiabetic subjects with CP in comparison to healthy controls, and they speculated that elevated glucagon in the early course of disease was due to chronic stress, inflammation and
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beta-cell dysfunction. Similarly, Kannan et al. [22] reported that pancreatic glucagon was declined to the nadir at 90 minutes in controls but paradoxically elevated at 60-120 minutes in CP subjects. They postulated that paradoxical elevated glucagon may be possible due to the
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alpha cell hyperplasia in CP patients. But inappropriate glucagon response to OGTT deteriorated with increasing glucose intolerance in CP patients [24]. The glucagon suppression was
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diminished in patients with CP and NGT, lost in CP patients and impaired glucose intolerance, and paradoxically reversed to a positive glucagon response in patients with CP and DM.
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Furthermore, the CP patients had a normal or near-normal ability to suppress glucagon in
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response to intravenous glucose tolerance test irrespective of their glycemic status, indicating the role of incretins in inappropriate glucagon response to orally administered glucose. Thus, in CP
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subjects, the non-suppression of glucagon following OGTT could be the result of a balance between stimulatory factors (GIP and GLP-2) and inhibitory factors (GLP-1 and insulin) acting upon the alpha cells; with the former outweighing the latter. The decreased digestion and absorption of nutrients in the small intestine due to exocrine pancreatic insufficiency is probably responsible for altered secretion of incretins in CCP subjects [25-27].
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In our study, the beta cell function evaluated by ISSI-2 did not change 3 months postoperation in comparison to pre-operation in the total study population. Only two studies prospectively studied the effect of Frey's procedure on beta cell function [10, 11]. Izbicki et al [10] reported that fasting insulin and C-peptide levels were normal in 55% of patients before
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Frey’s procedure compared to 41% after 1.5 years of follow-up, but did not mention whether this change in beta cell function was statistically significant or not. One of their patients with NGT became prediabetes after surgery. Similarly, there was no change in fasting C-peptide level 2 years after Frey’s procedure in 31 CP patients in another study. But two of their subjects with
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NGT became prediabetes during the follow-up [11]. In our study, two prediabetes subjects became diabetic after surgery. After Frey’s procedure, the incidence of new onset of diabetes in subjects with CP varies from 7%-36% in different studies [2-9]. This wide variation in the
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incidence of new onset of diabetes is possibly due to heterogeneous baseline characteristics like duration of symptoms, stage of disease, presence or absence of pancreatic calcification, history
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of alcohol intake and variable duration of follow-up [28, 29].
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The alpha-cell dysfunction was deteriorated without a change in insulin sensitivity and beta cell function in this study. This suggests that new onset of DM after surgery might be due to the
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deterioration in alpha-cell dysfunction leading to further rise in plasma glucagon level. This has clinical implications for management of CCP patients with DM. The glucose lowering agents
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inhibiting glucagon secretion in addition to stimulating insulin secretion might be helpful [30]. However, antidiabetic drugs stimulating insulin secretion and inhibiting glucagon secretion like GLP-1 analogues and dipeptidyl peptidase-4 inhibitor are contraindicated in patients with pancreatitis. Pramlintide, which inhibits postprandial glucagon secretion, can be used in these subjects in addition to beta cell secretagogues (sulfonylureas and meglitinides) or insulin for
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glycemic control. In the future, glucagon receptor antagonists may be another strategy to prevent deterioration of plasma glucose following Frey’s procedure [31]. Both ESR and amylase decreased after surgery without any change in beta cell function
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almost ruled out the role of inflammation and beta-cell dysfunction in worsening postoperative hyperglucagonemia in our subjects. But the post-surgery alteration in gastrointestinal hormones levels can explain the deterioration in alpha cell function in this study. Glucose stimulates pancreatic polypeptide (PP) secretion and PP inhibits glucagon release through the pancreatic
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polypeptide receptor (PPYR1) present on alpha cells [32]. The serum PP level is decreased in CP patients compared to healthy controls [33]. It is further decreased following Frey’s procedure as cells secreting PP are mainly located at the head of the pancreas [20, 33, 34]. But the alpha cells escaped as they are present mainly in the tail of the pancreas [34]. Therefore, the post-surgery
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decrease in PP levels can lead to increased glucagon level by stimulating alpha cells in these patients. However, the contribution of postoperative alteration in incretins to the deterioration of
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alpha-cell dysfunction can not be ruled out in our patients. Both GIP and GLP-2 stimulate
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glucagon secretion from alpha cells whereas GLP-1 inhibits glucagon secretion [24]. The secretion of incretin hormones is regulated by both the rate of delivery and assimilation of
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nutrients in the small intestine [25-27]. These are altered due to changes in gastrointestinal motility and pancreatic exocrine function after surgery [35]. The incretins (GLP-1, GLP-2 and
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GIP) and PP should be measured before and after surgery to find the mechanisms of alpha-cells dysfunction after Frey's operation in future studies. The strength of our study is the assessment of the beta cell function by ISSI-2, which is a validated OGTT-derived measure of beta cell function. We also assessed alpha cell function and insulin sensitivity indices, which has not been reported with Frey’s procedure in the literature. 12 / 20
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There were few limitations in our studies. First, the healthy controls were not included in the study. Second, the etiology work up for CCP was incomplete in our patients. Third, the postsurgery follow-up was only for 3 months.
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To conclude, Frey's procedure did not affect the beta cell function and insulin resistance in
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CCP patients. But there was a deterioration in alpha-cell dysfunction after surgery.
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Scheen AJ, Paquot N, Lefèbvre PJ. Investigational glucagon receptor antagonists in Phase I and II clinical trials for diabetes. Expert Opin Investig Drugs 2017;26:1373-1389.
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Aragón F, Karaca M, Novials A, Maldonado R, Maechler P, Rubí B. Pancreatic polypeptide
cells. Biochim Biophys Acta 2015;1850:343-351. 33
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regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-
Brunicardi FC, Chaiken RL, Ryan AS, Seymour NE, Hoffmann JA, Lebovitz HE, et al. Pancreatic polypeptide administration improves abnormal glucose metabolism in patients
34
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with chronic pancreatitis. J Clin Endocrinol Metab 1996;81:3566-3572.
Meier JJ. Insulin secretion In: Jameson JL, De Groot LJ, Giudice LC, Grossman AB, Kretser DD, Melmed S, eds. Endocrinology: adult and pediatric Philadelphia, PA: Elsevier
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Saunders; 2016:546-555.
Zhao Y, Zhang J, Lan Z, Jiang Q, Zhang S, Chu Y, et al. Duodenum-preserving resection of
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the pancreatic head versus pancreaticoduodenectomy for treatment of chronic pancreatitis with enlargement of the pancreatic head: Systematic review and meta-analysis. Biomed Res
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Int 2017;2017:3565438.
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Table 1. The baseline characteristics of study subjects DM group (1) (n=18)
Prediabetes group (2) (n=7)
NGT group (3) (n=5)
P value (1 vs 2 vs 3)
P value (1 vs 2)
P value (2 vs 3)
P value (1 vs 3)
Age (yr)
36.50 (32.70-44.00)
42.00 (18.00-49.00)
28.00 (18.00-37.50)
0.21
0.95
0.21
0.07
BMI (kg/m2)
19.39 (16.46-21.19)
19.15 (17.30-20.68)
18.80 (17.48-23.78)
0.58
0.76
0.68
0.60
HOMA2-IR
0.92 (0.67-1.33)
1.16 (0.69-2.50)
1.32 (0.84-1.67)
Matsuda index
5.70 (3.43-11.51)
4.40 (2.23-9.45)
4.26 (3.19-10.01)
ISSI-2
0.33 (0.12-0.55)
1.50 (0.83-1.61)
1.71 (1.64-2.07)
(Glucagon120 –glucagon0)/ (glucose120 –glucose0 )
0.07 (0.02-0.18)
0.32 (0.05-0.70)
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Parameters
0.30
0.83
0.28
0.69
0.43
0.81
0.50
<0.0001
<0.0001
0.019
0.001
0.14
0.57
0.19
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0.39
0.15 (0.06-0.31)
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BMI: body mass index; HOMA2-IR: homeostatic model assessment 2- insulin resistance; ISSI-2: insulin
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secretion –sensitivity index-2.
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Table 2. The trend of plasma glucose and glucagon level during oral glucose tolerance test before surgery
DM group (n=18)
Fasting plasma glucose (mg/dL)
123 (101-213)
60 minute Plasma glucose (mg/dL)
P value
P value
Reference
Prediabetes group (n=7) 96 (92-101)
P value
Reference
NGT group (n=5) 90 (80-91)
268 (248-406)
<0.0001
171 (151-195)
0.001
152 (134-179)
0.005
120 minute plasma glucose (mg/dL)
327 (265-483)
<0.0001
150 (115-173)
0.01
130 (120-131)
0.002
Fasting plasma glucagon (pg/mL)
21.8 (12.1-32.0)
Reference
30.2 (15.354.4)
Reference
12.5 (5.833.01)
Reference
60 minute plasma glucagon (pg/mL)
55.6 (34.2-80.4)
<0.0001
64.3 (34.4102.8)
0.01
24.2 (13.841.9)
0.04
120 minute plasma glucagon (pg/mL)
34.8 (25.9-82.4)
0.002
54.2 (28.868.5)
0.03
18.2 (13.638.7)
0.04
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Parameters
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Reference
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Table 3. Effect of surgery on endocrine function of pancreas in the whole study population Before surgery (n=30)
After surgery (n=30)
P value
Body weight (kg)
48.91±10.00
47.42±9.70
0.06
HbA1c (%)
6.95(5.80-9.90)
7.25 (5.70-10.35)
0.88
HOMA2-IR
1.12 (0.68-1.45)
0.95 (0.75-1.74)
0.54
Matsuda index
4.96 (3.43-9.75)
5.49 (3.87-8.82)
0.56
ISSI-2
0.59 (0.27-1.62)
0.46 (0.17-1.01)
0.46
Fasting plasma glucagon (pg/mL)
26.06±16.81
43.69±22.10
<0.0001
Plasma glucagon at 60 min (pg/mL)
54.06 ±29.51
89.73±44.24
<0.0001
Plasma glucagonat 120 min (pg/mL)
34.89 (21.22-67.33)
75.00 (57.58-110.8)
<0.0001
AUC-glucagon
89.74±48.03
156.18±71.01
<0.0001
(glucagon120–glucagon0)/(glucose120–glucose0 )
0.10 (0.03-0.27)
0.33 (0.09-0.68)
0.004
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Parameters
HbA1c: glycosylated hemoglobin; HOMA2-IR: homeostatic model assessment 2- insulin
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resistance; ISSI-2: Insulin secretion –sensitivity index -2; AUC: area under curve.
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Figure legend
Fig. 1. The plasma glucagon level during oral glucose tolerance test (OGTT) at baseline and 3
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months after surgery. *: P value <0.0001.
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Effect of Frey’s procedure on islet cell function in patients with chronic calcific pancreatitis Ritesh Kumar , Jaya Prakash Sahoo , Biju Pottakat , Sadishkumar Kamalanathan , Pazhanivel Mohan , Vikram Kate , Sitanshu Sekhar Kar , Jayakumar Selviambigapathy PII: DOI: Reference:
S1499-3872(18)30133-4 10.1016/j.hbpd.2018.06.001 HBPD 56
To appear in:
Hepatobiliary & Pancreatic Diseases International
Received date: Accepted date:
24 November 2017 4 June 2018
Please cite this article as: Ritesh Kumar , Jaya Prakash Sahoo , Biju Pottakat , Sadishkumar Kamalanathan , Pazhanivel Mohan , Vikram Kate , Sitanshu Sekhar Kar , Jayakumar Selviambigapathy , Effect of Frey’s procedure on islet cell function in patients with chronic calcific pancreatitis, Hepatobiliary & Pancreatic Diseases International (2018), doi: 10.1016/j.hbpd.2018.06.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Article Type: Original Article/Pancreas Article Title: Effect of Frey’s procedure on islet cell function in patients with chronic calcific pancreatitis
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Running Title: Frey’s procedure and islet cell function Authors: Ritesh Kumar1, Jaya Prakash Sahoo1, Biju Pottakat2, Sadishkumar Kamalanathan1, Pazhanivel Mohan3, Vikram Kate4, Sitanshu Sekhar Kar5, Jayakumar Selviambigapathy1
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(Kumar R, Sahoo JP, Pottakat B, Kamalanathan S, Mohan P, Kate V, Kar SS, Selviambigapathy J)
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Received 24 November 2017
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Author Affiliations:
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Accepted 4 June 2018
1. Department of Endocrinology & Metabolism, Jawaharlal Institute of Postgraduate
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Medical Education and Research (JIPMER), Pondicherry 605006, India
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2. Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India
3. Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India 4. Department of Surgery, Jawaharlal Institute of Postgraduate Medical Education and
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Research (JIPMER), Pondicherry 605006, India 5. Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India
Nagar, Pondicherry 605009, India (Email: [email protected])
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Corresponding Author: Dr. Jaya Prakash Sahoo, MD, DM, House No-28, Lane -B, VVP
Contributors: SJP, PB, KS and SJ designed the study and revised it critically for important
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intellectual content. KR acquired the data and drafted the work. MP, KV and KSS analyzed the data and revised it critically for important intellectual content. All authors approved the final version of the manuscript. SJP is the guarantor.
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Funding: This study was supported by Intramural research grant from Jawaharlal Institute of
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Postgraduate Medical Education and Research (JIPMER) (JIP/Res/Intra-DM-M.Ch/02/2014). Ethical approval: The study protocol was approved by the Institute Ethics Committee and
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written informed consent was obtained from all participants before enrolment in the study. The
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study was conducted based on the principles outlined in the Declaration of Helsinki. Competing interest: No benefits in any form have been received or will be received from a
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commercial party related directly or indirectly to the subject of this article.
Abstract Background: As Frey's procedure involves both drainage and resection of the pancreas in subjects with chronic calcific pancreatitis (CCP). The procedure may affect the pancreatic 2 / 20
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endocrine function after surgery. The present study was to evaluate the effect of Frey's procedure on both beta and alpha cell function in CCP patients. Methods: Thirty CCP patients who underwent Frey’s procedure were included. According to the
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glycemic status, patients were divided into the diabetes mellitus (DM), prediabetes, and normal glucose tolerance (NGT) groups. Islet cell function was assessed before and 3 months after surgery.
Results: At baseline, there was a significant difference in beta cell function among the three
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groups [NGT group 1.71 (1.64-2.07) vs prediabetes group1.50 (0.83-1.61) vs DM group 0.33 (0.12-0.55), P < 0.0001], but the insulin resistance was not different among them. Post glucose hyperglucagonemia representing alpha-cell dysfunction during oral glucose tolerance test was present in all of them, but showed no significant difference [NGT group 0.15 (0.06-0.31) vs
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prediabetes group 0.32 (0.05-0.70) vs DM group 0.07 (0.02-0.18), P = 0.20]. Frey's procedure
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did not change beta cell function and insulin resistance. However, alpha-cell dysfunction deteriorated after surgery [0.10 (0.03-0.27) vs 0.33 (0.09-0.68), P =0.004].
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Conclusions: Although Frey’s procedure does not affect the beta cell function and insulin
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resistance in CCP patients, the alpha-cell dysfunction deteriorates after surgery. Key words: Beta-cell; diabetes mellitus; glucagon; insulin secretion sensitivity index; Matsuda
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index
Introduction Chronic calcific pancreatitis (CCP) is a progressive inflammatory disease leading to 3 / 20
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destruction, fibrosis, and calcification of parenchyma [1]. There is dilatation of the main pancreatic duct due to multiple intraductal calculi and strictures. Chronic abdominal pain is the most common presentation, which deteriorates the quality of life and causes addiction to narcotic analgesics. Irreversible damage of pancreas ultimately leads to endocrine as well as exocrine
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insufficiency [1]. Another important cause of morbidity is diabetes mellitus (DM) which is brittle and insulin-dependent [1].
Chronic intractable abdominal pain is the most common indication for surgery in CCP
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patients. Increased intra-ductal pressure due to pancreatic duct obstruction and presence of an inflammatory mass in the head of the pancreas are two major contributors for pain in these subjects [1]. Different types of pancreatic surgery are available for the relief of abdomen pain. In drainage procedures, the whole pancreatic duct is decompressed and the major portion of
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pancreatic tissue is preserved. Pain relief is seen in most of the patients on short-term follow-up but these procedures fail to provide long-term relief in pain [1]. Frey's procedure includes both
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pancreatic drainage (longitudinal pancreatico-jejunostomy) and resection (coring of the head of
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the pancreas) [2]. Long-term pain relief is excellent in Frey’s procedure in comparison to simple drainage procedures.
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As Frey’s procedure involves both drainage and resection of the pancreas, it may affect pancreatic function after surgery. Various studies have observed the change in pancreatic
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exocrine function and glycaemic status following Frey’s procedure [3-11]. But only a few studies examined the effect of Frey’s procedure on islet cell function [10, 11]. The beta cell function was studied by measuring only fasting C-peptide and insulin but the alpha cell function was not evaluated. Therefore, we designed this study to evaluate the effect of Frey’s procedure on both beta and alpha cell function.
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Methods The study was conducted in Endocrinology, Surgical Gastroenterology and Medical
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Gastroenterology Departments of a tertiary care institute from February 2015 to November 2016. The study protocol was approved by the Institute Ethics Committee and written informed consent was obtained from all participants before enrolment in the study. The study was conducted based on the principles outlined in the Declaration of Helsinki.
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The patients aged between 18 to 65 years and diagnosed with CCP were included. Fortynine CCP patients were evaluated during this study period. Eleven patients were excluded: two patients had hypercalcemia, one pancreatic adenocarcinoma, one aged >65 years old, and seven
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having no indication for surgery. Additionally, eight patients did not turn up for evaluation after surgery (5 patients lost to follow-up and 3 died). Finally, 30 patients were included in the study.
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According to the glycemic status, patients were divided into the diabetes mellitus (DM, n =18), prediabetes (n =7), and normal glucose tolerance (NGT, n =5) groups. Basic demographic
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evaluation.
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characteristics were collected for all subjects. All patients underwent a detailed clinical
The diagnosis of CCP was based on clinical features (abdominal pain, diarrhea with/without
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DM) and imaging characteristics (calcifications in the pancreas or pancreatic duct on abdomen X-ray/ultrasonography/computed tomography scan). The decision for Frey's procedure was taken by the surgical gastroenterologist and it was based on persistence intractable pain in abdomen, dilated main pancreatic duct and the presence of an inflammatory mass in the head of the pancreas.
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DM was diagnosed on the basis of a 75-g oral glucose tolerance test (OGTT) and/or glycosylated hemoglobin (HbA1c) [12]. All the DM patients were on the basal-bolus regimen of insulin i.e. regular and neutral protamine Hagedorn (NPH) insulin. The last dose of regular and NPH insulin was given between 6:00 to 7:00 pm of the previous night. Morning insulin was
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withheld before OGTT. We measured the fasting, 60 and 120 minutes plasma glucose, insulin, and glucagon after giving 75 g of oral glucose. The plasma glucose, HbA1c, amylase, and erythrocyte sedimentation rate (ESR) were measured immediately in the fasting blood sample. For glucagon assay, venous blood was collected in pre-chilled ethylene diamine tetra-acetic acid
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tube, centrifuged immediately and plasma was stored at -80 0C until further analysis. For insulin assay, serum was separated and stored at -80 0C until further analysis. The area under the curve (AUC) was calculated by the linear trapezoidal method for glucagon, insulin, and glucose.
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Insulin secretion –sensitivity index -2 (ISSI-2) was used to measure the beta cell function. It was calculated as the product of (AUCinsulin/ AUCglucose) and Matsuda index. It is a validated OGTT-
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derived measure of beta cell function that is analogous to the disposition index obtained from the intravenous glucose tolerance test [13]. Alpha cell function was measured by AUCglucagon and
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[(glucagon120 –glucagon0)/ (glucose120 –glucose0)] [14, 15]. The homeostatic model assessment 2-
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insulin resistance (HOMA2-IR) & Matsuda index were calculated for hepatic insulin resistance and whole body insulin sensitivity, respectively [16,17]. Baseline investigations were done
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within one week before surgery and all the tests were repeated 3 months after the Frey’s procedure.
Plasma glucagon was measured by Quantikine enzyme-linked immunosorbent assay
(ELISA) glucagon kit (R&D Systems). Each sample was run in the same assay. The assay has <12% cross-reactivity with oxyntomodulin and no significant cross-reactivity with gastric
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inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP2), or glicentin related polypeptide. The assay has a minimum detection limit of 2.12 pg/mL. The inter-assay coefficient of variation was 5.8%-8.7% and the intra-assay coefficient of variation was 2.7%-3.6%. Serum insulin was estimated by chemiluminescence method using ADVIA
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Centaur XP Immunoassay system (Siemens Healthcare Global, New York, USA). The plasma glucose was measured by glucose oxidase method and the HbA1c was measured by Bio-Rad D10 system using a high performance liquid chromatography method.
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Statistical analysis
Statistical analysis was performed using Statistical Package for Social Sciences (SPSS, version 19.0). Kolmogorov-Smirnov test was used to verify data distribution. Continuous variables were expressed as mean ± standard deviation or median (interquartile range)
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respectively. Categorical variables were presented as the percentage. Kruskal-Wallis test was
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used to analyze the differences between the DM, prediabetes and NGT groups at baseline. MannWhitney U test was used to analyze the baseline differences between the two groups. Paired t test
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and Wilcoxon sign rank test were used to compare before and after surgery for parametric and
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nonparametric data, respectively. The P value < 0.05 was considered statistically significant.
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Results
Thirty CCP patients who underwent Frey’s procedure were included in the study. The mean
age of patients was 36.03±11.95 years and two-third of the study population was male. Sixteen patients (53%) of our subjects were alcoholic and 13 patients (43%) were smokers. The abdomen pain was present in all subjects and the median duration of abdomen pain was 3 years. The 7 / 20
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patients with exocrine insufficiency were on pancreatic enzyme replacement. The mean body mass index (BMI) of patients was 19.03±3.17 kg/m2. DM was detected only after the diagnosis of CCP. The family history of DM was present in
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4 CCP patients. However, none of the DM patients was overweight or obese. At baseline, the beta cell function (as measured by ISSI-2) was the highest in the NGT group followed by the prediabetes and DM groups [NGT group 1.71 (1.64-2.07), prediabetes group 1.50 (0.83-1.61), and DM group 0.33 (0.12-0.55), P <0.0001] (Table 1). Insulin resistance, measured by HOMA2-
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IR, was not different in all the 3 groups [NGT group 1.32 (0.84-1.67), prediabetes group 1.16 (0.69-2.5), and DM group 0.92 (0.67-1.33), P=0.39]. Similarly, there was no difference in wholebody insulin sensitivity measured by Matsuda index in all the 3 groups [NGT group 4.26 (3.1910.01), prediabetes group 4.40 (2.23-9.45), and DM group 5.7 (3.43-11.51), P=0.69]. Sixty and
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120 minutes plasma glucose were significantly elevated in comparison to fasting plasma glucose in all the 3 groups (Table 2). Post-OGTT 60 and 120 minutes plasma glucagon were also
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significantly elevated instead of suppression as compared to fasting state, suggesting the
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presence of alpha-cell dysfunction before surgery. The alpha cell function (measured by glucagon120–glucagon0)/ (glucose120 –glucose0) was not different among the 3 groups [NGT
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group 0.15 (0.06-0.31), prediabetes group 0.32 (0.05-0.70), and DM group 0.07 (0.02-0.18), P
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=0.20] (Table 1).
There was no difference in beta cell function [0.59 (0.27-1.62) vs 0.46 (0.17-1.01), P =
0.46] and glycaemic status before and 3 months after surgery in the whole study cohort (Table 3). Similarly, the beta cell function did not change in the NGT group [1.71 (1.64-2.07) vs 1.60 (0.87-1.98), P = 0.22], prediabetes group [1.50 (0.83-1.61) vs 1.11 (0.96-1.88), P = 0.73] and DM group [0.33 (0.12-0.55) vs 0.32 (0.17-0.46), P = 0.68]. HOMA2-IR and Matsuda index were 8 / 20
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also not affected by surgery. But plasma glucagon at 0, 60 and 120 minutes was significantly increased after surgery in comparison to baseline (Fig. 1). Similarly, AUCglucagon has also increased post-surgery compared to pre-surgery (89.74±48.03 vs 156.18±71.01), P<0.0001). Thus, alpha-cell dysfunction deteriorated after surgery compared to before surgery [0.10 (0.03-
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0.27) vs 0.33 (0.09-0.68), P =0.004]. The glucose profile has worsened in two patients from prediabetes to diabetes state after surgery and one of them had a family history of DM. Serum amylase [69.50 (35.5-107) vs 34 (23-68) IU/L, P =0.03] and ESR (35.23±19.63 vs 24.7±11.05
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mm/h, P =0.003) were also significantly decreased after surgery in comparison to before surgery.
Discussion
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Loss of beta cell function in chronic pancreatitis (CP) is due to fibrosis and atrophy of islet cells because of chronic inflammation [18]. The beta cell function was significantly lower in the
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DM group in comparison to both the prediabetes and NGT groups in our study. This difference
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in beta cell function was responsible for their glycemic status as there were no differences in insulin sensitivity, insulin resistance and alpha-cell dysfunction. In Mehrotra et al’s study [19],
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CCP subjects with DM had lower beta cell reserve compared to CCP-NGT patients, but there was no difference in insulin sensitivity. In a study by Cavallini et al [20], DM subjects had lower
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beta cell function compared to prediabetes and NGT patients, but CP patients with DM had more insulin resistance compared to CP subjects with NGT. Inconsistent results regarding the insulin sensitivity and insulin resistance may be possible due to heterogeneous study population, different etiology of CP, variable duration of disease, and the different method of measurement of insulin indices used in different studies.
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The plasma glucagon is normally suppressed in healthy subjects during OGTT [14]. However, in our study both 60 and 120 minutes plasma glucagon levels were significantly increased in comparison to fasting glucagon in all the three groups of CCP subjects before surgery, suggesting alpha-cell dysfunction presenting in CCP patients irrespective of their
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glycemic status. Other studies also reported similar findings in CP patients [21-23]. Lundberg et al. [21] found that both fasting as well as stimulated glucagon level were elevated after a mixed meal in nondiabetic subjects with CP in comparison to healthy controls, and they speculated that elevated glucagon in the early course of disease was due to chronic stress, inflammation and
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beta-cell dysfunction. Similarly, Kannan et al. [22] reported that pancreatic glucagon was declined to the nadir at 90 minutes in controls but paradoxically elevated at 60-120 minutes in CP subjects. They postulated that paradoxical elevated glucagon may be possible due to the
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alpha cell hyperplasia in CP patients. But inappropriate glucagon response to OGTT deteriorated with increasing glucose intolerance in CP patients [24]. The glucagon suppression was
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diminished in patients with CP and NGT, lost in CP patients and impaired glucose intolerance, and paradoxically reversed to a positive glucagon response in patients with CP and DM.
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Furthermore, the CP patients had a normal or near-normal ability to suppress glucagon in
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response to intravenous glucose tolerance test irrespective of their glycemic status, indicating the role of incretins in inappropriate glucagon response to orally administered glucose. Thus, in CP
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subjects, the non-suppression of glucagon following OGTT could be the result of a balance between stimulatory factors (GIP and GLP-2) and inhibitory factors (GLP-1 and insulin) acting upon the alpha cells; with the former outweighing the latter. The decreased digestion and absorption of nutrients in the small intestine due to exocrine pancreatic insufficiency is probably responsible for altered secretion of incretins in CCP subjects [25-27].
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In our study, the beta cell function evaluated by ISSI-2 did not change 3 months postoperation in comparison to pre-operation in the total study population. Only two studies prospectively studied the effect of Frey's procedure on beta cell function [10, 11]. Izbicki et al [10] reported that fasting insulin and C-peptide levels were normal in 55% of patients before
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Frey’s procedure compared to 41% after 1.5 years of follow-up, but did not mention whether this change in beta cell function was statistically significant or not. One of their patients with NGT became prediabetes after surgery. Similarly, there was no change in fasting C-peptide level 2 years after Frey’s procedure in 31 CP patients in another study. But two of their subjects with
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NGT became prediabetes during the follow-up [11]. In our study, two prediabetes subjects became diabetic after surgery. After Frey’s procedure, the incidence of new onset of diabetes in subjects with CP varies from 7%-36% in different studies [2-9]. This wide variation in the
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incidence of new onset of diabetes is possibly due to heterogeneous baseline characteristics like duration of symptoms, stage of disease, presence or absence of pancreatic calcification, history
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of alcohol intake and variable duration of follow-up [28, 29].
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The alpha-cell dysfunction was deteriorated without a change in insulin sensitivity and beta cell function in this study. This suggests that new onset of DM after surgery might be due to the
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deterioration in alpha-cell dysfunction leading to further rise in plasma glucagon level. This has clinical implications for management of CCP patients with DM. The glucose lowering agents
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inhibiting glucagon secretion in addition to stimulating insulin secretion might be helpful [30]. However, antidiabetic drugs stimulating insulin secretion and inhibiting glucagon secretion like GLP-1 analogues and dipeptidyl peptidase-4 inhibitor are contraindicated in patients with pancreatitis. Pramlintide, which inhibits postprandial glucagon secretion, can be used in these subjects in addition to beta cell secretagogues (sulfonylureas and meglitinides) or insulin for
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glycemic control. In the future, glucagon receptor antagonists may be another strategy to prevent deterioration of plasma glucose following Frey’s procedure [31]. Both ESR and amylase decreased after surgery without any change in beta cell function
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almost ruled out the role of inflammation and beta-cell dysfunction in worsening postoperative hyperglucagonemia in our subjects. But the post-surgery alteration in gastrointestinal hormones levels can explain the deterioration in alpha cell function in this study. Glucose stimulates pancreatic polypeptide (PP) secretion and PP inhibits glucagon release through the pancreatic
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polypeptide receptor (PPYR1) present on alpha cells [32]. The serum PP level is decreased in CP patients compared to healthy controls [33]. It is further decreased following Frey’s procedure as cells secreting PP are mainly located at the head of the pancreas [20, 33, 34]. But the alpha cells escaped as they are present mainly in the tail of the pancreas [34]. Therefore, the post-surgery
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decrease in PP levels can lead to increased glucagon level by stimulating alpha cells in these patients. However, the contribution of postoperative alteration in incretins to the deterioration of
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alpha-cell dysfunction can not be ruled out in our patients. Both GIP and GLP-2 stimulate
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glucagon secretion from alpha cells whereas GLP-1 inhibits glucagon secretion [24]. The secretion of incretin hormones is regulated by both the rate of delivery and assimilation of
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nutrients in the small intestine [25-27]. These are altered due to changes in gastrointestinal motility and pancreatic exocrine function after surgery [35]. The incretins (GLP-1, GLP-2 and
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GIP) and PP should be measured before and after surgery to find the mechanisms of alpha-cells dysfunction after Frey's operation in future studies. The strength of our study is the assessment of the beta cell function by ISSI-2, which is a validated OGTT-derived measure of beta cell function. We also assessed alpha cell function and insulin sensitivity indices, which has not been reported with Frey’s procedure in the literature. 12 / 20
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There were few limitations in our studies. First, the healthy controls were not included in the study. Second, the etiology work up for CCP was incomplete in our patients. Third, the postsurgery follow-up was only for 3 months.
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To conclude, Frey's procedure did not affect the beta cell function and insulin resistance in
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CCP patients. But there was a deterioration in alpha-cell dysfunction after surgery.
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Bachmann K, Kutup A, Mann O, Yekebas E, Izbicki JR. Surgical treatment in chronic
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pancreatitis timing and type of procedure. Best Pract Res Clin Gastroenterol 2010;24:299310.
Frey CF, Amikura K. Local resection of the head of the pancreas combined with
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Table 1. The baseline characteristics of study subjects DM group (1) (n=18)
Prediabetes group (2) (n=7)
NGT group (3) (n=5)
P value (1 vs 2 vs 3)
P value (1 vs 2)
P value (2 vs 3)
P value (1 vs 3)
Age (yr)
36.50 (32.70-44.00)
42.00 (18.00-49.00)
28.00 (18.00-37.50)
0.21
0.95
0.21
0.07
BMI (kg/m2)
19.39 (16.46-21.19)
19.15 (17.30-20.68)
18.80 (17.48-23.78)
0.58
0.76
0.68
0.60
HOMA2-IR
0.92 (0.67-1.33)
1.16 (0.69-2.50)
1.32 (0.84-1.67)
Matsuda index
5.70 (3.43-11.51)
4.40 (2.23-9.45)
4.26 (3.19-10.01)
ISSI-2
0.33 (0.12-0.55)
1.50 (0.83-1.61)
1.71 (1.64-2.07)
(Glucagon120 –glucagon0)/ (glucose120 –glucose0 )
0.07 (0.02-0.18)
0.32 (0.05-0.70)
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Parameters
0.30
0.83
0.28
0.69
0.43
0.81
0.50
<0.0001
<0.0001
0.019
0.001
0.14
0.57
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0.39
0.15 (0.06-0.31)
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BMI: body mass index; HOMA2-IR: homeostatic model assessment 2- insulin resistance; ISSI-2: insulin
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Table 2. The trend of plasma glucose and glucagon level during oral glucose tolerance test before surgery
DM group (n=18)
Fasting plasma glucose (mg/dL)
123 (101-213)
60 minute Plasma glucose (mg/dL)
P value
P value
Reference
Prediabetes group (n=7) 96 (92-101)
P value
Reference
NGT group (n=5) 90 (80-91)
268 (248-406)
<0.0001
171 (151-195)
0.001
152 (134-179)
0.005
120 minute plasma glucose (mg/dL)
327 (265-483)
<0.0001
150 (115-173)
0.01
130 (120-131)
0.002
Fasting plasma glucagon (pg/mL)
21.8 (12.1-32.0)
Reference
30.2 (15.354.4)
Reference
12.5 (5.833.01)
Reference
60 minute plasma glucagon (pg/mL)
55.6 (34.2-80.4)
<0.0001
64.3 (34.4102.8)
0.01
24.2 (13.841.9)
0.04
120 minute plasma glucagon (pg/mL)
34.8 (25.9-82.4)
0.002
54.2 (28.868.5)
0.03
18.2 (13.638.7)
0.04
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Parameters
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Table 3. Effect of surgery on endocrine function of pancreas in the whole study population Before surgery (n=30)
After surgery (n=30)
P value
Body weight (kg)
48.91±10.00
47.42±9.70
0.06
HbA1c (%)
6.95(5.80-9.90)
7.25 (5.70-10.35)
0.88
HOMA2-IR
1.12 (0.68-1.45)
0.95 (0.75-1.74)
0.54
Matsuda index
4.96 (3.43-9.75)
5.49 (3.87-8.82)
0.56
ISSI-2
0.59 (0.27-1.62)
0.46 (0.17-1.01)
0.46
Fasting plasma glucagon (pg/mL)
26.06±16.81
43.69±22.10
<0.0001
Plasma glucagon at 60 min (pg/mL)
54.06 ±29.51
89.73±44.24
<0.0001
Plasma glucagonat 120 min (pg/mL)
34.89 (21.22-67.33)
75.00 (57.58-110.8)
<0.0001
AUC-glucagon
89.74±48.03
156.18±71.01
<0.0001
(glucagon120–glucagon0)/(glucose120–glucose0 )
0.10 (0.03-0.27)
0.33 (0.09-0.68)
0.004
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Parameters
HbA1c: glycosylated hemoglobin; HOMA2-IR: homeostatic model assessment 2- insulin
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resistance; ISSI-2: Insulin secretion –sensitivity index -2; AUC: area under curve.
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Figure legend
Fig. 1. The plasma glucagon level during oral glucose tolerance test (OGTT) at baseline and 3
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months after surgery. *: P value <0.0001.
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