J Endocrinol Invest (2014) 37:449–454 DOI 10.1007/s40618-013-0040-y
ORIGINAL ARTICLE
Pantoprazole may improve beta cell function and diabetes mellitus F. Inci • M. Atmaca • M. Ozturk • S. Yildiz • R. Koceroglu • R. Sekeroglu • S. H. Ipekci • L. Kebapcilar
Received: 27 October 2013 / Accepted: 6 December 2013 / Published online: 9 January 2014 Ó Italian Society of Endocrinology (SIE) 2013
Abstract Background Proton pump inhibitors induce hypergastrinemia by suppressing gastric acidity. Gastrin has incretin-like stimulating actions on beta cells. Proton pump inhibitors have been shown to decrease glycosylated hemoglobin. Aim We aimed to observe changes in beta cell function in diabetic and non-diabetic subjects given pantoprazole for an acid-related ailment. Methods Seventy-nine male patients (38 non-diabetic and 41 type-2 diabetic receiving only metformin therapy) were followed for 12 weeks after pantoprazole 40 mg/day was given. Fasting plasma glucose, HbA1c, fasting insulin, Pancreatic B cell function (HOMA-B), proinsulin and c-peptide levels were measured before and after the treatment. Results In non-diabetic patients (n = 38), FPG decreased, whereas c-peptide, log-HOMA-B, increased significantly
F. Inci Department of Internal Medicine, University of Yuzuncu Yil, Van, Turkey M. Atmaca M. Ozturk S. Yildiz Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Yuzuncu Yil, Van, Turkey R. Koceroglu R. Sekeroglu Department of Biochemistry, University of Yuzuncu Yil, Van, Turkey S. H. Ipekci L. Kebapcilar Division of Endocrinology and Metabolism, Department of Internal Medicine, Selcuk University, Konya, Turkey L. Kebapcilar (&) Department of Endocrinology and Metabolism, Faculty of Medicine, Selcuk University, Konya, Turkey e-mail:
[email protected]
(p = 0.002, p = 0.03, p = 0.042, respectively) after 12 weeks of pantoprazole administration. In type 2 diabetic patients, FPG, HbA1c and weight decreased, whereas logHOMA-B, c-peptide and log-proinsulin levels increased significantly after pantoprazole treatment (p = 0.003, p = 0.007, p \ 0.001; p \ 0.001; p = 0.017, p = 0.05, respectively). After pantoprazole treatment, pancreatic B-cell function was correlated with c-peptide and insulin and inversely with FBG and HbA1c levels in the whole group (r = 0.37, p = 0.001; r = 0.60, p \ 0.001, r = -0.29, p = 0.011 and r = -0.28, p = 0.013, respectively). After pantoprazole treatment, HbA1c was correlated with FBG (r = 0.75, p \ 0.001) and inversely with only log-HOMA-B level (r = -0.28, p = 0.013). Conclusions Pantoprazole administration seems to correlate with increased beta cell function. Pantoprazole administration improves HbA1c, HOMA-B, c-peptide and proinsulin levels. Since beta cell loss plays a significant role in the pathogenesis of type 2 diabetes, PPI-based therapies may be useful in the treatment of diabetes. Keywords Diabetes mellitus Pantoprazole HOMA-B C-peptide Insulin Proinsulin
Introduction Beta cell loss and dysfunction play important roles in the pathogenesis of both type I and type II diabetes. However, none of the currently available agents are known to increase beta-cell population in humans, except GLP-1 agonists. Incretin-based therapies aim not only at promoting beta cell function, but also at decreasing apoptosis and increasing regeneration of beta cells. Beta cell turnover is affected by many factors including gastrointestinal
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hormones, like glucose-mimetic insulinotropic peptide (GIP), glucagon like peptide-1 (GLP-1), gastrin and cholecystokinin [1, 2]. Proton pump inhibitors are effective suppressors of gastric acid secretion. They have been commercially available for more than two decades and have been widely used in treating peptic disorders with minimal side effects and a very favorable tolerance. They increase gastrin secretion by suppression of acidity [3]. Gastrin, on the other hand, may act like an incretin, promoting beta cell differentiation [1, 4]. This could potentially affect beta cell mass and function and thereby improve glycemic control. Indeed, a recent study and a case report found that patients with type 2 diabetes that were using PPIs on average had lower HbA1c levels than patients not taking PPIs [5–8]. To date, there is little information about how exactly proton pump inhibitors improve glycemic control. Based on the hypothesis that PPIs might improve glycemic control, the aim of the current study was to prospectively analyze whether treatment with the pantoprazole, 40 mg, improved measures of beta cell function such as HOMA-B, fasting plasma glucose, HbA1c, fasting insulin, fasting proinsulin and c-peptide levels in normal and type-2 diabetic patients with hyperacidity related conditions
Materials and methods Written informed consent was obtained from each subject, and research protocols were approved by the Ethical Committee of our institution. The patients were selected among those who presented to our out-patient clinics with hyperacidity-related conditions in gastroesophageal reflux disease and who had no infection with H. pylori based on the 14C urea breath test. These subjects were prescribed pantoprazole, 40 mg daily, for 3 months.
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(7.0 mmol/L). Diabetic patients (n = 41) who required only metformin treatment were included in the study. The control subjects and diabetic cohort were considered to be H. pylori negative if rapid urease test was negative. Thirty eight healthy subjects were included in the study that had come for only gastroesophageal reflux disease and had no other complaints. The body weight was recorded before and after 12 weeks of pantoprazole, 40 mg daily, as were fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), insulin, c-peptide, HOMA-B and proinsulin Plasma glucose was measured by the glucose oxidase method. HbA1c was measured by HPLC, hormones were assayed with commercial kits using an Abbott Architect I4000 immunometric analyzer and insulin by electrochemiluminescence (COBAS 6000 analyzer; Roche, Basel, Switzerland). C-peptide levels were measured with the automated immunochemiluminometric method, ADVIA Centaur (Bayer Diagnostics). The smallest detectable level is 0.02 nmol/l (0.05 ng/ml, to convert C-peptide values from nmol/l to ng/ml, multiply by 3). The inter- and intraassay CV are 8.3 and 3.7 %, respectively. The normal range for fasting C-peptide levels is 0.26–0.63 nmol/l (0.78–1.89 ng/ml). There is no significant cross-reaction with proinsulin. Proinsulin was measured using the Human Proinsulin RIA kit, provided by Linco Research (St Charles, MO, USA). It yields no significant cross-reactivity with insulin (\0.1 %) or C-peptide (\0.1 %). The interand intra-assay CV are 7.7 and 6.9 %, respectively. Fasting insulin levels were determined by a chemiluminescent method utilizing an automatic immunoanalyzer (Roche Diagnostics, Mannheim, Germany). The intra- and interassay coefficients of variation for insulin were 4 and 3.5 %, respectively. The smallest detectable level is 2 pmol/L. Beta cell function was estimated using HOMA-Beta (360 9 [Insulin]/([Glucose] - 63) % (Glucose in mg/dl) [9].
Exclusion criteria for diabetic and non-diabetic patients Statistical analysis Patients with malignancies, osteoporosis, systemic or local infection, hepatic or renal disease (creatinine levels [2.0 mg/dl), patients receiving systemic glucocorticoids or immunosuppressants using supplemental vitamins, statins, antibiotics or those who smoked or used alcohol in the 12 weeks prior to the study were excluded from participation. Patients treated with bismuth salts, H2 receptor blockers or proton pump inhibitors in the preceding 3 months were also excluded. Among the available PPI’s, pantoprazole exhibits a relatively higher degree of safety, possibly because of its complete hepatic metabolism and minimal potential for drug–drug interactions. Diabetes was considered present if a patient was treated with metformin or had a fasting glucose level C126 mg/dL
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The results are presented as mean ± SD. The Kolmogorov– Smirnov test was used to determine whether continuous variables were normally distributed. According to the KS test, except HOMA-B and proinsulin levels, all variables including age, fasting plasma glucose, HbA1c and fasting insulin levels showed a normal distribution. HOMA-B and proinsulin were not normally distributed, and these (HOMA-B, and proinsulin) skewed data were log transformed for analysis. The Student’s t test was used for the comparison of continuous variables. A paired sample t test was used for the comparison of treatment effects on variables and the Pearson test was used for the evaluation of correlations among the variables. The relation between PPI
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and HbA1c was assessed using logistic regression analysis that adjusted for weight. The statistical analysis was carried out using Statistical Package for Social Sciences (SPSS), version 13.0 (SPSS Inc., Chicago, IL). A p value of \0.05 was considered to be statistically significant.
Results One hundred nine patients with gastroesophageal reflux disease or hyperacidity were screened between February 2012 and March 2013, and 79 eligible male subjects were included in the present study. This group consisted of 38 non-diabetics and 41 diagnosed type-2 diabetics who either had a fasting plasma glucose C126 mg/dl or were taking the oral anti-diabetic medication, metformin. The type 2 diabetic patients had the mean disease duration for 8.2 ± 3.7 years. The mean age of the patients was 47.9 ± 17 (18–73) years. Fasting plasma glucose, HbA1C, fasting insulin, pancreatic beta-cell function (HOMA-B), proinsulin and c-peptide levels as well as weight were measured before and after treatment in both diabetic and non-diabetic patients. In non-diabetic patients (n = 38), FPG decreased; c-peptide and HOMA-B levels increased significantly after pantoprazole medication (Table 1; Fig. 1, p = 0.002, p = 0.03, p = 0.042, respectively). Fasting plasma glucose, HbA1c, fasting insulin, Pancreatic B-cell function (HOMA-B), proinsulin and c-peptide levels were measured before and after the treatment in diabetic patients. Diabetic patients had better glycemic control after 12 weeks of pantoprazole treatment (Table 2). After 12 weeks of pantoprazole therapy, there was a significant decrease in the FPG, HbA1c (Fig. 1) and weight (p = 0.003, p = 0.007, p \ 0.001, respectively), whereas log-HOMA-B, log-proinsulin and c-peptide levels increased (p \ 0.001, p = 0.05, p = 0.017, respectively) in the diabetic patients. Changes in HbA1c for each diabetic patient before and after treatment with pantoprazole are shown in Fig. 2. Similar results are seen when the entire group is considered (diabetics ? non-diabetics). Pantoprazole therapy increased log-HOMA-B (1.76 ? 0.39 before, vs. 1.95 ? 0.46 after, p \ 0.001). Pantoprazole therapy increased c-peptide and insulin levels (p = 0.001, p = 0.037, respectively), whereas HbA1c and FBG levels were decreased in the whole group (p = 0.005, p \ 0.001, respectively). After pantoprazole treatment, pancreatic B-cell function was correlated with c-peptide and insulin and inversely with FBG and HbA1c levels in whole group (r = 0.37, p = 0.001; r = 0.60, p \ 0.001, r = -0.29, p = 0.011 and r = -0.28, p = 0.013, respectively). After
451 Table 1 The effect of Pantoprazole Treatment on b-cell function in cases with non-diabetic patients Parameter
Pre treatment mean ± SD
Post-treatment mean ± SD
p
Weight (kg)
71.18 ± 10.71
71.55 ± 11.04
0.1
Fasting plasma glucose (mg/dl)
95.61 ± 12.75
88.47 ± 12.37
0.002
C-peptide (ng/ml)
2.30 ± 1.69
2.92 ± 2.50
0.03
HbA1c (%)
5.00 ± 0.68
4.97 ± 0.71
0.4
Insulin (lU/ml)
8.70 ± 8.52
10.08 ± 13.28
0.3
Log-proinsulin (pmol/L)
0.95 ± 0.46
1.03 ± 0.43
0.4
Log-HOMA beta
1.89 ± 0.29
2.02 ± 0.45
0.042
Fig. 1 Pantoprazole therapy increases HOMA-B index and decreases HbA1c levels
pantoprazole treatment, HbA1c was correlated with FBG (r = 0.75, p \ 0.001) and inversely with only log-HOMAB (Fig. 3; r = -0.54, p \ 0.001) in the diabetic group. The relation between PPI medication and HbA1c was assessed using logistic regression analysis that adjusted for weight in the diabetic group.(weight-adjusted: OR 1.68, 95 % CI 1.06–2.31, p \ 0.001).
Discussion This study was designed to extract information on the effects of pantoprazole administration in both normal controls and type-2 diabetics on islet cell activity, insulin secretion and diabetes control. Multiple lines of evidence
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Table 2 The effect of Pantoprazole Treatment on b-cell function in cases with diabetic patients Parameter Weight (kg) Fasting plasma glucose (mg/dl)
Pre treatment mean ± SD
Post-treatment mean ± SD
p
75.0 ± 13.1
74.0 ± 13.2
\0.001
144.2 ± 59.1
124.0 ± 41.2
0.003
C-peptide (ng/ml)
2.7 ± 2.5
3.7 ± 4.3
0.017
HbA1c (%)
7.2 ± .1.3
6.8 ± 1.0
0.007
Insulin (lU/ml)
11.0 ± 9.0
16.4 ± 22.5
0.06
Log-proinsulin (pmol/L)
0.86 ± 0.3
0.93 ± 0.3
0.05
Log-HOMA beta
1.64 ± 0.43
1.88 ± 0.47
\0.001
Fig. 3 After pantoprazole treatment, HbA1c was inversely correlated with log-HOMA-B in diabetic group
Fig. 2 Alterations in HbA1c levels in diabetic subjects after PPI treatment
suggest that proton pump inhibitors may improve beta cell function and diabetes mellitus. We report results from a paired cohort of 41 patients with type 2 diabetes and 38 non-diabetic subjects who received 12 weeks of pantoprazole therapy and were evaluated for effects on glycemic control and beta-cell function and investigated improvements in both groups. PPI therapy was associated with significantly lower levels of HbA1c in patients with type-2 diabetics who were taking only metformin. The reduction of HbA1c in those diabetics after taking pantoprazole for 12 weeks was 0.6 % and was statistically significant. In the diabetic group, weight, FPG and HbA1c levels decreased significantly while pancreatic beta cell function
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(HOMA-B), proinsulin and c-peptide levels increased significantly after pantoprazole treatment. Further, there was a negative relationship between HbA1c and log-HOMA-B after pantoprazole treatment. There is a gradual deterioration in b-cell function in patients with type 2 diabetes. Type 2 diabetes is a progressive disease characterized by both insulin resistance and increasing dysfunction of pancreatic beta cells, either through inactivation or apoptosis. At diagnosis, islet function may be reduced by up to 50 % compared with healthy control subjects, and there is also likely to be a reduction in b-cell mass of up to 60 %. The reduction in bcell mass is due to accelerated apoptosis [9]. A survey of the literature failed to show any publication detailing an effect or relationship of PPI administration on proinsulin levels, c-peptide levels or pancreatic beta cell function in subjects receiving medication for type 2 diabetes mellitus. A variety of lines of evidence suggest a role for gastrin in the regulation of pancreatic beta cell function [1, 6–8]. Gastrin is a cousin of incretin hormones since they are both gastrointestinal peptides, so PPIs could lower glycemia by a mechanism similar to incretin-based therapies [1, 6–8]. In fact, it is known that PPIs slow gastric emptying [10, 11] which could decrease postprandrial hyperglycemic excursions, as glucagon-like peptide 1 does. Glucagon-like peptide (GLP)-1, has a number of protective effects on the b-cells, including a reduction in apoptosis and enhancement of b-cell proliferation and neogenesis. These effects are impaired to a significant extent in patients with diabetes. GLP-1 has been shown to stimulate ductal cells to transform into islet cells. They also stimulate betacell regeneration within the islets [2]. Since beta cell loss plays a significant role in the pathogenesis of type 2
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diabetes, PPI-based therapies may offer a new approach in the treatment of diabetes In healthy humans, acute administration of gastrin to achieve supraphysiological levels leads to a modest release of insulin under basal glucose conditions and a more pronounced potentiation of insulin release when co-administered with glucose [12, 13], evidence supporting an incretin-like role for gastrin. In pancreatic duct-ligated rat model of diabetes iv-infused gastrin enhanced beta-cell neogenesis and insulin secretion, resulting in improved blood glucose control [1]. Also a study treating diabetic Psammomys obesus with the PPI lansoprazole showed significant improvement of glycaemic control, as well as increased beta cell mass and beta cell insulin content [14]. Like glucagon-like peptide-1, gastrin has also been shown to induce b-cell proliferation and neogenesis in various model systems and also appears to increase the insulin content of individual b-cells. This was substantiated by Meier et al. [12] who showed increased beta-cell replication adjacent to human pancreatic gastrinomas, suggesting a possible correlation between gastrin and beta cell proliferation. Like GLP-1 effects, 12 weeks of pantoprazole therapy significantly increased the Pancreatic B-cell function (HOMA-Beta) by 16.2 % in whole diabetic group in our study. Furthermore, after pantoprazole treatment, pancreatic B-cell function was correlated with an increase in proinsulin, c-peptide and insulin levels, whereas negatively with HbA1c levels in whole group. HbA1c is considered the best parameter for evaluating the glycemic control and assessing the efficacy of antidiabetic medications. PPIs were shown to decrease HbA1c [6–8]. In our study, pantoprazole treatment decreased HbA1c in type 2 diabetics after 12 weeks. Mefford and Wade reports as firstly the hypothesis [5] and observed report to be continued in a retrospective analysis of two separate databases, a significant improvement in type 2 diabetes concurrently taking proton pump inhibitors (PPIs) [6]. Singh et al. showed improved betacell function and HbA1c levels in their randomized clinical trial. Twelve weeks of pantoprazole therapy significantly increased the fasting plasma gastrin, HOMA B, insulin levels and reduced HbA1c. Our reduction is in concordance with the earlier reports where it was 0.5–0.7 % with PPIs [6–8]. However, all these reports have their inherent limitations such as retrospective design [7], relatively smaller sample size [8] and absence of a nondiabetic control group [8]. In the present cohort study consisting of diabetic and non-diabetic control groups, we emphasize new information of the effects of PPI treatment on proinsulin and c-peptide level. These parameters have been shown to be useful tools for the assessment of beta-cell function in diabetic patients and were enhanced following PPI treatment.
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Despite the short treatment period, the effects of PPI treatment in our study groups were significant. After PPI treatment, log-HOMA-beta was negatively correlated with HbA1c levels in diabetic group. The effect of pantoprazole on HbA1c levels may be due to the incretin-like effect of gastrin because gastrointestinal peptides stimulate beta-cell insulin secretion and/or proliferation, resulting in enhanced glucose-dependent insulin release [15]. Preclinical studies have shown that PPI administration can induce beta-cell neogenesis and improve diabetes control in an animal model of type 2 diabetes. In rodents, gastrin induces islet bcell neogenesis [16, 17] and in in vitro studies, this hormone increases the b-cells mass. Proinsulin is a stable precursor of insulin, the hormone modulating blood glucose. Inside the pancreatic b-cell, proinsulin is synthesized and then transformed into mature insulin, ready to be released into the blood-stream, mainly under glucose stimulation. However, not all of the proinsulin becomes insulin, and a low percentage of the secretion product still contains proinsulin-like molecules [18]. In terms of blood concentration, proinsulin accounts for 10–20 % of normal fasting insulin, but it may reach values as high as 50 % in type 2 diabetes, leading to the hypothesis that conversion from proinsulin to insulin is impaired in this disease [19]. Our findings confirm the increased fasting log-proinsulin levels observed in T2DM and yielding a significantly increased log-proinsulin level in diabetic group. Like GLP-1 [20], gastrin may stimulate proinsulin biosynthesis. The increase of insulin levels were not significant but c-peptide levels increased more robustly. Insulin is metabolized in the liver and hence changes in hepatic insulin metabolism directly affect insulin levels [21]. Knowing that insulin secretion at the b-cell level is better described by C-peptide, increased C-peptide levels suggest that the increase in insulin levels was related to increased secretion, and not to a reduction in insulin clearance. In the current treatment of diabetes, attention is focused increasingly on promoting beta cell survival and function. It is well known that insulin and C-peptide are released from the B cells in equimolar amounts. Therefore, C-peptide levels give an estimate of the endogenous insulin secretion. Serum C-peptide levels increased in the diabetic group after a 12-week PPI treatment. We show in the present study that pantoprazole can effectively decrease fasting plasma glucose, HbA1c and improve beta cell function. The findings, especially in light of the relatively good control noted in the diabetic population (mean HbA1c of 7.2 %), suggest that proton pump inhibitors may represent an alternative medication for the management of type-2 diabetes. It is also relevant that the observations are confirmed to some degree in the control population, showing that the effect of the PPI on pancreatic beta cells is
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general, increasing HOMA and c-peptide in each group. Well-controlled studies on this subject are needed to further elucidate this effect. PPIs may be a useful adjunctive therapy for type 2 diabetes. Clinical trials are warranted to further investigate this possibility. Acknowledgments grant.
This work was not supported by any specific
Conflict of interest F. Inci, M. Atmaca, M. Ozturk, S. Yildiz, R. Koceroglu, R. Sekeroglu, S. H. Ipekci, L. Kebapcilar declare they have no conflict of interest.
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