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Hejazi N, Ghalandari H, Rahmanian R, Haghpanah F, Makhtoomi M, Asadi A, Askarpour M. Effects of probiotics supplementation on glycemic profile in adults with type 2 diabetes mellitus: A grade-assessed systematic review and dose-response meta-analysis of randomized controlled trials. Clin Nutr ESPEN 2024; 64:133-143. [PMID: 39349104 DOI: 10.1016/j.clnesp.2024.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 08/12/2024] [Accepted: 09/23/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND Disturbed glycemia and the resulting type 2 diabetes (T2D) are significant health concerns. Various approaches have been examined to improve glycemic control in patients with T2D. Modification of gut microbiome via administering probiotics has been extensively studied. The present study aims to sum up the existing literature which investigated the effect of probiotics on glycemic indices in individuals with T2D in the format of randomized controlled trials (RCTs). METHODS Online medical databases (PubMed, Scopus, and Web of Science) were searched from inception to January 2024. Eligible studies were included using pre-defined inclusion and exclusion criteria. Outcome variables included fasting blood sugar (FBS), insulin, hemoglobin A1c (HbA1c), and homeostatic model of insulin resistance (HOMA-IR). Weighted mean differences (WMDs) were estimated. Subgroup and dose-response analyses were conducted. P-values <0.05 were considered as statistically significant. RESULTS Out of 5636 records retrieved by the initial search, thirty-two RCTs were included in the final analyses. Supplementation with probiotics was observed to significantly improve indices of glycemic control; including FBS (WMD: -13.27 mg/dl; 95 % CI: -18.31, -8.22), HbA1c (WMD: -0.44 %; 95 % CI: -0.59, -0.28), insulin (WMD: -1.33 μIU/ml; 95 % CI: -2.57, -0.08), and HOMA-IR (WMD: -0.95; 95 % CI: -1.71, -0.18). Dose-response analysis revealed that increased duration of intervention results in a larger reduction only in FBS. CONCLUSION Supplementation with probiotics seems to improve indices of glycemic control. Nonetheless, taken into account the notable heterogeneity (with regard to dosage, duration, and the species/strains used) between the included studies and low quality of evidence, caution must be considered, especially when long-term clinical implications are intended.
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Affiliation(s)
- Najmeh Hejazi
- Department of Clinical Nutrition, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamid Ghalandari
- Students' Research Committee, School of Nutrition and Food Science, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Community Nutrition, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Raha Rahmanian
- Department of Clinical Nutrition, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran; Students' Research Committee, School of Nutrition and Food Science, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Haghpanah
- Department of Clinical Nutrition, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran; Students' Research Committee, School of Nutrition and Food Science, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maede Makhtoomi
- Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Students' Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirhossein Asadi
- Students' Research Committee, School of Nutrition and Food Science, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Moein Askarpour
- Department of Clinical Nutrition, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran; Students' Research Committee, School of Nutrition and Food Science, Shiraz University of Medical Sciences, Shiraz, Iran.
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Peng CCH, Tu YK, Lee GY, Chang RHE, Huang Y, Bukhari K, Tsai YC, Fu Y, Huang HK, Munir KM. Effects of Proton Pump Inhibitors on Glycemic Control and Incident Diabetes: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab 2021; 106:3354-3366. [PMID: 34170301 DOI: 10.1210/clinem/dgab353] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Indexed: 12/22/2022]
Abstract
CONTEXT Whether proton pump inhibitors (PPI) can improve glycemic control among individuals with diabetes or decrease the risk of incident diabetes in the general population is unclear. OBJECTIVE To evaluate the impact of PPI therapy on glycemic control among individuals with diabetes and the risk of diabetes among those without diabetes. RESULTS PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to November 21, 2020. We included studies comparing glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG) among individuals with diabetes treated with and without PPI therapy as an add-on to standard therapy. Studies evaluating the risk of incident diabetes among individuals taking PPI were assessed. We performed dual independent review, data extraction, and quality assessment. Weighted mean differences between groups or relative risks were imputed using random-effects models. RESULTS Seven studies (n = 342) for glycemic control and 5 studies (n = 244 439) for risk of incident diabetes were included. Compared with standard therapy, add-on PPI was associated with a significant decrease in HbA1c (WMD, -0.36 %; 95% CI, -0.68 to -0.05; P = 0.025) and FBG (WMD, -10.0 mg/dL; 95% CI, -19.4 to -0.6; P = 0.037). PPI use did not reduce the risk of incident diabetes (pooled RR, 1.10; 95% CI, 0.89 to 1.34; P = 0.385). CONCLUSION Add-on PPI improved glycemic indices among individuals with diabetes but did not alter the risk of incident diabetes. The effects of PPI on glycemic control should be considered when prescribing antacids to patients with diabetes.
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Affiliation(s)
- Carol Chiung-Hui Peng
- Department of Internal Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MarylandUSA
| | - Yu-Kang Tu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, TaipeiTaiwan
- Department of Dentistry, National Taiwan University Hospital and School of Dentistry, National Taiwan University, TaipeiTaiwan
- Research Center of Big Data and Meta-analysis, Wan Fang Hospital, Taipei Medical University, TaipeiTaiwan
| | - Gin Yi Lee
- Department of Medicine, Danbury Hospital, Danbury, ConnecticutUSA
| | | | - Yuting Huang
- Department of Internal Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MarylandUSA
| | - Khulood Bukhari
- Department of Internal Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MarylandUSA
| | - Yao-Chou Tsai
- Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, TaipeiTaiwan
- Department of Urology, Taipei Medical University Hospital, Taipei Medical University, TaipeiTaiwan
| | - Yunting Fu
- Health Sciences and Human Services Library, University of Maryland, Baltimore, MDUSA
| | - Huei-Kai Huang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, TaipeiTaiwan
- Departments of Family Medicine and Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, HualienTaiwan
| | - Kashif M Munir
- Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MarylandUSA
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Gastrin and the Moderate Hypergastrinemias. Int J Mol Sci 2021; 22:ijms22136977. [PMID: 34209478 PMCID: PMC8269006 DOI: 10.3390/ijms22136977] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
The antral hormone gastrin potently regulates gastric acid secretion and fundic mucosal growth. Consequently, appropriate gastrin secretion and plasma concentrations are important for the early phases of digestion. This review describes as the first premise the normal biogenesis of gastrin in the antral mucosa, but also mentions the extraantral expression. Subsequently, the molecular nature and concentration levels of gastrin in serum or plasma are overviewed. Third, assays for accurate measurements of plasma or serum concentrations are commented. Finally, the problem of moderate hypergastrinemia due to Helicobacter pylori infections and/or treatment with proton-pump inhibitors (PPI) is discussed. The review concludes that accurate measurement of the true concentrations of bioactive gastrins in plasma is important. Moreover, it suggests that moderate hypergastrinemias are also essential health issues that require serious attention.
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Bozkuş Y, Mousa U, İyidir ÖT, Kırnap N, Demir CÇ, Nar A, Tütüncü NB. Short-Term Effect of Hypergastrinemia Following Esomeprazole Treatment On Well-Controlled Type 2 Diabetes Mellitus: A Prospective Study. Endocr Metab Immune Disord Drug Targets 2020; 20:1090-1096. [DOI: 10.2174/1871530320666200129124555] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 11/16/2019] [Accepted: 11/18/2019] [Indexed: 02/08/2023]
Abstract
Objective:
Proton pump inhibitor (PPI) drugs reduce gastric acid secretion and lead to an
increase in serum gastrin levels. Many preclinical and some clinical researches have established some
positive effects of gastrin or PPI therapy on glucose regulation. The aim of this study was to prospectively
investigate the short term effects of esomeprazole on glycaemic control in patients with type 2
diabetes mellitus. In addition, the presence of an association between this effect and gastrin levels was
evaluated.
Methods:
Thirty-two subjects with type 2 diabetes mellitus were enrolled and grouped as intervention
(n=16) and control (n=16). The participants in the intervention group were prescribed 40 mg of esomeprazole
treatment for three months. At the beginning of the study and at the 3rd month, HbA1c level
(%) and gastrin levels (pmol/L) of participants were assessed. Then, the groups were compared in
terms of their baseline and 3rd month values.
Results:
In the intervention group, the mean gastrin level increased significantly from 34.3±14.4
pmol/L to 87.4±43.6 pmol/L (p<0.001). The mean HbA1c level was similar to the pre-treatment level
(6.3±0.7% vs. 6.4±0.9%, p=0.441). There were no statistically significant differences in all parameters
of the control group. The majority of individuals were on metformin monotherapy (65.6 %). The subgroup
analysis of metformin monotherapy revealed that, in intervention group, there was a significant
increase in gastrin levels (39.9±12.6 vs. 95.5±52.5, p=0.026), but the HbA1c levels did not change
(6.0±0.4 % vs. 5.9±0.6 %, p=0.288); and in control group, gastrin levels did not change (37.5 ± 26.7
vs. 36.1 ±23.3, p=0.367), but there was an increase in HbA1c levels (6.1 ± 0.50 vs. 6.4 ± 0.60, p=0.01).
Conclusion:
Our study demonstrates that esomeprazole has no extra benefit for the controlled diabetic
patient in three months. However, in only the metformin-treated subgroup, esomeprazole may prevent
the rise in HbA1c level.
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Affiliation(s)
- Yusuf Bozkuş
- Department of Endocrinology and Metabolism, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Umut Mousa
- Department of Endocrinology and Metabolism, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Özlem T. İyidir
- Department of Endocrinology and Metabolism, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Nazlı Kırnap
- Department of Endocrinology and Metabolism, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Canan Ç. Demir
- Department of Endocrinology and Metabolism, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Aslı Nar
- Department of Endocrinology and Metabolism, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Neslihan B. Tütüncü
- Department of Endocrinology and Metabolism, Faculty of Medicine, Baskent University, Ankara, Turkey
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Rajput MA, Ali F, Zehra T, Zafar S, Kumar G. The effect of proton pump inhibitors on glycaemic control in diabetic patients. J Taibah Univ Med Sci 2020; 15:218-223. [PMID: 32647517 PMCID: PMC7336010 DOI: 10.1016/j.jtumed.2020.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 03/07/2020] [Accepted: 03/10/2020] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVE This study aimed to evaluate the effect of proton pump inhibitors on glycaemic control amongst diabetic patients taking anti-diabetic medications. METHODS This randomised interventional clinical study was conducted in Basic Medical Sciences Institute, Jinnah Postgraduate Medical Centre, Karachi. Eighty patients of either sex (aged 30-60 years) with type 2 diabetes mellitus and without any known comorbidities were equally divided into two groups (i.e., n = 40 for each group) and were included in this study. Group A received metformin and glimepiride, while Group B, metformin and glimepiride plus omeprazole. The efficacy of the combination medications was evaluated based on fasting blood sugar (FBS) and glycosylated haemoglobin (HbA1c) levels. Serum creatinine and liver function tests were reviewed to evaluate patients' safety profile at the initial visit and after 12 weeks. RESULTS After 12 weeks of omeprazole therapy, we observed a more significant improvement in glycaemic control in group B compared to group A based on the patients' FBS (108 ± 2.37 vs. 126 ± 2.9, P = 0.001) and HbA1c levels (7.29 ± 0.07 vs. 7.47 ± 0.04, P = 0.030). CONCLUSION The addition of a proton pump inhibitor along with anti-diabetic medications was considered effective in achieving better glycaemic control.
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Affiliation(s)
- Muhammad Ali Rajput
- Department of Pharmacology, Multan Medical and Dental College, Multan, Pakistan
| | - Fizzah Ali
- Department of Pharmacology, Liaquat National Medical College, Karachi, Pakistan
| | - Tabassum Zehra
- Department of Pharmacology, Liaquat National Medical College, Karachi, Pakistan
| | - Shahid Zafar
- Department of Pathology, Liaquat College of Medicine & Dentistry, Karachi, Pakistan
| | - Gunesh Kumar
- Department of Pharmacology, Liaquat University of Medical & Health Sciences, Jamshoro, Pakistan
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Sánchez-García A, Simental-Mendía M, Simental-Mendía LE. Effect of Proton-Pump Inhibitors on Glucose and Insulin Metabolism on Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Curr Pharm Des 2020; 26:4007-4013. [PMID: 32445448 DOI: 10.2174/1381612826666200523170718] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 03/18/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND Some studies have revealed an improvement in glucose metabolism after proton-pump inhibitors (PPI) therapy; however, this evidence is inconclusive and limited. OBJECTIVE The study aimed to examine the effect of PPI on glucose and insulin metabolism in patients with type 2 diabetes through a systematic review and meta-analysis. METHODS Only randomized controlled trials evaluating the impact of PPI on glucose or insulin concentrations in type 2 diabetes were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases. A meta-analysis was conducted using a random-effects model and generic inverse variance method. Sensitivity analysis was performed using the leave-one-out method. RESULTS Meta-analysis revealed no significant effect of PPI intervention on fasting glucose (mean difference [MD] -11.42 [95% CI, -29.68 to 6.83], I2 = 80%, p = 0.22), fasting insulin (MD 1.51 [95% CI, -0.36 to 3.37], I2 = 32%, p = 0.11), HOMA-IR (MD -0.16 [-0.98 to 0.65], I2 = 0%, p = 0.70), HOMA-β (MD 19.97 [-21.59 to 61.52], I2 = 71%, p = 0.35), and HbA1c concentrations (MD -0.34 [-0.99 to 0.31], I2 = 89%, p = 0.30). CONCLUSION The treatment with PPI, in the short term, had no significant effects on glucose and insulin metabolism in patients with type 2 diabetes.
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Affiliation(s)
- Adriana Sánchez-García
- Endocrinology Division, Hospital Universitario "Dr. Jose E. Gonzalez", Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Monterrey, NL, Mexico
| | - Mario Simental-Mendía
- Department of Orthopedics and Traumatology, Hospital Universitario "Dr. Jose E. Gonzalez", Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Monterrey, NL, Mexico
| | - Luis E Simental-Mendía
- Unidad de Investigacion Biomedica, Delegacion Durango, Instituto Mexicano del Seguro Social, Durango, Mexico
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Abstract
The novel understanding that the presence of multiple islet autoantibodies, indicating islet autoimmunity, inevitably leads to type 1 diabetes mellitus (T1DM) has necessitated the development of a new staging classification system for the condition. Coupled with an improved understanding of the disease course, the realization that T1DM appears to be more heterogeneous than previously thought has led to unique opportunities to develop more targeted therapies that may be applied even before the onset of dysglycemia or symptoms. To date, several therapies have been trialed to delay or halt disease progression in both presymptomatic and clinical T1DM, each demonstrating varying degrees of effectiveness, toxicity, and utility. Key research supports the eventual implementation of immunotherapy in autoimmune diabetes, potentially calling for a paradigm shift among care providers. It will likely be necessary to develop new approaches to trial design and to address potential barriers to progress before an effective treatment for the disease may be achieved.
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Lenz A, Lenz G, Ku HT, Ferreri K, Kandeel F. Islets from human donors with higher but not lower hemoglobin A1c levels respond to gastrin treatment in vitro. PLoS One 2019; 14:e0221456. [PMID: 31430329 PMCID: PMC6701795 DOI: 10.1371/journal.pone.0221456] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 08/08/2019] [Indexed: 12/12/2022] Open
Abstract
Gastrin is a peptide hormone, which in combination with other factors such as TGFα, EGF or GLP-1, is capable of increasing beta cell mass and lowering blood glucose levels in adult diabetic mice. In humans, administration of a bolus of gastrin alone induces insulin secretion suggesting that gastrin may target islet cells. However, whether gastrin alone is sufficient to exert an effect on isolated human islets has been controversial and the mechanism remained poorly understood. Therefore, in this study we started to examine the effects of gastrin alone on cultured adult human islets. Treatment of isolated human islets with gastrin I for 48 h resulted in increased expression of insulin, glucagon and somatostatin transcripts. These increases were significantly correlated with the levels of donor hemoglobin A1c (HbA1c) but not BMI or age. In addition, gastrin treatment resulted in increased expression of PDX1, NKX6.1, NKX2.2, MNX1 and HHEX in islets from donors with HbA1c greater than 42 mmol/mol. The addition of YM022, an antagonist of the gastrin receptor cholecystokinin B receptor (CCKBR), together with gastrin eliminated these effects, verifying that the effects of gastrin are mediated through CCKBR.CCKBR is expressed in somatostatin-expressing delta cells in islets from all donors. However, in the islets from donors with higher HbA1c (greater than 42 mmol/mol [6.0%]), cells triple-positive for CCKBR, somatostatin and insulin were detected, suggesting a de-differentiation or trans-differentiation of endocrine cells. Our results demonstrate a direct effect of gastrin on human islets from prediabetic or diabetic individuals that is mediated through CCKBR+ cells. Further, our data imply that gastrin may be a potential treatment for diabetic patients.
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Affiliation(s)
- Ayelet Lenz
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States of America
- * E-mail:
| | - Gal Lenz
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States of America
| | - Hsun Teresa Ku
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States of America
| | - Kevin Ferreri
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States of America
| | - Fouad Kandeel
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, United States of America
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Austin GL, Weiskopf JR, Czwornog JL. Association of Proton Pump Inhibitor Use With Serum Biomarkers of Inflammation, Insulin Resistance, Cardiovascular Risk, and Renal Function. J Clin Gastroenterol 2018; 52:691-695. [PMID: 29099466 DOI: 10.1097/mcg.0000000000000921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND GOALS Proton pump inhibitor (PPI) use has been associated with cardiovascular disease, chronic kidney disease, and dementia. Prior studies did not account for key confounders and little is known about the association of PPIs with serum biomarkers of inflammation, insulin resistance, cardiovascular risk, and renal function. Our aims were to investigate differences in these biomarkers between PPI users and nonusers. METHODS Our data are from the National Health and Nutrition Examination Survey (NHANES), a complex cross-sectional multistage probability sample of the US civilian population. We used data on 5189 eligible adults aged 18 to 85 years. Appropriate survey commands were used and potential confounding variables (including BMI, duration of PPI use, use of other non-PPI medications, and health behaviors) were included in multivariable regression models assessing biomarker outcomes. RESULTS PPI use was associated with differences in mean (±SE) fasting low-density lipoprotein (LDL) (by 11.7±3.7 mg/dL; P=0.006), and apolipoprotein B (by 7.6±2.6 mg/dL; P=0.01). PPI use was not associated with significant differences in total cholesterol (P=0.13), high-density lipoprotein (P=0.27), triglycerides (P=0.70), c-reactive protein (P=0.52), the homeostatic model assessment-insulin resistance (P=0.48), hemoglobin A1c (P=0.39), or homocysteine (P=0.87). PPI use was associated with a decrease in blood urea nitrogen (by 1.0±0.3 mg/dL; P=0.008) but not creatinine (P=0.38) or uric acid (P=0.34). CONCLUSION PPI was not associated with clinically significant differences in serum biomarkers of inflammation, insulin resistance, cardiovascular risk, and renal function. Rather, increasing BMI was strongly associated with PPI use and clinically significant differences in these biomarkers.
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Affiliation(s)
| | - Jennifer R Weiskopf
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
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Carlström M, Lundberg JO, Weitzberg E. Mechanisms underlying blood pressure reduction by dietary inorganic nitrate. Acta Physiol (Oxf) 2018; 224:e13080. [PMID: 29694703 DOI: 10.1111/apha.13080] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 03/28/2018] [Accepted: 04/18/2018] [Indexed: 12/20/2022]
Abstract
Nitric oxide (NO) importantly contributes to cardiovascular homeostasis by regulating blood flow and maintaining endothelial integrity. Conversely, reduced NO bioavailability is a central feature during natural ageing and in many cardiovascular disorders, including hypertension. The inorganic anions nitrate and nitrite are endogenously formed after oxidation of NO synthase (NOS)-derived NO and are also present in our daily diet. Knowledge accumulated over the past two decades has demonstrated that these anions can be recycled back to NO and other bioactive nitrogen oxides via serial reductions that involve oral commensal bacteria and various enzymatic systems. Intake of inorganic nitrate, which is predominantly found in green leafy vegetables and beets, has a variety of favourable cardiovascular effects. As hypertension is a major risk factor of morbidity and mortality worldwide, much attention has been paid to the blood pressure reducing effect of inorganic nitrate. Here, we describe how dietary nitrate, via stimulation of the nitrate-nitrite-NO pathway, affects various organ systems and discuss underlying mechanisms that may contribute to the observed blood pressure-lowering effect.
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Affiliation(s)
- M. Carlström
- Department of Physiology and Pharmacology; Karolinska Institutet; Stockholm Sweden
| | - J. O. Lundberg
- Department of Physiology and Pharmacology; Karolinska Institutet; Stockholm Sweden
| | - E. Weitzberg
- Department of Physiology and Pharmacology; Karolinska Institutet; Stockholm Sweden
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Grong E, Nord C, Arbo IB, Eriksson M, Kulseng BE, Ahlgren U, Mårvik R. The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats. J Endocrinol Invest 2018; 41:691-701. [PMID: 29168078 DOI: 10.1007/s40618-017-0793-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 11/12/2017] [Indexed: 01/30/2023]
Abstract
PURPOSE Metabolic surgery alters the secretion of gastrointestinal hormones that influence glycemic control. Elevated gastrin has been suggested to benefit patients with type 2 diabetes and has been reported following sleeve gastrectomy in rats. The present study compares the effect of hypergastrinemia following sleeve gastrectomy with proton-pump inhibitor therapy on glycemic control and beta-cell mass in lean, diabetic animals. METHODS Thirty-three diabetic Goto-Kakizaki rats were randomized into pantoprazole + sham operation (GK-PPI), sleeve gastrectomy (GK-SG) and vehicle + sham operation (GK-V). Body weight, glucose parameters, HbA1c, glucagon-like peptide 1, gastrin, insulin and lipids were evaluated for eighteen postoperative weeks. Total beta-cell mass was quantified by optical projection tomography. RESULTS After surgery, body weight development was equal among groups (P g = 0.75). Fasting and stimulated gastrin increased for GK-PPI and GK-SG vs. GK-V (p < 0.05 for all). Fasting blood glucose was decreased for GK-PPI and GK-SG vs. GK-V (p < 0.05 and p = 0.052). HbA1c was lower for GK-SG vs. GK-V at 6 weeks and for GK-PPI vs. GK-V at twelve- and eighteen weeks postoperative (p < 0.05 for all); a borderline difference was observed for GK-SG vs. GK-V at 18 weeks (p = 0.054). Total- and LDL cholesterol was elevated for GK-PPI compared to the other two groups (p < 0.05 for all). Beta-cell mass did not differ among groups (p = 0.35). CONCLUSIONS Hypergastrinemia following sleeve gastrectomy and pantoprazole has a similar, modest effect on glycemic control in Goto-Kakizaki rats but does not enhance beta-cell mass after 18 weeks. Hypergastrinemia in the setting of T2DM might be of clinical relevance.
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Affiliation(s)
- E Grong
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Post Box 8905, 7491, Trondheim, Norway.
- Department of Gastrointestinal Surgery and Norwegian National Advisory Unit on Advanced Laparoscopic Surgery (NSALK), St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
| | - C Nord
- Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå, Sweden
| | - I B Arbo
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Post Box 8905, 7491, Trondheim, Norway
| | - M Eriksson
- Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå, Sweden
| | - B E Kulseng
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Post Box 8905, 7491, Trondheim, Norway
- Centre for Obesity Research and Innovation (ObeCe), St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
- Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - U Ahlgren
- Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå, Sweden
| | - R Mårvik
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Post Box 8905, 7491, Trondheim, Norway
- Centre for Obesity Research and Innovation (ObeCe), St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
- Department of Gastrointestinal Surgery and Norwegian National Advisory Unit on Advanced Laparoscopic Surgery (NSALK), St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
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The Influence of Proton-Pump Inhibitors on Glycemic Control: A Systematic Review of the Literature and a Meta-Analysis. Can J Diabetes 2017; 41:351-361. [PMID: 28373033 DOI: 10.1016/j.jcjd.2016.11.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 11/07/2016] [Accepted: 11/11/2016] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Proton-pump inhibitors (PPIs) have shown antihyperglycemic effects by stimulating insulin secretion. The aim of this study was to analyze the effect of PPIs on glucose metabolism in general and any potential antidiabetes effects in patients with type 2 diabetes. METHODS A systematic search was conducted in MEDLINE, Embase, Cochrane and PubMed. Studies using PPIs as interventions and reporting glucose levels, glycated hemoglobin (A1C) levels and insulin levels were selected. Weighted-mean differences (WMDs) were calculated for all outcomes. A random-effects model was used for moderate and high heterogeneity and a fixed-effects model for low heterogeneity data. RESULTS The research included 9 studies have involving 320 patients in total. Among patients with type 2 diabetes, those exposed to PPIs did not see significant reductions in A1C levels; WMD -0.36, 95% confidence interval (CI) -0.87, 0.15; p=0.17. Pantoprazole resulted in a statistically significant reduction in A1C levels in patients with type 2 diabetes when compared to control interventions; WMD -0.93, 95% CI -1.49, -0.37; p=0.001. There was no statistically significant difference in other outcomes (p≥0.05). CONCLUSIONS This meta-analysis demonstrates that PPIs, in general, do not decrease A1C levels in patients with type 2 diabetes. However, pantoprazole produced significant reductions in A1C levels in patients with type 2 diabetes. Given the limitations and the presence of bias in the primary studies, larger and better-quality studies are warranted.
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Montenegro MF, Sundqvist ML, Larsen FJ, Zhuge Z, Carlström M, Weitzberg E, Lundberg JO. Blood Pressure–Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor. Hypertension 2017; 69:23-31. [DOI: 10.1161/hypertensionaha.116.08081] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 07/19/2016] [Accepted: 08/29/2016] [Indexed: 11/16/2022]
Abstract
Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure. The mechanisms for nitrite bioactivation are unclear, but recent studies in rodents suggest that gastric acidity may influence the systemic effects of this anion. In a randomized, double-blind, placebo-controlled crossover study, we tested the effects of a proton pump inhibitor on the acute cardiovascular effects of nitrite. Fifteen healthy nonsmoking, normotensive subjects, aged 19 to 39 years, were pretreated with placebo or esomeprazole (3×40 mg) before ingesting sodium nitrite (0.3 mg kg
−1
), followed by blood pressure monitoring. Nitrite reduced systolic blood pressure by a maximum of 6±1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect. Peak plasma nitrite, nitrate, and nitroso species levels after nitrite ingestion were similar in both interventions. In 8 healthy volunteers, we then infused increasing doses of sodium nitrite (1, 10, and 30 nmol kg
−1
min
−1
) intravenously. Interestingly, although plasma nitrite peaked at similar levels as with orally ingested nitrite (≈1.8 µmol/L), no changes in blood pressure were observed. In rodents, esomeprazole did not affect the blood pressure response to the NO donor, DEA NONOate, or vascular relaxation to nitroprusside and acetylcholine, demonstrating an intact downstream NO-signaling pathway. We conclude that the acute blood pressure–lowering effect of nitrite requires an acidic gastric environment. Future studies will reveal if the cardiovascular complications associated with the use of proton pump inhibitors are linked to interference with the nitrate–nitrite–NO pathway.
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Affiliation(s)
- Marcelo F. Montenegro
- From the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.F.M., M.S., Z.Z., M.C., E.W., J.O.L.); and Åstrand Laboratory, The Swedish School of Sport and Health Sciences, Stockholm, Sweden (F.J.L.)
| | - Michaela L. Sundqvist
- From the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.F.M., M.S., Z.Z., M.C., E.W., J.O.L.); and Åstrand Laboratory, The Swedish School of Sport and Health Sciences, Stockholm, Sweden (F.J.L.)
| | - Filip J. Larsen
- From the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.F.M., M.S., Z.Z., M.C., E.W., J.O.L.); and Åstrand Laboratory, The Swedish School of Sport and Health Sciences, Stockholm, Sweden (F.J.L.)
| | - Zhengbing Zhuge
- From the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.F.M., M.S., Z.Z., M.C., E.W., J.O.L.); and Åstrand Laboratory, The Swedish School of Sport and Health Sciences, Stockholm, Sweden (F.J.L.)
| | - Mattias Carlström
- From the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.F.M., M.S., Z.Z., M.C., E.W., J.O.L.); and Åstrand Laboratory, The Swedish School of Sport and Health Sciences, Stockholm, Sweden (F.J.L.)
| | - Eddie Weitzberg
- From the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.F.M., M.S., Z.Z., M.C., E.W., J.O.L.); and Åstrand Laboratory, The Swedish School of Sport and Health Sciences, Stockholm, Sweden (F.J.L.)
| | - Jon O. Lundberg
- From the Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (M.F.M., M.S., Z.Z., M.C., E.W., J.O.L.); and Åstrand Laboratory, The Swedish School of Sport and Health Sciences, Stockholm, Sweden (F.J.L.)
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14
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Kruszelnicka O, Kuźma M, Pena IZ, Perera IB, Chyrchel B, Wieczorek-Surdacka E, Surdacki A. No Association of Proton Pump Inhibitor Use with Fasting or Postload Glycaemia in Patients with Cardiovascular Disease: A Cross-Sectional Retrospective Study. Int J Med Sci 2017; 14:1015-1021. [PMID: 28924374 PMCID: PMC5599926 DOI: 10.7150/ijms.19457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 06/20/2017] [Indexed: 12/23/2022] Open
Abstract
Background: Proton pump inhibitor (PPI) use was reportedly associated with an excess of adverse cardiovascular (CV) events, thus making their systemic effects relevant to public health. PPIs reduce gastric acid secretion, causing increased gastrin release. Gastrin stimulates β-cell neogenesis and enhances insulin release, exerting an incretin-like effect. Our aim was to assess, if PPI usage is associated with altered glycaemia in patients with CV disease. Methods: We retrospectively analyzed medical records of 102 subjects (80 with ischemic heart disease) who underwent a routine oral glucose tolerance test while hospitalized in a cardiology department. Fasting and 2-h postload glucose levels were compared according to PPI use for ≥1 month prior to admission. Results: Compared to 51 subjects without PPIs, those on a PPI were older, more frequently male, had a lower body-mass index and a tendency to a worse renal function. PPI users and non-users exhibited similar glucose levels at baseline (5.6 ± 0.9 vs. 5.5 ± 1.1 mmol/l, P = 0.5) and 2-hrs post glucose intake (9.8 ± 3.0 vs. 9.9 ± 3.4 mmol/l, P = 0.9). This was consistent across subgroups stratified by gender or diabetes status. The results were substantially unchanged after adjustment for different characteristics of subjects with and without PPIs. Conclusions: PPI use does not appear associated with altered glycaemia in subjects with CV disease. Unchanged glucose tolerance despite PPI usage may result from simultaneous activation of pathways that counteract the putative PPI-induced incretin-like effect.
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Affiliation(s)
- Olga Kruszelnicka
- Department of Coronary Artery Disease and Heart Failure, John Paul II Hospital, Cracow, Poland
| | - Marcin Kuźma
- Students' Scientific Group at the Second Department of Cardiology, School of Medicine in English, Jagiellonian University Medical College, Cracow, Poland
| | - Iwona Z Pena
- Students' Scientific Group at the Second Department of Cardiology, School of Medicine in English, Jagiellonian University Medical College, Cracow, Poland
| | - Ian B Perera
- Students' Scientific Group at the Second Department of Cardiology, School of Medicine in English, Jagiellonian University Medical College, Cracow, Poland
| | - Bernadeta Chyrchel
- Second Department of Cardiology, Jagiellonian University Medical College, Cracow, Poland
| | | | - Andrzej Surdacki
- Second Department of Cardiology, Jagiellonian University Medical College, Cracow, Poland
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15
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Breuer TGK, Borker L, Quast DR, Tannapfel A, Schmidt WE, Uhl W, Meier JJ. Impact of proton pump inhibitor treatment on pancreatic beta-cell area and beta-cell proliferation in humans. Eur J Endocrinol 2016; 175:467-76. [PMID: 27562401 DOI: 10.1530/eje-16-0320] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 08/24/2016] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Gastrin has been shown to promote beta-cell proliferation in rodents, but its effects in adult humans are largely unclear. Proton pump inhibitors (PPIs) lead to endogenous hypergastrinaemia, and improved glucose control during PPI therapy has been reported in patients with diabetes. Therefore, we addressed whether PPI treatment is associated with improved glucose homoeostasis, islet cell hyperplasia or increased new beta-cell formation in humans. PATIENTS AND METHODS Pancreatic tissue specimens from 60 patients with and 33 patients without previous PPI therapy were examined. The group was subdivided into patients without diabetes (n = 27), pre-diabetic patients (n = 31) and patients with diabetes (n = 35). RESULTS Fasting glucose and HbA1c levels were not different between patients with and without PPI therapy (P = 0.34 and P = 0.30 respectively). Beta-cell area was higher in patients without diabetes than in patients with pre-diabetes or diabetes (1.33 ± 0.12%, 1.05 ± 0.09% and 0.66 ± 0.07% respectively; P < 0.0001). There was no difference in beta-cell area between patients with and without PPI treatment (1.05 ± 0.08% vs 0.87 ± 0.08%, respectively; P = 0.16). Beta-cell replication was rare and not different between patients with and without PPI therapy (P = 0.20). PPI treatment was not associated with increased duct-cell replication (P = 0.18), insulin expression in ducts (P = 0.28) or beta-cell size (P = 0.63). CONCLUSIONS These results suggest that in adult humans, chronic PPI treatment does not enhance beta-cell mass or beta-cell function to a relevant extent.
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Affiliation(s)
- Thomas G K Breuer
- Diabetes DivisionSt. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Laura Borker
- Diabetes DivisionSt. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Daniel R Quast
- Diabetes DivisionSt. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | | | - Wolfgang E Schmidt
- Diabetes DivisionSt. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Waldemar Uhl
- Department of SurgerySt. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Juris J Meier
- Diabetes DivisionSt. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
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17
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Gastrin Secretion After Bariatric Surgery—Response to a Protein-Rich Mixed Meal Following Roux-En-Y Gastric Bypass and Sleeve Gastrectomy: a Pilot Study in Normoglycemic Women. Obes Surg 2015; 26:1448-56. [DOI: 10.1007/s11695-015-1985-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Barchetta I, Guglielmi C, Bertoccini L, Calella D, Manfrini S, Secchi C, Pozzilli P, Cavallo MG. Therapy with proton pump inhibitors in patients with type 2 diabetes is independently associated with improved glycometabolic control. Acta Diabetol 2015; 52:873-80. [PMID: 25716766 DOI: 10.1007/s00592-015-0721-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 02/02/2015] [Indexed: 02/08/2023]
Abstract
AIMS Experimental data demonstrated that gastrin has incretin-like stimulating actions on β-cells, resulting in a promotion of glucose-induced insulin secretion. As proton pump inhibitors (PPIs) consistently increase plasma gastrin levels, a possible effect of this treatment on glucose-insulin homeostasis may be hypothesized. Therefore, the aim of this study was to evaluate the effect of chronic PPIs treatment on glycemic control in patients affected by type 2 diabetes. METHODS This is an observational, retrospective study. A total of 548 consecutive patients with type 2 diabetes (mean age ± SD: 67.1 ± 10.9 years, M/F: 309/239, diabetes duration: 12.4 ± 9.8 years) referring to our diabetes outpatient clinics were enrolled; among them, 45 %were treated with PPIs longer than 2 years for preventive/therapeutic purposes. Fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), serum lipids and transaminases were measured by standard laboratory methods. Major cardiovascular events and concomitant medications were recorded in all participants, and daily insulin requirement was calculated in insulin-treated subjects. RESULTS PPIs-treated patients had significantly lower HbA1c (7.1 ± 1.07 %-54.1 ± 12 vs 7.4 ± 1.4 %-57.4 ± 8 mmol/mol, p = 0.011) and FPG (127 ± 36.9 vs 147.6 ± 49.4 mg/dl, p < 0.001) levels than those untreated. These differences increased in patients under insulin therapy and in those with concomitant PPIs + GLP-1-based therapy. The multivariate regression analysis demonstrated that the association between chronic PPIs treatment and HbA1c was independent from possible confounders (p = 0.01). CONCLUSIONS PPIs treatment is associated with greater glycemic control in patients with type 2 diabetes, particularly in those on insulin- or GLP-1-based therapy. Our results suggest a role for PPIs in glucose-insulin homeostasis and may open a new scenario for diabetes therapy.
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Affiliation(s)
- Ilaria Barchetta
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | | | - Laura Bertoccini
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - Damiano Calella
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | | | | | | | - Maria Gisella Cavallo
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
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19
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Takebayashi K, Inukai T. Effect of proton pump inhibitors on glycemic control in patients with diabetes. World J Diabetes 2015; 6:1122-1131. [PMID: 26322158 PMCID: PMC4549663 DOI: 10.4239/wjd.v6.i10.1122] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 07/06/2015] [Accepted: 07/27/2015] [Indexed: 02/05/2023] Open
Abstract
Gastrin is a linear peptide hormone which is secreted mostly in the stomach pyloric antrum G cells. Although the main role of this hormone is the promotion of the secretion of gastric acid from the stomach parietal cells, gastrin can also behave as a growth factor and stimulate gastric cell proliferation. It is also reported that gastrin promotes β cell neogenesis in the pancreatic ductal complex, modest pancreatic β cell replication, and improvement of glucose tolerance in animal models, in which the remodeling of pancreatic tissues is promoted. These findings suggest the possibility that gastrin has the potential to promote an increase of β cell mass in pancreas, and therefore that gastrin may improve glucose tolerance. Proton pump inhibitors (PPIs) are wildly used clinically for the therapy of gastro-esophageal reflex disease, gastritis due to excess stomach acid, and gastric ulcers. PPIs indirectly elevate serum gastrin levels via a negative feedback effect. Recent evidence has revealed the beneficial effect of PPIs on glycemic control especially in patients with type 2 diabetes mellitus (T2DM), probably via the elevation of the levels of serum gastrin, although the detailed mechanism remains unclear. In addition, the beneficial effects of a combination therapy of gastrin or a PPI with a glucagon-like peptide-1 receptor agonist on glycemic control in animal models have been demonstrated. Although PPIs may be possible candidates for a new approach in the therapy of diabetes, a prospective, long-term, randomized, double-blind, placebo-controlled study is needed to establish the effect of PPIs on glycemic control in a large number of patients with T2DM.
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20
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Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography. Surg Endosc 2015; 30:532-542. [DOI: 10.1007/s00464-015-4236-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2015] [Accepted: 04/21/2015] [Indexed: 12/31/2022]
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Abstract
Immunotherapies for type 1 diabetes mellitus (T1DM) have been the focus of intense basic and clinical research over the past few decades. Restoring β-cell function is the ultimate goal of intervention trials that target the immune system in T1DM. In an attempt to achieve this aim, different combination therapies have been proposed over the past few years that are based on treatments tackling the various mechanisms involved in the destruction of β cells. The results of clinical trials have not matched expectations based on the positive results from preclinical studies. The heterogeneity of T1DM might explain the negative results obtained, but previous trials have not addressed this issue. However, novel promising combination therapies are being developed, including those that couple immunomodulators with drugs that stimulate β-cell regeneration in order to restore normoglycaemia. This strategy is an encouraging one to pursue the goal of finding a cure for T1DM. This Review summarizes the available data about combination immunotherapies in T1DM, particularly addressing their clinical importance. The available data supporting the use of registered drugs, such as proton pump inhibitors and incretin-based agents, that have been shown to induce β-cell regeneration will also be discussed.
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Affiliation(s)
- Paolo Pozzilli
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Via Álvaro del Portillo 21, Rome 00128, Italy
| | - Ernesto Maddaloni
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Via Álvaro del Portillo 21, Rome 00128, Italy
| | - Raffaella Buzzetti
- Department of Experimental Medicine, "Sapienza" University, Viale Regina Elena 324, Rome 00161 Italy
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González-Ortiz M, Martínez-Abundis E, Mercado-Sesma AR, Álvarez-Carrillo R. Effect of pantoprazole on insulin secretion in drug-naïve patients with type 2 diabetes. Diabetes Res Clin Pract 2015; 108:e11-3. [PMID: 25704601 DOI: 10.1016/j.diabres.2015.01.039] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 01/14/2015] [Accepted: 01/29/2015] [Indexed: 02/09/2023]
Abstract
To evaluate the effect of pantoprazole during 45 days on insulin secretion in drug-naïve patients with type 2 diabetes, a randomized, double blind, placebo control clinical trial was performed in 14 drug-naïve volunteers. Significant increases in late insulin phase and total insulin secretion, and decreases in HbA1c levels were found.
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Affiliation(s)
- Manuel González-Ortiz
- Institute of Experimental and Clinical Therapeutics, Physiology Department, Health Science University Center, University of Guadalajara, Guadalajara, Mexico; Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center, Mexican Institute of Social Security, Guadalajara, Mexico.
| | - Esperanza Martínez-Abundis
- Institute of Experimental and Clinical Therapeutics, Physiology Department, Health Science University Center, University of Guadalajara, Guadalajara, Mexico
| | - Arieh R Mercado-Sesma
- Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center, Mexican Institute of Social Security, Guadalajara, Mexico
| | - Rebeca Álvarez-Carrillo
- Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center, Mexican Institute of Social Security, Guadalajara, Mexico
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23
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Hove KD, Brøns C, Færch K, Lund SS, Rossing P, Vaag A. Effects of 12 weeks of treatment with fermented milk on blood pressure, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind placebo-controlled study. Eur J Endocrinol 2015; 172:11-20. [PMID: 25300285 DOI: 10.1530/eje-14-0554] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Studies have indicated a blood pressure (BP)-lowering effect of milk-derived peptides in non-diabetic individuals, but the cardiometabolic effects of such peptides in patients with type 2 diabetes (T2D) are not known. We investigated the effect of milk fermented with Lactobacillus helveticus on BP, glycaemic control and cardiovascular risk factors in T2D. DESIGN A randomised, double-blinded, prospective, placebo-controlled study. METHODS In one arm of a factorial study design, 41 patients with T2D were randomised to receive 300 ml milk fermented with L. helveticus (Cardi04 yogurt) (n=23) or 300 ml artificially acidified milk (placebo yogurt) (n=18) for 12 weeks. BPs were measured over 24-h, and blood samples were collected in the fasting state and during a meal test before and after the intervention. RESULTS Cardi04 yogurt did not reduce 24-h, daytime or nighttime systolic or diastolic BPs compared with placebo (P>0.05). Daytime and 24-h heart rate (HR) were significantly reduced in the group treated by Cardi04 yogurt compared with the placebo group (P<0.05 for both). There were no differences in HbA1c, plasma lipids, C-reactive protein, plasminogen activator inhibitor-1, tumour necrosis factor alpha, tissue-type plasminogen activator: Ag, and von Willebrand factor: Ag between the groups. The change in fasting blood glucose concentration differed significantly between the two groups with a larger increase in the placebo group (P<0.05). CONCLUSIONS Ingestion of milk fermented with L. helveticus compared with placebo for 12 weeks did not significantly reduce BP in patients with T2D. Our finding of lower HRs and fasting plasma glucose levels in T2D patients during ingestion of fermented milk needs further validation.
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Affiliation(s)
- K D Hove
- Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - C Brøns
- Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - K Færch
- Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - S S Lund
- Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - P Rossing
- Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - A Vaag
- Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Steno Diabetes Center A/SNiels Steensens Vej 2, DK-2820 Gentofte, DenmarkHealthUniversity of Aarhus, Aarhus, DenmarkNNF Center for Basic Metabolic ResearchDepartment of EndocrinologyDiabetes and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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24
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Han N, Oh M, Park SM, Kim YJ, Lee EJ, Kim TK, Kim TN, Kwon MJ, Kim MK, Lee SH, Rhee BD, Park JH. The effect of proton pump inhibitors on glycated hemoglobin levels in patients with type 2 diabetes mellitus. Can J Diabetes 2014; 39:24-8. [PMID: 25305802 DOI: 10.1016/j.jcjd.2013.10.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 10/28/2013] [Accepted: 10/28/2013] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Gastrin increases the growth and neogenesis of the islets of Langerhans. Oral proton pump inhibitors (PPIs) increase the circulating gastrin level in animals and humans, but the therapeutic benefit of PPIs for diabetes mellitus has not been resolved. We examined whether treatment with a PPI for ≥2 months affected the glycated hemoglobin (A1C) level in patients with type 2 diabetes. METHODS The electronic medical records of patients treated at the Busan Paik Hospital in South Korea were examined. The primary outcome measure was the change in A1C before and after PPI treatment for ≥2 months. We also tested if the primary outcome measure was affected by sex, age, duration of diabetes, body mass index, PPI molecule, duration of treatment with PPI or concurrent therapy with other antidiabetes agents. RESULTS In total, 43 patients (17 men and 26 women) were studied (mean age 63.8 years). Patients were treated with a PPI for a mean of 180 days. The A1C levels before and after treatment were not significantly different (6.86%±1.10% and 6.77%±1.07%, respectively; p=0.406). Metformin monotherapy did not lower A1C levels as compared with a combination therapy including metformin and antidiabetes medication not including metformin. CONCLUSIONS Proton pump inhibitor treatment of patients with type 2 diabetes did not reduce A1C levels. The data of this study were obtained from a retrospective chart review and included a small number of subjects. Furthermore, large randomized controlled studies are needed to define the effect of PPIs for type 2 patients with diabetes.
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Affiliation(s)
- Na Han
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Minkyung Oh
- Department of Pharmacology and Clinical Trial Centre, Inje University, Busan Paik Hospital, Busan, South Korea
| | - Su Min Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - You Jeong Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Eun Ju Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Tae Kyoon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Tae Nyun Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Min Jeong Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea.
| | - Mi-Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Soon Hee Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Byoung Doo Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Jeong Hyun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
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Grong E, Arbo IB, Thu OKF, Kuhry E, Kulseng B, Mårvik R. The effect of duodenojejunostomy and sleeve gastrectomy on type 2 diabetes mellitus and gastrin secretion in Goto-Kakizaki rats. Surg Endosc 2014; 29:723-33. [PMID: 25106717 DOI: 10.1007/s00464-014-3732-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 07/08/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND Bariatric surgery is a highly effective treatment of type 2 diabetes in patients with morbid obesity. The weight-loss independent improvement of glycemic control observed after these procedures has led to the discussion whether bariatric surgery can be introduced as treatment for type 2 diabetes in patients with a body mass index < 35 kg/m(2). We have studied the effects of two bariatric procedures on type 2 diabetes and on gastrointestinal hormone secretion in a lean diabetic animal model. METHODS Male Goto-Kakizaki rats, 17-18 weeks old, were randomized into three groups: duodenojejunostomy (DJ), sleeve gastrectomy (SG), or sham operation. During 36 postoperative weeks we evaluated body weight, fasting blood glucose, glucose tolerance, insulin, HbA1c, glucagon-like peptide 1, cholesterol parameters, triglycerides, total ghrelin, and gastrin. RESULTS Oral glucose tolerance was significantly improved for both DJ and SG at four weeks after surgery (p < 0.05). At the 34th postoperative week, SG had significantly lower area under the curve during oral glucose tolerance test compared to sham (p = 0.007). SG had significantly lower HbA1c compared to sham at 12 weeks; (mean ± SEM) 4.3 ± 0.1 % versus 5.2 ± 0.3 % (p < 0.05) and compared to both DJ and sham 34 weeks after surgery [median (75 %;25 %)] 5.2 (6.0; 4.3) % versus 7.0 (7.5; 6.7) % and 7.3 (7.6; 6.7) % (p = 0.009). Serum gastrin levels were markedly elevated for SG compared to DJ and sham; 188.0 (318.0; 121.0) versus 77.5 (114.0; 58.0) and 68.0 (90.0; 59.5) pmol/L (p = 0.004) at six weeks and 192.0 (587.8; 110.8) versus 65.5 (77.0; 59.0) and 69.5 (113.0; 55.5) (p = 0.001) 36 weeks after surgery. CONCLUSION Sleeve gastrectomy induces hypergastrinemia, lowers HbA1c, and improves glycemic control in Goto-Kakizaki rats. Sleeve gastrectomy is superior to duodenojejunostomy as treatment of type 2 diabetes mellitus in this animal model.
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Affiliation(s)
- Eivind Grong
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), PB 8905, 7491, Trondheim, Norway,
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Kim A, Chung I, Yoon SH, Yu KS, Lim KS, Cho JY, Lee H, Jang IJ, Chung JY. Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics. Drug Metab Dispos 2014; 42:1174-9. [PMID: 24764147 DOI: 10.1124/dmd.113.055616] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
As inhibitors of organic cation transporters (OCTs), proton pump inhibitors (PPIs) may affect the plasma levels of metformin, an OCT substrate. We investigated the effects of two PPIs, pantoprazole and rabeprazole, on metformin pharmacokinetics and glucose levels in healthy subjects. In this open, randomized, six-sequence, three-period crossover study, 24 participants were administered metformin, either alone or in combination with pantoprazole or rabeprazole. The plasma concentrations of metformin and serum concentrations of glucose after a 75-g oral glucose tolerance test (OGTT) were determined. The area under the concentration-time curve (AUC) for metformin was 15% and 16% greater following coadministration with pantoprazole and rabeprazole, respectively. The maximum plasma metformin concentrations (Cmax) also increased by 15% and 22%, respectively, compared with when it was administered without the PPIs. The percentage change in the AUC for glucose concentration versus time for metformin plus rabeprazole was significantly lower than that for metformin plus pantoprazole [geometric mean ratio: 0.96 (90% confidence interval: 0.92-0.99) and 0.77 (0.63-0.93), respectively]. There was no significant difference in the maximum glucose concentration. In conclusion, concomitant administration of PPIs with metformin significantly increased plasma metformin exposure, but the effects on glucose disposition were minor and varied depending on the PPI administered.
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Affiliation(s)
- AnHye Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.)
| | - Inbum Chung
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.)
| | - Seo Hyun Yoon
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.)
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.)
| | - Kyoung Soo Lim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.)
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.)
| | - Howard Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.)
| | - In-Jin Jang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.)
| | - Jae Yong Chung
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.)
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Abstract
The existence of the hormone gastrin in the distal stomach (antrum) has been known for almost 110 years, and the physiological function of this amidated peptide in regulating gastric acid secretion via the CCK2 receptor is now well established. In this brief review we consider important additional roles of gastrin, including regulation of genes encoding proteins such as plasminogen activator inhibitors and matrix metalloproteinases that have important actions on extracellular matrix remodelling. These actions are, at least in part, effected by paracrine signalling pathways and make important contributions to maintaining functional integrity of the gastric epithelium. Recent studies also provide support for the idea that gastrin, in concert with other hormones, could potentially contribute a post-prandial incretin effect. We also review recent developments in the biology of other gastrin gene products, including the precursor progastrin, which causes proliferation of the colonic epithelium and in certain circumstances may induce cancer formation. Glycine-extended biosynthetic processing intermediates also have proliferative effects in colonic mucosa and in some oesophageal cancer cell lines. Whether these additional gene products exert their effects through the CCK2 receptor or a separate entity is currently a matter of debate.
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Affiliation(s)
- Rod Dimaline
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Andrea Varro
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
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Hao S, Sun J, Tian X, Sun X, Zhang Z, Gao Y. Lansoprazole enhances the antidiabetic effect of sitagliptin in mice with diet-induced obesity and healthy human subjects. ACTA ACUST UNITED AC 2014; 66:1133-9. [PMID: 24628303 DOI: 10.1111/jphp.12237] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Accepted: 02/02/2014] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Proton pump inhibitors as adjunctive therapy would improve diabetes control and could enhance the hypoglycaemic activity of DPP-4 inhibitors. The aim of the study was to investigate the short-term effects of lansoprazole (LPZ), sitagliptin (SITA) and their combination therapy on glucose regulation and gut peptide secretion. METHODS Glucose and gut peptide were determined and compared after short-term administration of LPZ or SITA, or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects (n = 16) in a 75 g oral glucose tolerance test (OGTT) by a crossover design. KEY FINDINGS In DIO mice, LPZ significantly improve glucose metabolism, increase plasma C-peptide and insulin compared with vehicle treatment. Furthermore, the combination of LPZ and SITA improved glucose tolerance additively, with higher plasma insulin and C-peptide levels compared with SITA-treated mice. Similarly, in human in the OGTT, the combination showed significant improvement in glucose-lowering and insulin increase vs SITA-treated group. However, no significant differences in area under curve (AUC) of insulin, glucose and C-peptide between the LPZ-treated group and baseline, except that mean AUCgastrin was significantly increased by LPZ. CONCLUSIONS LPZ and SITA combination therapy appears to have complementary mechanisms of action and additive antidiabetic effect.
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Affiliation(s)
- ShaoJun Hao
- Department of Pharmacy and Equipment, No. 371 Hospital of PLA, Xin'xiang, China
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Takebayashi K, Sakurai S, Suzuki T, Hori K, Terasawa T, Naruse R, Hara K, Suetsugu M, Tsuchiya T, Aoki H, Hamasaki T, Shuutou H, Inukai T. Effect of combination therapy with alogliptin and lansoprazole on glycemic control in patients with type 2 diabetes. Endocr J 2014; 61:1031-9. [PMID: 25185672 DOI: 10.1507/endocrj.ej14-0208] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The main purpose of the current study was to investigate the effect of a combination of alogliptin [a dipeptydil peptidase (DPP)-4 inhibitor] and lansoprazole [a proton pump inhibitor (PPI)] compared with alogliptin mono-therapy on glycemic control in patients with type 2 diabetes. This study was a multicenter randomized open-label study. One hundred type 2 diabetic patients were randomly assigned to either the alogliptin with lansoprazole group or the alogliptin mono-therapy group. After 3 months of treatment, the changes in hemoglobin (Hb)A1c, fasting plasma glucose (FPG), serum gastrin, homeostasis model assessment (HOMA)-β, and HOMA-insulin resistance (IR) were evaluated. A significant decrease in HbA1c and FPG, and a significant increase in HOMA-β were observed in both groups (all with P <0.0001). However, there were no significant differences in changes in HbA1c, FPG, or HOMA-β before and after therapy between the combination and alogliptin mono-therapy group (P =0.2945, P =0.1901, P =0.3042, respectively). There was a significant elevation of serum gastrin in the combination group compared with the alogliptin mono-therapy group (P =0.0004). This study showed that, although combination therapy with alogliptin and lansoprazole more effectively elevated serum gastrin levels compared with alogliptin mono-therapy, the effect of the combination therapy on glycemic control was equal to that of alogliptin mono-therapy during a 3-month study period.
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Affiliation(s)
- Kohzo Takebayashi
- Department of Internal Medicine, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan
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Sertorio JTC. Proton pump inhibitors and nitric oxide mechanisms in type 2 diabetes. Diabetologia 2013; 56:2763-4. [PMID: 24048672 DOI: 10.1007/s00125-013-3054-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 08/28/2013] [Indexed: 10/26/2022]
Affiliation(s)
- Jonas T C Sertorio
- Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil,
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Abstract
Peptide hormones and proteins control body weight and glucose homeostasis by engaging peripheral and central metabolic signalling pathways responsible for the maintenance of body weight and euglycaemia. The development of obesity, often in association with type 2 diabetes mellitus (T2DM), reflects a dysregulation of metabolic, anorectic and orexigenic pathways in multiple organs. Notably, therapeutic attempts to normalize body weight and glycaemia with single agents alone have generally been disappointing. The success of bariatric surgery, together with emerging data from preclinical studies, illustrates the rationale and feasibility of using two or more agonists, or single co-agonists, for the treatment of obesity and T2DM. Here, we review advances in the science of co-agonist therapy, and highlight promising areas and challenges in co-agonist development. We describe mechanisms of action for combinations of glucagon-like peptide 1, glucagon, gastric inhibitory polypeptide, gastrin, islet amyloid polypeptide and leptin, which enhance weight loss whilst preserving glucoregulatory efficacy in experimental models of obesity and T2DM. Although substantial progress has been achieved in preclinical studies, the putative success and safety of co-agonist therapy for the treatment of patients with obesity and T2DM remains uncertain and requires extensive additional clinical validation.
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Affiliation(s)
- Sharon A Sadry
- Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue TCP5-1004, Toronto M5G 1X5, ON, Canada
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