|
1
|
Fang YJ, Hsieh HH, Lin CL, Lee WY, Chen CH, Tsai FJ, You BJ, Tien N, Lim YP. Impact of anti-peptic ulcer disease medications on type 2 diabetes mellitus risk in patients with PUD: a population-based retrospective cohort study. Ther Adv Endocrinol Metab 2025; 16:20420188251323945. [PMID: 40110098 PMCID: PMC11921004 DOI: 10.1177/20420188251323945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 02/03/2025] [Indexed: 03/22/2025] Open
Abstract
Background The etiology of type 2 diabetes mellitus (T2DM) is complex, with environmental factors playing a significant role in its pathophysiology. Nonsteroidal anti-inflammatory drugs usage and Helicobacter pylori infection are the two most frequent causes of peptic ulcer disease (PUD). The link between PUD and T2DM is unclear, and comprehensive analyses of anti-PUD medications' impact on T2DM risk, especially in Asian populations, are lacking. This study aimed to determine the relationship between PUD, anti-PUD medications, and the likelihood of developing T2DM. Objectives Using a population-based cohort study conducted in Taiwan, we investigated the impact of PUD and anti-PUD medications on the risk of T2DM. Design This is a retrospective, population-based cohort study using the largest database used in Taiwan. Methods An 18-year follow-up period study was conducted on a cohort of patients with PUD diagnosed between 2001 and 2018 using the Taiwan National Health Insurance Research Database. The risk of PUD as well as anti-PUD medications use were examined using Cox proportional regression model. Results Based on multivariable Cox proportional hazards regression analysis, patients with PUD had a higher overall T2DM incidence (22.7 vs 21.3 per 1000 person-years) than patients without PUD. The adjusted hazard ratio was 1.12 (95% confidence interval = 1.10, 1.13). Patients with PUD have a higher risk of T2DM in both genders and age groups. Patients with anti-PUD medications, such as H2 receptor antagonists, proton-pump inhibitors, antibiotics, prostaglandin analogs, anticholinergics, and antacids usage, are associated with a lower risk of developing T2DM than those without. Patients with PUD who underwent surgery were found to have a higher risk of T2DM. Conclusion Patients with PUD are more likely to develop T2DM. Nevertheless, patients receiving anti-PUD medications have a lower incidence of T2DM.
Collapse
Affiliation(s)
- Yi-Jen Fang
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung-Hsing University, Taichung, Taiwan
- Digestive Disease Center, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Hui-Hsia Hsieh
- Department of Pharmacy, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 66, Sec. 1, Fengxing Road, Tanzi Dist., Taichung 427213, Taiwan
- Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Wan-Yi Lee
- Department of Pharmacy, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan
- Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
| | - Chi-Hua Chen
- Department of Pharmacy, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan
| | - Fuu-Jen Tsai
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
- Division of Medical Genetics, China Medical University Children's Hospital, Taichung, Taiwan
- Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan
| | - Bang-Jau You
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan
| | - Ni Tien
- Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
| | - Yun-Ping Lim
- Department of Pharmacy, College of Pharmacy, China Medical University, No. 100, Sec. 1, Jingmao Road, Beitun Dist., Taichung 406040, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| |
Collapse
|
|
2
|
Liu FS, Wang S, Guo XS, Ye ZX, Zhang HY, Li Z. State of art on the mechanisms of laparoscopic sleeve gastrectomy in treating type 2 diabetes mellitus. World J Diabetes 2023; 14:632-655. [PMID: 37383590 PMCID: PMC10294061 DOI: 10.4239/wjd.v14.i6.632] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 04/01/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
Obesity and type-2 diabetes mellitus (T2DM) are metabolic disorders. Obesity increases the risk of T2DM, and as obesity is becoming increasingly common, more individuals suffer from T2DM, which poses a considerable burden on health systems. Traditionally, pharmaceutical therapy together with lifestyle changes is used to treat obesity and T2DM to decrease the incidence of comorbidities and all-cause mortality and to increase life expectancy. Bariatric surgery is increasingly replacing other forms of treatment of morbid obesity, especially in patients with refractory obesity, owing to its many benefits including good long-term outcomes and almost no weight regain. The bariatric surgery options have markedly changed recently, and laparoscopic sleeve gastrectomy (LSG) is gradually gaining popularity. LSG has become an effective and safe treatment for type-2 diabetes and morbid obesity, with a high cost-benefit ratio. Here, we review the me-chanism associated with LSG treatment of T2DM, and we discuss clinical studies and animal experiments with regard to gastrointestinal hormones, gut microbiota, bile acids, and adipokines to clarify current treatment modalities for patients with obesity and T2DM.
Collapse
Affiliation(s)
- Fa-Shun Liu
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Song Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Xian-Shan Guo
- Department of Endocrinology, Xinxiang Central Hospital, Xinxiang 453000, Henan Province, China
| | - Zhen-Xiong Ye
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Hong-Ya Zhang
- Central Laboratory, Yangpu District Control and Prevention Center, Shanghai 200090, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| |
Collapse
|
|
3
|
Lin MH, Wu WT, Chen YC, Lin TK, Chou YC, Sun CA. Association between clinical use of lansoprazole and the risk of type 2 diabetes mellitus: a pharmacoepidemiological cohort study. Diabetol Metab Syndr 2023; 15:96. [PMID: 37165435 PMCID: PMC10170833 DOI: 10.1186/s13098-023-01051-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 03/31/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are common and widely used for gastrointestinal-related disorders. Lansoprazole is one of PPIs with potential benefits of anti-inflammation, reduced oxidative stress, and anti-diabetes. The aims of this study are to determine whether lansoprazole imparts differential risk of type 2 diabetes as compared with other PPIs. METHODS A population-based retrospective cohort study was conducted using the National Health Insurance Research Database in Taiwan. Patients who received lansoprazole more than 90 days and without records of use of other PPIs between January 1, 2000 and December 31, 2005 (the exposure period) were considered as the exposed cohort (n = 1668). In comparison, patients who received other PPIs more than 90 days and without use of lansoprazole in the exposure period were treated as the comparison cohort (n = 3336).The primary outcome was the new-onset of type 2 diabetes mellitus (T2DM). The association between use of lansoprazole and the risk of T2DM was determined by hazard ratios (HRs) and 95% confidence intervals (CIs) derived from multivariable Cox proportional hazards models. RESULTS The lansoprazole cohort showed a significantly reduced risk of T2DM with an adjusted HR of 0.65 (95% CI 0.56-0.76). Interestingly, the inverse association between use of lansoprazole and risk of T2DM was observed in both genders and in various age groups. CONCLUSION The present study findings suggest that lansoprazole was associated with a reduced risk of T2DM compared with other PPIs. Further studies are needed to determine the clinical implications of the present study.
Collapse
Affiliation(s)
- Ming-Hsun Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, 114, Taiwan
| | - Wen-Tung Wu
- Department of Pharmacy, Tri-Service General Hospital, National Defense Medical Center, Taipei City, 114, Taiwan
| | - Yong-Chen Chen
- Department of Public Health, College of Medicine, Fu-Jen Catholic University, No.510, Zhongzheng Road, Xinzhuang District, New Taipei City, 242, Taiwan
- Department of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, 242, Taiwan
| | - Tsung-Kun Lin
- School of Pharmacy, National Defense Medical Center, Taipei City, 114, Taiwan
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, Taipei City, 114, Taiwan
| | - Chien-An Sun
- Department of Public Health, College of Medicine, Fu-Jen Catholic University, No.510, Zhongzheng Road, Xinzhuang District, New Taipei City, 242, Taiwan.
| |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
Trang A, Bushman J, Halalau A. Effect of Long-Term Proton Pump Inhibitor Use on Glycemic Control in Patients with Type Two Diabetes Mellitus. J Diabetes Res 2021; 2021:5578265. [PMID: 34368365 PMCID: PMC8346311 DOI: 10.1155/2021/5578265] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 07/04/2021] [Accepted: 07/20/2021] [Indexed: 11/28/2022] Open
Abstract
There have been conflicting results regarding the effect of proton pump inhibitors (PPIs) as an adjunctive therapy to oral antidiabetic medication (OAM) in those with type 2 diabetes (T2DM). PPIs increase gastrin levels, causing a rise in insulin. No studies have evaluated the duration of PPI therapy and its effect on glycemic control. Medical records across 8 hospitals between 2007 and 2016 were reviewed for 14,602 patients with T2DM (not on insulin therapy) taking PPIs. Values of HbA1c (baseline, follow-up, and the difference between the two) in those prescribed with PPIs and years of therapy were compared to HbA1c values of those who had no record of PPI use. Baseline and follow-up HbA1c for patients on PPIs were 6.8 and 7.0, respectively, compared to 7.1 and 7.2 in their untreated counterparts (p < 0.001 in both comparisons). For both groups, an increase in baseline HbA1c was seen with time. Those on PPI had an increase in HbA1c of 0.16 compared to 0.08 in those not prescribed PPI. Our results show no relationship between the length of PPI therapy and HbA1c reduction.
Collapse
Affiliation(s)
- Amy Trang
- Oakland University William Beaumont School of Medicine, Rochester Hills, MI, USA
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Jordan Bushman
- Department of Internal Medicine, William Beaumont Hospital, Royal Oak, MI, USA
| | - Alexandra Halalau
- Oakland University William Beaumont School of Medicine, Rochester Hills, MI, USA
- Department of Internal Medicine, William Beaumont Hospital, Royal Oak, MI, USA
| |
Collapse
|
|
6
|
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.
Collapse
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
| |
Collapse
|
|
7
|
Cho J, Scragg R, Pandol SJ, Petrov MS. Exocrine Pancreatic Dysfunction Increases the Risk of New-Onset Diabetes Mellitus: Results of a Nationwide Cohort Study. Clin Transl Sci 2020; 14:170-178. [PMID: 32692901 PMCID: PMC7877819 DOI: 10.1111/cts.12837] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/03/2020] [Indexed: 12/11/2022] Open
Abstract
It is well established that individuals with diabetes mellitus (DM) may develop exocrine pancreatic dysfunction (EPD) requiring pancreatic enzyme replacement therapy, whereas the converse relationship has been poorly studied. Pancreatitis is a disease that is well suited to investigate the latter as it is often characterized by the development of EPD and/or new‐onset DM. The aim was to investigate the association between EPD and the risk of new‐onset DM in individuals after the first attack of pancreatitis. Using nationwide pharmaceutical dispensing data and hospital discharge data, this cohort study included a total of 9,124 post‐pancreatitis individuals. EPD was defined as having two or more dispensing records of pancreatic enzymes. Considering EPD as a time‐dependent variable, multivariable Cox regression analysis was conducted. A 1‐year lag period between EPD and DM was introduced to minimize reverse causality. Age, sex, ethnicity, alcohol consumption, tobacco smoking, social deprivation index, Charlson comorbidity index, and use of proton pump inhibitors were adjusted for. In the overall cohort, EPD was associated with a significantly higher risk for new‐onset DM (adjusted hazard ratio, 3.83; 95% confidence interval, 2.37–6.18). The association remained statistically significant when a 1‐year lag period was applied (adjusted hazard ratio, 2.51; 95% confidence interval, 1.38–4.58), as well as when the analysis was constrained to mild acute pancreatitis (4.65; 2.18–9.93). The findings suggest that individuals with EPD, even those without extensive mechanistic destruction of the pancreas, are at an increased risk for new‐onset DM. Purposely designed studies are warranted to investigate mechanisms behind the association and if the mechanisms could be targeted therapeutically.
Collapse
Affiliation(s)
- Jaelim Cho
- School of Medicine, University of Auckland, Auckland, New Zealand
| | - Robert Scragg
- School of Population Health, University of Auckland, Auckland, New Zealand
| | - Stephen J Pandol
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Maxim S Petrov
- School of Medicine, University of Auckland, Auckland, New Zealand
| |
Collapse
|
|
8
|
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.
Collapse
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
| |
Collapse
|
|
9
|
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.
Collapse
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
| |
Collapse
|
|
10
|
Dahabiyeh LA, Abu-Rish EY, Taha MO. Inhibition of monoglyceride lipase by proton pump inhibitors: investigation using docking and in vitro experiments. Pharmacol Rep 2020; 72:435-442. [PMID: 32048247 DOI: 10.1007/s43440-019-00013-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 08/26/2019] [Accepted: 10/18/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Currently, there is overwhelming evidence linking elevated plasma free fatty acids with insulin resistance and inflammation. Monoglyceride lipase (MGL) plays a crucial metabolic role in lipolysis by mediating the release of fatty acids. Therefore, inhibiting MGL should be a promising pharmacological approach for treating type 2 diabetes and inflammatory disorders. Proton pump inhibitors (PPIs) have been reported to improve glycemic control in type 2 diabetes albeit via largely unknown mechanism. METHODS The anti-MGL bioactivities of three PPIs, namely, lansoprazole, rabeprazole, and pantoprazole, were investigated using docking experiments and in vitro bioassay. RESULTS The three PPIs inhibited MGL in low micromolar range with rabeprazole exhibiting the best IC50 at 4.2 µM. Docking experiments showed several binding interactions anchoring PPIs within MGL catalytic site. CONCLUSION Our study provides evidence for a new mechanism by which PPIs improve insulin sensitivity independent of serum gastrin. The three PPIs effectively inhibit MGL and, therefore, serve as promising leads for the development of new clinical MGL inhibitors.
Collapse
Affiliation(s)
- Lina A Dahabiyeh
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Queen Rania St, Amman, 11942, Jordan.
| | - Eman Y Abu-Rish
- Department of Clinical Pharmacy and Biopharmaceutics, School of Pharmacy, The University of Jordan, Amman, Jordan
| | - Mutasem O Taha
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Queen Rania St, Amman, 11942, Jordan.
| |
Collapse
|
|
11
|
Gamil NM, Abd El Fattah MA, Ahmed MAE, Maklad YA, Gamal El Din AA, Eid NI. Lansoprazole enhances the antidiabetic effect of dapagliflozin in fortified diet-fed streptozotocin-treated diabetic rats. J Biochem Mol Toxicol 2020; 34:e22451. [PMID: 31975531 DOI: 10.1002/jbt.22451] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 11/29/2019] [Accepted: 01/08/2020] [Indexed: 12/19/2022]
Abstract
Dapagliflozin (DAPA) is used for treating type 2 diabetes, whereas lansoprazole (LPZ) is used as a traditional antiulcer drug. The present study investigated the possible antidiabetic effects of LPZ on fortified diet-fed streptozotocin (FDF/STZ)-induced insulin-resistant diabetic rats. On the basis of the current results, it can be concluded that LPZ could be used as an add-on drug along with the conventional treatment for T2D as it showed beneficial effects in the current experimental model of insulin resistance.
Collapse
Affiliation(s)
- Noha M Gamil
- Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt
| | - Mai A Abd El Fattah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Maha A E Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt
| | - Yousreya A Maklad
- Medicinal and Pharmaceutical Chemistry Department (Pharmacology Group), Pharmaceutical and Drug Industries Research Division, National Research Centre, Giza, Egypt
| | - Amina A Gamal El Din
- Medical Research Division, Pathology Department, National Research Centre, Giza, Egypt
| | - Nihad I Eid
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| |
Collapse
|
|
12
|
Ala M, Jafari RM, Dehpour AR. Diabetes Mellitus and Osteoporosis Correlation: Challenges and Hopes. Curr Diabetes Rev 2020; 16:984-1001. [PMID: 32208120 DOI: 10.2174/1573399816666200324152517] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 02/02/2020] [Accepted: 02/24/2020] [Indexed: 01/14/2023]
Abstract
Diabetes and osteoporosis are two common diseases with different complications. Despite different therapeutic strategies, managing these diseases and reducing their burden have not been satisfactory, especially when they appear one after the other. In this review, we aimed to clarify the similarity, common etiology and possible common adjunctive therapies of these two major diseases and designate the known molecular pattern observed in them. Based on different experimental findings, we want to illuminate that interestingly similar pathways lead to diabetes and osteoporosis. Meanwhile, there are a few drugs involved in the treatment of both diseases, which most of the time act in the same line but sometimes with opposing results. Considering the correlation between diabetes and osteoporosis, more efficient management of both diseases, in conditions of concomitant incidence or cause and effect condition, is required.
Collapse
Affiliation(s)
- Moein Ala
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, 13145-784, Tehran, Iran
| | - Razieh Mohammad Jafari
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, 13145-784, Tehran, Iran
| |
Collapse
|
|
13
|
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.
Collapse
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
| |
Collapse
|
|
14
|
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.
Collapse
Affiliation(s)
| | - Jennifer R Weiskopf
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | | |
Collapse
|
|
15
|
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.
Collapse
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
| |
Collapse
|
|
16
|
Muscogiuri G, Balercia G, Barrea L, Cignarelli A, Giorgino F, Holst JJ, Laudisio D, Orio F, Tirabassi G, Colao A. Gut: A key player in the pathogenesis of type 2 diabetes? Crit Rev Food Sci Nutr 2017; 58:1294-1309. [PMID: 27892685 DOI: 10.1080/10408398.2016.1252712] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The gut regulates glucose and energy homeostasis; thus, the presence of ingested nutrients into the gut activates sensing mechanisms that affect both glucose homeostasis and regulate food intake. Increasing evidence suggest that gut may also play a key role in the pathogenesis of type 2 diabetes which may be related to both the intestinal microbiological profile and patterns of gut hormones secretion. Intestinal microbiota includes trillions of microorganisms but its composition and function may be adversely affected in type 2 diabetes. The intestinal microbiota may be responsible of the secretion of molecules that may impair insulin secretion/action. At the same time, intestinal milieu regulates the secretion of hormones such as GLP-1, GIP, ghrelin, gastrin, somatostatin, CCK, serotonin, peptide YY, GLP-2, all of which importantly influence metabolism in general and in particular glucose metabolism. Thus, the aim of this paper is to review the current evidence on the role of the gut in the pathogenesis of type 2 diabetes, taking into account both hormonal and microbiological aspects.
Collapse
Affiliation(s)
| | - Giancarlo Balercia
- b Division of Endocrinology, Department of Clinical and Molecular Sciences , Umberto I Hospital, Polytechnic University of Marche , Ancona , Italy
| | | | - Angelo Cignarelli
- c Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases , University of Bari Aldo Moro , Bari , Italy
| | - Francesco Giorgino
- c Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases , University of Bari Aldo Moro , Bari , Italy
| | - Jens J Holst
- d NNF Center for Basic Metabolic Research and Department of Biomedical Sciences , Panum Institute, University of Copenhagen, Copenhagen , Denmark
| | | | - Francesco Orio
- e Endocrinology, Department of Sports Science and Wellness , "Parthenope" University Naples , Naples , Italy
| | - Giacomo Tirabassi
- b Division of Endocrinology, Department of Clinical and Molecular Sciences , Umberto I Hospital, Polytechnic University of Marche , Ancona , Italy
| | - Annamaria Colao
- f Department of Clinical Medicine and Surgery , "Federico II" University of Naples , Naples , Italy
| |
Collapse
|
|
17
|
A Narrative Review of Potential Future Antidiabetic Drugs: Should We Expect More? Indian J Clin Biochem 2017; 33:121-131. [PMID: 29651202 DOI: 10.1007/s12291-017-0668-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 05/24/2017] [Indexed: 02/06/2023]
Abstract
Prevalence of diabetes mellitus, a chronic metabolic disease characterized by hyperglycemia, is growing worldwide. The majority of the cases belong to type 2 diabetes mellitus (T2DM). Globally, India ranks second in terms of diabetes prevalence among adults. Currently available classes of therapeutic agents are used alone or in combinations but seldom achieve treatment targets. Diverse pathophysiology and the need of therapeutic agents with more favourable pharmacokinetic-pharmacodynamics profile make newer drug discoveries in the field of T2DM essential. A large number of molecules, some with novel mechanisms, are in pipeline. The essence of this review is to track and discuss these potential agents, based on their developmental stages, especially those in phase 3 or phase 2. Unique molecules are being developed for existing drug classes like insulins, DPP-4 inhibitors, GLP-1 analogues; and under newer classes like dual/pan PPAR agonists, dual SGLT1/SGLT2 inhibitors, glimins, anti-inflammatory agents, glucokinase activators, G-protein coupled receptor agonists, hybrid peptide agonists, apical sodium-dependent bile acid transporter (ASBT) inhibitors, glucagon receptor antagonists etc. The heterogeneous clinical presentation and therapeutic outcomes in phenotypically similar patients is a clue to think beyond the standard treatment strategy.
Collapse
|
|
18
|
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.
Collapse
|
|
19
|
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.
Collapse
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
| |
Collapse
|
|
20
|
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.
Collapse
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
| |
Collapse
|
|
21
|
Affiliation(s)
- Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
| |
Collapse
|
|
22
|
Yi D. Letter: Prevalence and Risk Factors of Gastroesophageal Reflux Disease in Patients with Type 2 Diabetes Mellitus ( Diabetes Metab J 2016;40:297-307). Diabetes Metab J 2016; 40:418-419. [PMID: 27766250 PMCID: PMC5069399 DOI: 10.4093/dmj.2016.40.5.418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Dongwon Yi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| |
Collapse
|
|
23
|
|
|
24
|
Lin HC, Hsiao YT, Lin HL, Uang YS, Cheng HW, Wang Y, Wang LH. The use of proton pump inhibitors decreases the risk of diabetes mellitus in patients with upper gastrointestinal disease: A population-based retrospective cohort study. Medicine (Baltimore) 2016; 95:e4195. [PMID: 27428221 PMCID: PMC4956815 DOI: 10.1097/md.0000000000004195] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES The aim of this study was to investigate the effects of proton pump inhibitors (PPIs) on the risk of diabetes mellitus (DM) among patients with upper gastrointestinal disease (UGID). METHODS This was a retrospective cohort study with a follow-up period of 5 years. We identified 388,098 patients who were diagnosed with UGID between 2000 and 2006 from the Longitudinal Health Insurance Database of the Taiwan National Health Insurance program. We used Cox proportional hazard ratio (HR) to compare the risk of DM between UGID patients received PPIs and those did not receive PPIs. HRs were adjusted for possible confounders, including age, sex, hypertension, gout and/or hyperuricemia, coronary artery disease, stroke, pancreatitis, hyperlipidemia, obesity, H2-blocker use, and clozapine or olanzapine use. The dose-related effects of PPIs on the risk of DM were evaluated according to the defined daily dose (DDD). RESULTS The adjusted HR was 0.80 (95% CI, 0.73-0.88) for the study group (UGID patients with PPIs) compared with comparison group I (UGID patients without PPIs). Among patients who used PPIs, those older than 60 years of age had a lower risk of DM (HR, 0.73; 95% CI, 0.63-0.83) than those younger than 40 years. Additionally, the effect of PPIs was significantly dose-dependent (P for trend <0.001). Patients with UGID who received >540 DDDs of PPIs exhibited the greatest reduction in the risk of DM. CONCLUSIONS Our results demonstrated a decreased risk of DM in UGID patients who used PPIs; the risk appeared to be significantly dose-dependent.
Collapse
Affiliation(s)
- Hsiu-Chen Lin
- Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei
- Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei
- School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei
| | - Yu-Ting Hsiao
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei
| | - Hsiu-Li Lin
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei
- Department of Neurology, Cathy General Hospital, Sijhih Branch, New Taipei City
| | - Yow-Shieng Uang
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei
| | - Hui-Wen Cheng
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei
| | - Ying Wang
- Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei
| | - Li-Hsuan Wang
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei
- Department of Pharmacy, Taipei Medical University Hospital, Taipei, Taiwan
- Correspondence: Li-Hsuan Wang, School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wu-Hsing St., Taipei 11031, Taiwan (e-mail: )
| |
Collapse
|
|
25
|
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]
|
|
26
|
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.
Collapse
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.
| |
Collapse
|
|
27
|
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.
Collapse
|
|
28
|
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]
|
|
29
|
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.
Collapse
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
| |
Collapse
|
|
30
|
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.
Collapse
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
| |
Collapse
|
|
31
|
Cao Y, Cao X, Liu XM. Expression of cholecystokinin2-receptor in rat and human L cells and the stimulation of glucagon-like peptide-1 secretion by gastrin treatment. Acta Histochem 2015; 117:205-10. [PMID: 25601282 DOI: 10.1016/j.acthis.2014.12.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 11/30/2014] [Accepted: 12/18/2014] [Indexed: 12/21/2022]
Abstract
Gastrin is a gastrointestinal hormone secreted by G cells. Hypergastrinemia can improve blood glucose and glycosylated hemoglobin levels. These positive effects are primarily due to the trophic effects of gastrin on β-cells. In recent years, many receptors that regulate secretion of glucagon-like peptide 1 (GLP-1) have been identified in enteroendocrine L cell lines. This led us to hypothesize that, in addition to the trophic effects of gastrin on β-cells, L cells also express cholecystokinin2-receptor (CCK2R), which may regulate GLP-1 secretion and have synergistic effects on glucose homeostasis. Our research provides a preliminary analysis of CCK2R expression and the stimulating effect of gastrin treatment on GLP-1 secretion in a human endocrine L cell line, using RT-PCR, Western blot, immunocytochemistry, and ELISA analyses. The expression of proglucagon and prohormone convertase 3, which regulate GLP-1 biosynthesis, were also analyzed by real-time PCR. Double immunofluorescence labeling was utilized to assess the intracellular localization of CCK2R and GLP-1 in L cells harvested from rat colon tissue. Our results showed that CCK2R was expressed in both the human L cell line and the rat L cells. We also showed that treatment with gastrin, a CCK2R agonist, stimulated the secretion of GLP-1, and that this effect was likely due to increased expression of proglucagon and PCSK1 (also known as prohormone convertase 3 (PC3 gene)). These results not only provide a basis for the role gastrin may play in intestinal L cells, and may also provide the basis for the development of a method of gastrin-mediated glycemic regulation.
Collapse
Affiliation(s)
- Yang Cao
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xun Cao
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xiao-Min Liu
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China.
| |
Collapse
|
|
32
|
Cao Y, Liu XM. Should we still be concerned about the potential side effects of glucagon-like peptide-1 receptor agonists on thyroid C cells? Endocrine 2015; 48:47-52. [PMID: 25033998 DOI: 10.1007/s12020-014-0354-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 06/29/2014] [Indexed: 12/15/2022]
Abstract
In recent years, numerous novel anti-diabetic drugs have emerged. Among them, glucagon-like peptide-1 receptor (GLP-1R) agonists developed on the basis of the incretin theory are the most popular and surprising. Thus far, the clinical and experimental efficiency and safety data seem to be good. However, questions about the side effects of GLP-1R agonists, especially on thyroid C cells, still remain. In vivo and in vitro rodent experiments have shown the potential risks of GLP-1R agonists on thyroid C cells. However, the effects of GLP-1R agonists in humans, which have only been studied in experiments using untreated thyroid tissues or C-cell lines, are questionable and differ from that in rodents. C-cell abnormalities are not only dependent on GLP-1R, as many other factors also influence the structure and function of thyroid C cells. Furthermore, there is not enough information from patients with diabetes or tissue samples from subjects treated with GLP-1R agonists and related drugs--especially data obtained during the prandial period or from a long-term study. Therefore, it is important to focus on the possible side effects of GLP-1R agonists on thyroid C cells.
Collapse
Affiliation(s)
- Yang Cao
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, No. 24 Youzheng Street, Harbin, 150001, Heilongjiang Province, China
| | | |
Collapse
|
|
33
|
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.
Collapse
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
| |
Collapse
|
|
34
|
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.
Collapse
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,
| | | | | | | | | | | |
Collapse
|
|
35
|
Dalbøge LS, Almholt DLC, Neerup TSR, Vrang N, Jelsing J, Fosgerau K. The novel GLP-1-gastrin dual agonist ZP3022 improves glucose homeostasis and increases β-cell mass without affecting islet number in db/db mice. J Pharmacol Exp Ther 2014; 350:353-60. [PMID: 24902584 DOI: 10.1124/jpet.114.215293] [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: 12/25/2022] Open
Abstract
Antidiabetic treatments aiming to preserve or even to increase β-cell mass are currently gaining increased interest. Here we investigated the effect of chronic treatment with the novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist ZP3022 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2) on glycemic control, β-cell mass and proliferation, and islet number. Male db/db mice were treated with ZP3022, liraglutide, or vehicle for 2, 4, or 8 weeks, with terminal assessment of hemoglobin A1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of β-cell mass, islet numbers, proliferation, and apoptosis. Treatment with ZP3022 or liraglutide led to a significant improvement in glycemic control. ZP3022 treatment resulted in a sustained increase in β-cell mass after 4 and 8 weeks of treatment, whereas the effect of liraglutide was transient. The expansion in β-cell mass observed in the ZP3022-treated mice appeared to be driven by increased β-cell proliferation in existing islets rather than by formation of new islets, as mean islet mass increased but the number of islets remained constant. Our data demonstrate that the GLP-1-gastrin dual agonist ZP3022 causes a sustained improvement in glycemic control accompanied by an increase in β-cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1-gastrin dual agonist increases β-cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of antidiabetic treatments.
Collapse
Affiliation(s)
- Louise S Dalbøge
- Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
| | - Dorthe L C Almholt
- Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
| | - Trine S R Neerup
- Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
| | - Niels Vrang
- Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
| | - Jacob Jelsing
- Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
| | - Keld Fosgerau
- Gubra ApS, Hørsholm, Denmark (L.S.D., N.V., J.J.); and Zealand Pharma A/S, Glostrup, Denmark (D.L.C.A., T.S.R.N., K.F.)
| |
Collapse
|
|
36
|
Inci F, Atmaca M, Ozturk M, Yildiz S, Koceroglu R, Sekeroglu R, Ipekci SH, Kebapcilar L. Pantoprazole may improve beta cell function and diabetes mellitus. J Endocrinol Invest 2014; 37:449-54. [PMID: 24682913 DOI: 10.1007/s40618-013-0040-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Accepted: 12/06/2013] [Indexed: 01/02/2023]
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 (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 log-HOMA-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.
Collapse
Affiliation(s)
- F Inci
- Department of Internal Medicine, University of Yuzuncu Yil, Van, Turkey
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
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.
Collapse
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
| |
Collapse
|
|
38
|
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.
Collapse
Affiliation(s)
- ShaoJun Hao
- Department of Pharmacy and Equipment, No. 371 Hospital of PLA, Xin'xiang, China
| | | | | | | | | | | |
Collapse
|
|
39
|
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.
Collapse
Affiliation(s)
- Kohzo Takebayashi
- Department of Internal Medicine, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Abstract
This review provides an overview of the vast gastrointestinal tract complications of diabetes that can occur from the mouth to the anus. The presentation, diagnosis, and management of gastrointestinal disorders, ranging from gastroparesis, celiac disease, and bacterial overgrowth to nonalcoholic fatty liver disease, are reviewed to heighten awareness. When managing care of patients with diabetes, one should keep in mind the potential gastrointestinal complications, as well as the frequent disorders that are not related to diabetes.
Collapse
Affiliation(s)
- Brigid S Boland
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
| | | | | |
Collapse
|
|
41
|
Levetan C, Pozzilli P, Jovanovic L, Schatz D. Proposal for generating new beta cells in a muted immune environment for type 1 diabetes. Diabetes Metab Res Rev 2013; 29:604-6. [PMID: 23853103 PMCID: PMC4237549 DOI: 10.1002/dmrr.2435] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 07/10/2013] [Indexed: 01/13/2023]
Abstract
BACKGROUND Over the past decade, many immune tolerance agents have shown promise in the non-obese diabetic mouse model for prevention and reversal of type 1 diabetes but have not been successful in clinical trials among recently diagnosed type 1 patients. The trials from decades ago using Cyclosporine A in significantly lower dosages than used for organ transplantation and in similar dosages that have increased T regulatory cell populations in conditions such as atopic dermatitis, demonstrated very high initial insulin-free remission rates when administered immediately after diagnosis. Over time, all newly diagnosed type 1 patients given Cyclosporine A required insulin. Human trials with immune tolerance agents suggest that in addition to an immune tolerance agent, a beta cell regeneration agent may also be necessary to induce long-lasting remission among patients with recent onset type 1 diabetes. METHODS A randomized, double-blind prospective trial among recent onset type 1 diabetes patients has been designed using Cyclosporine A and a proton-pump inhibitor, which increases gastrin levels and has been shown to work through the Reg receptor to transform pancreatic duct cells into islets.
Collapse
Affiliation(s)
- Claresa Levetan
- Department of Endocrinology, Chestnut Hill HospitalPhiladelphia, PA, USA
| | - Paolo Pozzilli
- Department of Endocrinology, Chestnut Hill HospitalPhiladelphia, PA, USA
| | - Lois Jovanovic
- Department of Endocrinology, Chestnut Hill HospitalPhiladelphia, PA, USA
| | - Desmond Schatz
- Department of Endocrinology, Chestnut Hill HospitalPhiladelphia, PA, USA
| |
Collapse
|
|
42
|
Affiliation(s)
- Satish K Garg
- 1 Barbara Davis Center for Diabetes, University of Colorado Denver , Aurora, Colorado
| | | | | |
Collapse
|
|
43
|
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.
Collapse
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
| | | |
Collapse
|