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Park J, Yamamoto Y, Hidaka K, Wada-Takahashi S, Takahashi SS, Morozumi T, Kubota N, Saita M, Saruta J, Sakaguchi W, To M, Shimizu T, Mikuni-Takagaki Y, Tsukinoki K. Effects of Diabetes and Voluntary Exercise on IgA Concentration and Polymeric Immunoglobulin Receptor Expression in the Submandibular Gland of Rats. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59040789. [PMID: 37109747 PMCID: PMC10144866 DOI: 10.3390/medicina59040789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/08/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023]
Abstract
Background and Objectives: Patients with diabetes are more susceptible to upper respiratory tract infections (URTIs) because they are easily infected. Salivary IgA (sali-IgA) levels play a major role in transmitting URTIs. Sali-IgA levels are determined by salivary gland IgA production and polymeric immunoglobulin receptor (poly-IgR) expression. However, it is unknown whether salivary gland IgA production and poly-IgR expression are decreased in patients with diabetes. While exercise is reported to increase or decrease the sali-IgA levels, it is unclear how exercise affects the salivary glands of patients with diabetes. This study aimed to determine the effects of diabetes and voluntary exercise on IgA production and poly-IgR expression in the salivary glands of diabetic rats. Materials and Methods: Ten spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats (eight-week-old) were divided into two groups of five rats each: a non-exercise group (OLETF-C) and a voluntary wheel-running group (OLETF-E). Five Long-Evans Tokushima Otsuka (LETO) rats without diabetes were bred under the same conditions as the OLETF-C. Sixteen weeks after the study began, the submandibular glands (SGs) were collected and analyzed for IgA and poly-IgR expression levels. Results: IgA concentrations and poly-IgR expression levels in SGs were lower in OLETF-C and OLETF-E than in LETO (p < 0.05). These values did not differ between the OLETF-C and OLETF-E. Conclusions: Diabetes decreases IgA production and poly-IgR expression in the salivary glands of rats. Moreover, voluntary exercise increases sali-IgA levels but does not increase IgA production and poly-IgR expression in the salivary glands of diabetic rats. Increasing IgA production and poly-IgR expression in the salivary glands, which is reduced in diabetes, might require slightly higher-intensity exercise than voluntary exercise under the supervision of a doctor.
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Affiliation(s)
- Jaebum Park
- Department of Environmental Pathology, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Yuko Yamamoto
- Department of Dental Hygiene, Kanagawa Dental University, Junior College, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Kouki Hidaka
- Department of Restorative Dentistry, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Satoko Wada-Takahashi
- Department of Oral Physiology, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Shun-Suke Takahashi
- Department of Pharmacology, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Toshiya Morozumi
- Department of Endodontics, The Nippon Dental University School of Life Dentistry at Niigata, 1-8 Hamaura-cho, Chuo-ku, Niigata 9518580, Niigata, Japan
| | - Nobuhisa Kubota
- Department of Diagnostic Pathology, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Makiko Saita
- Department of Fixed Prosthodontics, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Juri Saruta
- Department of Education Planning, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Wakako Sakaguchi
- Department of Environmental Pathology, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Masahiro To
- Department of Clinical Oral Anatomy, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
| | - Tomoko Shimizu
- Department of Implantology and Periodontology, Kanagawa Dental University, 3-31-6 Tsuruya, Kanagawa-ku, Yokohama 2210835, Kanagawa, Japan
| | | | - Keiichi Tsukinoki
- Department of Environmental Pathology, Kanagawa Dental University, 82 Inaoka, Yokosuka 2388580, Kanagawa, Japan
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Ajabnoor GMA, Hashim KT, Alzahrani MM, Alsuheili AZ, Alharbi AF, Alhozali AM, Enani S, Eldakhakhny B, Elsamanoudy A. The Possible Effect of the Long-Term Use of Glucagon-like Peptide-1 Receptor Agonists (GLP-1RA) on Hba1c and Lipid Profile in Type 2 Diabetes Mellitus: A Retrospective Study in KAUH, Jeddah, Saudi Arabia. Diseases 2023; 11:diseases11010050. [PMID: 36975599 PMCID: PMC10046996 DOI: 10.3390/diseases11010050] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/17/2023] Open
Abstract
(1) Background: Type 2 diabetes (T2DM) is a chronic metabolic disease with serious health complications. T2DM is associated with many chronic illnesses, including kidney failure, cardiovascular diseases (CVD), vision loss, and other related diseases. Obesity is one of the major factors associated with insulin resistance and dyslipidemia. Recently, the development of GLP-1 Receptor agonist (GLP-1RA) showed great therapeutic potential for T2DM. Aim: To retrospectively investigate the association of the long-term use of GLP-1RA therapy in T2DM patients with HbA1c levels and dyslipidemia. (2) Methods: Retrospective data collection and analysis of demographic, clinical records, and biochemical parameters were carried out for 72 T2DM taking GLP-1RA treatments for six months. (3) Results: A total of 72 T2DM patients with a mean age = 55 (28 male and 44 female) were divided into two groups. Group 1 received statins (n = 63), and group 2 did not receive statins (n = 9). The GLP-1RA effect on BMI was significantly decreased in group 1 (p < 0.01). A significant effect was observed for HbA1c in both groups for six months of treatment duration (p < 0.05). The AST levels significantly decreased in group 2 from 25.2 to 19.4 U\L (p = 0.011). (4) Conclusions: GLP-1RA treatments were associated with weight reduction and improved glycemic control for T2DM patients. Moreover, it is suggested that it has anti-inflammatory and hepatoprotective effects. However, no direct association was found with the lipid profile in all groups of T2DM.
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Affiliation(s)
- Ghada M. A. Ajabnoor
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
- King Abdulaziz University Hospital, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
| | - Kamal Talat Hashim
- Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
| | | | | | | | - Amani Matook Alhozali
- King Abdulaziz University Hospital, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
- Department of Medicine, College of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
| | - Sumia Enani
- Department of Food and Nutrition, Faculty of Human Sciences and Design, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Basmah Eldakhakhny
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
| | - Ayman Elsamanoudy
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 22252, Saudi Arabia
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
- Correspondence:
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Swarbrick MM, Cox CL, Graham JL, Knudsen LB, Stanhope K, Raun K, Havel PJ. Growth hormone treatment does not augment the anti-diabetic effects of liraglutide in UCD-T2DM rats. Endocrinol Diabetes Metab 2022; 6:e392. [PMID: 36480511 PMCID: PMC9836246 DOI: 10.1002/edm2.392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/29/2022] [Accepted: 11/02/2022] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION The incretin hormone glucagon-like peptide-1 (GLP-1) slows gastric emptying, increases satiety and enhances insulin secretion. GLP-1 receptor agonists, such as liraglutide, are used therapeutically in humans to improve glycaemic control and delay the onset of type 2 diabetes mellitus (T2DM). In UCD-T2DM rats, a model of polygenic obesity and insulin resistance, we have previously reported that daily liraglutide administration delayed diabetes onset by >4 months. Growth hormone (GH) may exert anti-diabetic effects, including increasing β-cell mass and insulin secretion, while disrupting GH signalling in mice reduces both the size and number of pancreatic islets. We therefore hypothesized that GH supplementation would augment liraglutide's anti-diabetic effects. METHODS Male UCD-T2DM rats were treated daily with GH (0.3 mg/kg) and/or liraglutide (0.2 mg/kg) from 2 months of age. Control (vehicle) and food-restricted (with food intake matched to liraglutide-treated rats) groups were also studied. The effects of treatment on diabetes onset and weight gain were assessed, as well as measures of glucose tolerance, lipids and islet morphology. RESULTS Liraglutide treatment significantly reduced food intake and body weight and improved glucose tolerance and insulin sensitivity, relative to controls. After 4.5 months, none of the liraglutide-treated rats had developed T2DM (overall p = .019). Liraglutide-treated rats also displayed lower fasting triglyceride (TG) concentrations and lower hepatic TG content, compared to control rats. Islet morphology was improved in liraglutide-treated rats, with significantly increased pancreatic insulin content (p < .05 vs. controls). Although GH treatment tended to increase body weight (and gastrocnemius muscle weight), there were no obvious effects on diabetes onset or other diabetes-related outcomes. CONCLUSION GH supplementation did not augment the anti-diabetic effects of liraglutide.
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Affiliation(s)
- Michael M. Swarbrick
- Departments of Nutrition and Department of Molecular Biosciences, School of Veterinary MedicineUniversity of California, DavisOne Shielad AvenueDavisCaliforniaUSA,Present address:
Bone Research Program, ANZAC Research InstituteThe University of SydneyConcordNew South WalesAustralia,Present address:
Concord Clinical School, Faculty of Medicine and HealthThe University of SydneyAustralia
| | - Chad L. Cox
- Departments of Nutrition and Department of Molecular Biosciences, School of Veterinary MedicineUniversity of California, DavisOne Shielad AvenueDavisCaliforniaUSA
| | - James L. Graham
- Departments of Nutrition and Department of Molecular Biosciences, School of Veterinary MedicineUniversity of California, DavisOne Shielad AvenueDavisCaliforniaUSA
| | | | - Kimber Stanhope
- Departments of Nutrition and Department of Molecular Biosciences, School of Veterinary MedicineUniversity of California, DavisOne Shielad AvenueDavisCaliforniaUSA
| | | | - Peter J. Havel
- Departments of Nutrition and Department of Molecular Biosciences, School of Veterinary MedicineUniversity of California, DavisOne Shielad AvenueDavisCaliforniaUSA
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Ma X, Liu Z, Ilyas I, Little PJ, Kamato D, Sahebka A, Chen Z, Luo S, Zheng X, Weng J, Xu S. GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential. Int J Biol Sci 2021; 17:2050-2068. [PMID: 34131405 PMCID: PMC8193264 DOI: 10.7150/ijbs.59965] [Citation(s) in RCA: 139] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/28/2021] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is closely associated with cardiovascular diseases (CVD), including atherosclerosis, hypertension and heart failure. Some anti-diabetic medications are linked with an increased risk of weight gain or hypoglycemia which may reduce the efficacy of the intended anti-hyperglycemic effects of these therapies. The recently developed receptor agonists for glucagon-like peptide-1 (GLP-1RAs), stimulate insulin secretion and reduce glycated hemoglobin levels without having side effects such as weight gain and hypoglycemia. In addition, GLP1-RAs demonstrate numerous cardiovascular protective effects in subjects with or without diabetes. There have been several cardiovascular outcomes trials (CVOTs) involving GLP-1RAs, which have supported the overall cardiovascular benefits of these drugs. GLP1-RAs lower plasma lipid levels and lower blood pressure (BP), both of which contribute to a reduction of atherosclerosis and reduced CVD. GLP-1R is expressed in multiple cardiovascular cell types such as monocyte/macrophages, smooth muscle cells, endothelial cells, and cardiomyocytes. Recent studies have indicated that the protective properties against endothelial dysfunction, anti-inflammatory effects on macrophages and the anti-proliferative action on smooth muscle cells may contribute to atheroprotection through GLP-1R signaling. In the present review, we describe the cardiovascular effects and underlying molecular mechanisms of action of GLP-1RAs in CVOTs, animal models and cultured cells, and address how these findings have transformed our understanding of the pharmacotherapy of T2DM and the prevention of CVD.
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Affiliation(s)
- Xiaoxuan Ma
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Zhenghong Liu
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Iqra Ilyas
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Peter J Little
- Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, QLD 4575, Australia.,School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Danielle Kamato
- School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Amirhossein Sahebka
- Halal Research Center of IRI, FDA, Tehran, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad, Iran
| | - Zhengfang Chen
- Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu 215500, Jiangsu Province, China
| | - Sihui Luo
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Xueying Zheng
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Jianping Weng
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Suowen Xu
- Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
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Yin J, Han M, Li L, Li Y, Liu Z, Yang J, Liu Y. To Assess Liraglutide's Therapeutic Effect in Patients with Type 2 Diabetes Mellitus Using Flash Glucose Monitoring System. Diabetes Metab Syndr Obes 2021; 14:4399-4407. [PMID: 34744445 PMCID: PMC8565899 DOI: 10.2147/dmso.s331833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Liraglutide, a type of glucagon-like peptide-1 receptor agonist, has significant anti-hyperglycaemic activity without increasing the incidence of hypoglycaemia. In addition, it can improve β-cell function and insulin resistance. The flash glucose monitoring system (FGMS) is a novel method to document consecutive and detailed interstitial glucose levels, further reflecting blood glucose levels. This study aimed to investigate the therapeutic effect of liraglutide on blood glucose management (glucose variability, hyperglycaemia, and the incidence of hypoglycaemia), β-cell function, and insulin resistance in patients with diabetes. PATIENTS AND METHODS Thirty-three patients with type 2 diabetes mellitus were recruited in this study. On the basis of metformin monotherapy, these patients received liraglutide add-on treatment for 3 months. The FGMS was used to document glucose levels before and after add-on treatment. Parameters of glucose variability, blood glucose levels at specific time periods, and the incidence of hypoglycaemia were assessed according to FGMS data and compared before and after liraglutide add-on treatment. Further, β-cell function and insulin resistance were assessed and compared before and after liraglutide add-on treatment. RESULTS According to FGMS monitoring data, liraglutide add-on treatment significantly improved general, within-day, and day-to-day glucose variability and the glucose-target-rate. Further, the specifically analysed blood glucose levels at different time periods showed that blood glucose levels significantly decreased at nocturnal, fasting, and postprandial periods after add-on treatment. The incidence of hypoglycaemia was comparable during the whole day, daytime, and night-time according to the prespecified cutoffs (3.9 mmol/L and 3.0 mmol/L) before and after add-on treatment. Analysis of other assessed parameters revealed significant differences in glycosylated hemoglobin A1c and fasting blood glucose levels as well as parameters of β-cell function and insulin resistance before and after add-on treatment. CONCLUSION In type 2 diabetes mellitus, liraglutide treatment can effectively decrease glucose variability and ameliorate hyperglycaemia without increasing the incidence of hypoglycaemia. In addition, liraglutide can significantly improve the β-cell function and insulin resistance.
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Affiliation(s)
- Jianhong Yin
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Minmin Han
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
- First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Linhui Li
- Department of Endocrinology, Taiyuan Central Hospital, Taiyuan, Shanxi, People’s Republic of China
| | - Yang Li
- Department of Infectious Diseases, Linfen People’s Hospital, Linfen, Shanxi, People’s Republic of China
| | - Zi’ang Liu
- Third Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
- The Affiliated Bethune Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Jing Yang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
- Correspondence: Jing Yang; Yunfeng Liu Department of Endocrinology, First Hospital of Shanxi Medical University, No. 85 Jiefang Nan Road, Yingze District, Taiyuan, Shanxi Province, People’s Republic of ChinaTel +86 18703416196Fax +86 351-4639758 Email ;
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
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Gabery S, Salinas CG, Paulsen SJ, Ahnfelt-Rønne J, Alanentalo T, Baquero AF, Buckley ST, Farkas E, Fekete C, Frederiksen KS, Helms HCC, Jeppesen JF, John LM, Pyke C, Nøhr J, Lu TT, Polex-Wolf J, Prevot V, Raun K, Simonsen L, Sun G, Szilvásy-Szabó A, Willenbrock H, Secher A, Knudsen LB, Hogendorf WFJ. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 2020; 5:133429. [PMID: 32213703 DOI: 10.1172/jci.insight.133429] [Citation(s) in RCA: 360] [Impact Index Per Article: 72.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 02/26/2020] [Indexed: 12/16/2022] Open
Abstract
Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.
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Affiliation(s)
| | | | | | | | | | - Arian F Baquero
- Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, Hungary
| | - Stephen T Buckley
- Global Research Technologies, Novo Nordisk A/S, Måløv, Denmark, and Seattle, Washington, USA
| | - Erzsébet Farkas
- Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, Hungary
| | - Csaba Fekete
- Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, Hungary
| | | | - Hans Christian C Helms
- Global Research Technologies, Novo Nordisk A/S, Måløv, Denmark, and Seattle, Washington, USA
| | | | | | | | | | | | | | - Vincent Prevot
- Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, Lille, France
| | | | | | - Gao Sun
- Global Research Technologies, Novo Nordisk A/S, Måløv, Denmark, and Seattle, Washington, USA
| | - Anett Szilvásy-Szabó
- Institute of Experimental Medicine Hungarian Academy of Sciences, Budapest, Hungary
| | - Hanni Willenbrock
- Global Research Technologies, Novo Nordisk A/S, Måløv, Denmark, and Seattle, Washington, USA
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Papaetis GS. Liraglutide Therapy in a Prediabetic State: Rethinking the Evidence. Curr Diabetes Rev 2020; 16:699-715. [PMID: 31886752 DOI: 10.2174/1573399816666191230113446] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/20/2019] [Accepted: 12/12/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Prediabetes is defined as a state of glucose metabolism between normal glucose tolerance and type 2 diabetes. Continuous β-cell failure and death are the reasons for the evolution from normal glucose tolerance to prediabetes and finally type 2 diabetes. INTRODUCTION The necessity of new therapeutic approaches in order to prevent or delay the development of type 2 diabetes is obligatory. Liraglutide, a long-acting GLP-1 receptor agonist, has 97% homology for native GLP-1. Identification of the trophic and antiapoptotic properties of liraglutide in preclinical studies, together with evidence of sustained β-cell function longevity during its administration in type 2 diabetes individuals, indicated its earliest possible administration during this disease, or even before its development, so as to postpone or delay its onset. METHODS Pubmed and Google databases have been thoroughly searched and relevant studies were selected. RESULTS This paper explores the current evidence of liraglutide administration both in humans and animal models with prediabetes. Also, it investigates the safety profile of liraglutide treatment and its future role to postpone or delay the evolution of type 2 diabetes. CONCLUSION Liralgutide remains a valuable tool in our therapeutic armamentarium for individuals who are overweight or obese and have prediabetes. Future well designed studies will give valuable information that will help clinicians to stratify individuals who will derive the most benefit from this agent, achieving targeted therapeutic strategies.
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Affiliation(s)
- Georgios S Papaetis
- Internal Medicine and Diabetes Clinic, Eleftherios Venizelos Avenue 62, Paphos, Cyprus
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Modulatory effect of empagliflozin on cellular parameters of endocrine pancreas in experimental pre-diabetes. Ann Anat 2019; 224:153-160. [PMID: 31108190 DOI: 10.1016/j.aanat.2019.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/17/2019] [Accepted: 05/02/2019] [Indexed: 01/09/2023]
Abstract
The effect of empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), on the structure of endocrine pancreas in pre-diabetes (Pre-DM) is not yet elucidated. In the current study the relatively enlarged islets of Langerhans seen in the Pre-DM group was restored to control size by administration of EMPA. In addition the disbalance in the percentage of β-cells and α-cells in islets of the Pre-DM was corrected in the Pre-DM + EMPA group with reversal of the significantly increased islet mass, β-cell mass and neogenesis. Administrating EMPA in Pre-DM decreased level of caspase-3, increased that of Bcl-2 to control level and reduced the significantly increased inflammatory cytokines to levels approximated to those of the control group. In Pre-DM + EMPA group, EMPA had efficiently restored the significantly impaired glucose hemostasis to levels nearly similar to those of the control animals. This may indicate that the modulatory effect of EMPA on cells of the islets in Pre-DM is associated with a local pleotropic effect on inflammatory cytokines.
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Rehman K, Ali MB, Akash MSH. Genistein enhances the secretion of glucagon-like peptide-1 (GLP-1) via downregulation of inflammatory responses. Biomed Pharmacother 2019; 112:108670. [PMID: 30784939 DOI: 10.1016/j.biopha.2019.108670] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 01/31/2019] [Accepted: 02/04/2019] [Indexed: 02/07/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) an incretin hormone, is known to regulate the glucose-mediated insulin secretion. However, reduction in the level of GLP-1 is considered to be a major cause for the reduction of GLP-1-dependent insulin secretory response. Genistein an isoflavone, is an important polyphenol and has wide range of therapeutic potentials, but its therapeutic effects alone and/or in combination with metformin on GLP-1 secretion have not been investigated yet. Hence, we aimed to investigate the stimulatory action of genistein in combination with metformin on GLP-1 via downregulation of inflammatory mediators, hyperlipidemia and hyperglycemia in alloxan-induced diabetic rats. Diabetes was induced in experimental rats by single administration of alloxan intraperitoneally. Metformin (50 mg/kg/day), genistein (20 mg/kg/day) and combination of genistein and metformin was administered in alloxan-induced diabetic rats. We found that genistein alone and/or in combination with metformin significantly increased the serum level (P < 0.01) and tissue content (P < 0.05) of GLP-1 in intestine when compared with that of metformin-treated animals. Similarly, genistein alone and/or in combination with metformin also resulted in normoglycemia (P < 0.001), glucose tolerance (P < 0.01), insulin sensitivity (P < 0.0001), hyperlipidemia (P < 0.01), liver and kidney function biomarkers (P < 0.01) as compared to that of metformin-treated experimental animals. Moreover, genistein alone and/or in combination with metformin also downregulated the inflammatory responses by decreasing the levels of interleuin-6, tumor necrosis factor-α and C-reactive protein in serum (P < 0.05) and intestine (P < 0.001) more efficiently as compared to that of metformin-treated experimental animals. The downregulation of inflammatory responses in intestine, was positively associated with increased secretion of GLP-1 from intestine. Histopathology of pancreas and intestine also showed that genistein significantly improved the deleterious effects of alloxan on pancreas and intestine. Hence, our work provides new insights on the synergistic effects of genistein and metformin on GLP-1 secretion. This may significantly improve the perception for proposing new GLP-1-based synergistic approaches for the treatment of diabetes mellitus.
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Affiliation(s)
- Kanwal Rehman
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Mehwish Bagh Ali
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
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Bretón‐Romero R, Weisbrod RM, Feng B, Holbrook M, Ko D, Stathos MM, Zhang J, Fetterman JL, Hamburg NM. Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus. J Am Heart Assoc 2018; 7:e009379. [PMID: 30371206 PMCID: PMC6222937 DOI: 10.1161/jaha.118.009379] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 07/27/2018] [Indexed: 02/06/2023]
Abstract
Background Prior studies have shown that nutrient excess induces endoplasmic reticulum ( ER ) stress in nonvascular tissues from patients with diabetes mellitus ( DM ). ER stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether ER stress contributes to endothelial dysfunction in patients with DM remains unknown. Methods and Results To characterize vascular ER stress, we isolated endothelial cells from 42 patients with DM and 37 subjects without DM. Endothelial cells from patients with DM displayed higher levels of ER stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase-like ER eukaryotic initiation factor-2a kinase and inositol-requiring ER-to-nucleus signaling protein 1 ( P=0.02, P=0.007, respectively), and the chronic ER stress response evidenced by higher C/ EBP α-homologous protein ( P=0.02), were activated in patients with DM . Higher inositol-requiring ER-to-nucleus signaling protein 1 activation was associated with lower flow-mediated dilation, consistent with endothelial dysfunction ( r=0.53, P=0.02). Acute treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, reduced p-inositol-requiring ER-to-nucleus signaling protein 1 ( P=0.01), and the activation of its downstream target c-jun N-terminal kinase ( P=0.025) in endothelial cells from patients with DM . Furthermore, liraglutide restored insulin-stimulated endothelial nitric oxide synthase activation in patients with DM ( P=0.019). Conclusions In summary, our data suggest that ER stress contributes to vascular insulin resistance and endothelial dysfunction in patients with DM . Further, we have demonstrated that liraglutide ameliorates ER stress, decreases c-jun N-terminal kinase activation and restores insulin-mediated endothelial nitric oxide synthase activation in endothelial cells from patients with DM .
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Affiliation(s)
- Rosa Bretón‐Romero
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Robert M. Weisbrod
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Bihua Feng
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Monika Holbrook
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Darae Ko
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Mary M. Stathos
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Ji‐Yao Zhang
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | | | - Naomi M. Hamburg
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
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Li J, Fu LZ, Liu L, Xie F, Dai RC. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist Liraglutide Alters Bone Marrow Exosome-Mediated miRNA Signal Pathways in Ovariectomized Rats with Type 2 Diabetes. Med Sci Monit 2017; 23:5410-5419. [PMID: 29133778 PMCID: PMC5699170 DOI: 10.12659/msm.906603] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Compared with normal postmenopausal women, estrogen deficiency and hyperglycemia in postmenopausal women with type 2 diabetes (T2DM) lead to more severe bone property degradation. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been reported to improve bone condition among people with T2DM but the precise mechanisms remain unclear. Exosomes work as mediators in cell-to-cell communication, delivering functional miRNAs between cells. We aimed to explore the role of exosomes in T2DM-related bone metabolic disorders and the bone protective mechanisms of liraglutide. Material/Methods We made comparative analyses of bone marrow-derived exosomal miRNAs from ovariectomized (OVX) control rats, OVX + T2DM rats, and OVX + T2DM + liraglutide-treated rats. miRNA profiles were generated using high-throughput sequencing. Target gene prediction and pathway analysis were performed to investigate the signal pathway alterations. Three miRNAs were randomly chosen to validate their absolute expression levels by real-time quantitative PCR. Results Bone marrow-derived exosomal miRNAs were different with respect to miRNA numbers, species, and expression levels. miRNA spectra varied under T2DM condition and after liraglutide treatment. By bioinformatics analysis, we found T2DM and liraglutide administration lead to significant changes in exosomal miRNAs which targeted to insulin secretion and insulin-signaling pathway. Wnt signaling pathway alteration was the critical point regarding bone metabolism. Conclusions Our findings show the selective packaging of functional miRNA cargoes into exosomes due to T2DM and liraglutide treatment. Bone marrow exosome-mediated Wnt signaling pathway alteration may play a part in the bone protective effect of liraglutide.
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Affiliation(s)
- Jin Li
- Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Ling-Zhi Fu
- Department of Endocrinology and Metabolism, The Third People's Hospital of Chenzhou, Chenzhou, Hunan, China (mainland)
| | - Lu Liu
- Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Fen Xie
- Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
| | - Ru-Chun Dai
- Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (mainland)
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Li J, Liu X, Fang Q, Ding M, Li C. Liraglutide attenuates atherosclerosis via inhibiting ER-induced macrophage derived microvesicles production in T2DM rats. Diabetol Metab Syndr 2017; 9:94. [PMID: 29213335 PMCID: PMC5710066 DOI: 10.1186/s13098-017-0289-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 11/01/2017] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND We investigated the effects of liraglutide on the formation and progression of atherosclerosis in type 2 diabetes mellitus (T2DM) rats. METHODS Sprague-Dawley rats were divided into control group, diabetes group and liraglutide treated group. The T2DM rats model with atherosclerosis were induced by high fat diet followed small dosage streptozotocin injection. Body weight and blood glucose levels were monitored once a week for 3 months and then the rats were sacrificed.Peripheral blood and aorta tissues were collected for further biochemical and pathological estimation respectively. Moreover, immunohistochemistry staining was used to detect the infiltration of macrophages and cell apoptosis in tissue samples. The amount of microvesicles of atherosclerotic plaques was determined by ELISA. Western blot was applied to detect the protein expressions of CHOP, GRP78 and caspase-3 in tissue samples. The mRNA expressions of SREBP-1c and FAS were detected by RT-PCR. RESULTS The rat model of diabetic atherosclerosis was established successfully. Compared with the control group, glucose, triglycerides, total cholesterol, AST, ALT, BUN, fasting insulin and homeostatic model assessment insulin resistance levels in peripheral blood were significantly increased in the diabetes group. While, these indicators in the liraglutide group were significantly lower than that in the diabetes group. Moreover, the atherosclerotic plaques were observed in the rats of diabetes group but not remarkable in the liraglutide group. The ratio between aorta intima and media thickness was significantly greater in the diabetes group than that in the liraglutide group. Compared with the diabetes group, the infiltration and apoptosis of macrophages were milder in the liraglutide group. The expressions of CD68, caspase-3, CHOP and GRP78 in aorta tissue samples were significantly downregulated in the liraglutide group than that in the diabetes group. Furthermore, the microvesicles of aorta tissues in the liraglutide group were significantly decreased than that in the diabetes group. The mRNA expressions of SREBP-1c and FAS were lower in the liraglutide group than that in the diabetes group. CONCLUSION Liraglutide attenuates diabetic atherosclerosis by inhibition of ER stress and subsequent macrophage apoptosis and microvesicles production in T2DM rats.
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Affiliation(s)
- Jinjin Li
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, No. 22, Qixiangtai Road, Tianjin, 300070 People’s Republic of China
| | - Xiaojuan Liu
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, No. 22, Qixiangtai Road, Tianjin, 300070 People’s Republic of China
| | - Qianhua Fang
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, No. 22, Qixiangtai Road, Tianjin, 300070 People’s Republic of China
| | - Min Ding
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, No. 22, Qixiangtai Road, Tianjin, 300070 People’s Republic of China
| | - Chunjun Li
- Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, No. 22, Qixiangtai Road, Tianjin, 300070 People’s Republic of China
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Fukuyama N, Tsukamoto Y, Takizawa S, Ikeya Y, Fujii T, Shinozaki Y, Takahari Y, Kawabe N, Wakana N, Umetani K, Todoroki K, Fukui S, Tanaka C, Tanaka E, Mori H. Altered blood flow in cerebral perforating arteries of rat models of diabetes: A synchrotron radiation microangiographic study toward clinical evaluation of white matter hyperintensities. Geriatr Gerontol Int 2016; 15 Suppl 1:74-80. [PMID: 26671161 DOI: 10.1111/ggi.12658] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2015] [Indexed: 11/29/2022]
Abstract
AIM As altered blood flow in the cerebral perforating arteries (PA) might be related to development of cerebral white matter hyperintensities, we examined whether the hemodynamic relationship of the PA and middle cerebral artery (MCA) is altered in rat models of diabetes, compared with normal rats and a rat model of sinoatrial denervation (blood pressure fluctuation model). METHODS We used microangiography with monochromatic synchrotron radiation to measure the diameters of the PA and MCA at 4.5 μm resolution in five groups of rats: (i) Long-Evans Tokushima Otsuka (LETO); (ii) Otsuka Long-Evans Tokushima Fatty (a model of type 2 diabetes with obesity); (iii) LETO with sinoaortic denervation (LETO + SAD); (iv) F344; and (v) F344 + streptozotocin (a model of type 1 diabetes). RESULTS Compared with LETO, Otsuka Long-Evans Tokushima Fatty rats showed a significant reduction in the diameter of both PA and MCA, though the PA/MCA diameter ratio was unchanged. In contrast, compared with LETO, LETO + SAD rats showed an increased MCA diameter, and the PA/MCA diameter ratio was decreased. Compared with F344 rats, the MCA diameter was increased in F344 + streptozotocin rats, and the PA/MCA diameter ratio was decreased. Scatter diagrams showed that the diameters of the PA and MCA were essentially independent of each other in the two types of diabetic models. CONCLUSION PA were consistently visualized at high resolution by means of microangiography using synchrotron radiation. The present results show that rat diabetic models exhibit changes in PA diameter and PA/MCA diameter ratio, which might be related to the development of diabetes-associated cerebral white matter hyperintensities.
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Affiliation(s)
- Naoto Fukuyama
- Department of Physiology, Tokai University School of Medicine, Isehara, Kanagawa
| | - Yuko Tsukamoto
- Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa
| | - Shunya Takizawa
- Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa
| | - Yoshimori Ikeya
- Department of Physiology, Tokai University School of Medicine, Isehara, Kanagawa
| | - Toshiharu Fujii
- Department of Cardiology, Tokai University School of Medicine, Isehara, Kanagawa
| | - Yoshiro Shinozaki
- Support Center for Medical Research and Education, Tokai University School of Medicine, Isehara, Kanagawa
| | - Yoko Takahari
- Support Center for Medical Research and Education, Tokai University School of Medicine, Isehara, Kanagawa
| | - Noboru Kawabe
- Support Center for Medical Research and Education, Tokai University School of Medicine, Isehara, Kanagawa
| | - Noriaki Wakana
- Department of Nutritional Science, Tokyo University of Agriculture, Tokyo, Japan
| | - Keiji Umetani
- Japan Synchrotron Radiation Research Institute, SPring-8, Hyogo, Japan
| | - Kikue Todoroki
- Department of Physiology, Tokai University School of Medicine, Isehara, Kanagawa
| | - Sayato Fukui
- Department of Physiology, Tokai University School of Medicine, Isehara, Kanagawa
| | - Chiharu Tanaka
- Department of Cardiology, Tokai University School of Medicine, Isehara, Kanagawa
| | - Etsuro Tanaka
- Department of Nutritional Science, Tokyo University of Agriculture, Tokyo, Japan
| | - Hidezo Mori
- Department of Physiology, Tokai University School of Medicine, Isehara, Kanagawa
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Nakamura Y, Hasegawa H, Tsuji M, Oguchi T, Mihara M, Suzuki H, Nishida K, Inoue M, Shimizu T, Ohsawa I, Gotoh H, Goto Y, Inagaki M, Oguchi K. Linagliptin inhibits lipopolysaccharide-stimulated interleukin-6 production, intranuclear p65 expression, and p38 mitogen-activated protein kinase phosphorylation in human umbilical vein endothelial cells. RENAL REPLACEMENT THERAPY 2016. [DOI: 10.1186/s41100-016-0030-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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¿Existe un espacio para los análogos de la incretina como terapia para el sobrepeso, la obesidad y la prevención de la enfermedad cardio-metabólica? REVISTA COLOMBIANA DE CARDIOLOGÍA 2016. [DOI: 10.1016/j.rccar.2015.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
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Effect of Modified Roux-en-Y Gastric Bypass Surgery on GLP-1, GIP in Patients with Type 2 Diabetes Mellitus. Gastroenterol Res Pract 2015; 2015:625196. [PMID: 26167177 PMCID: PMC4488585 DOI: 10.1155/2015/625196] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 06/05/2015] [Accepted: 06/10/2015] [Indexed: 12/15/2022] Open
Abstract
The type 2 diabetes mellitus (T2DM) is one of the most serious diseases that threaten public health. Modified gastric bypass surgery has been applied to the treatment of T2DM patients in the 1990s, but the therapeutic mechanism to this function is still unclear. The aim of this study was to further clarify the effect and the mechanism of modified gastric bypass surgery on glucose metabolism in patients with T2DM. In the study, the incretin indexes and blood glucose indexes were analyzed before surgery and 1 week and 1, 3, and 6 months after surgery. The results suggested that modified Roux-en-Y gastric bypass can promote GLP-1 secretion in patients with T2DM, while reducing the secretion of GIP. Thus it could effectively control blood glucose of patients with T2DM.
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Xiong SW, Zhang DY, Liu XM, Liu Z, Zhang FT. Comparison of different gastric bypass procedures in gastric carcinoma patients with type 2 diabetes mellitus. World J Gastroenterol 2014; 20:18427-18431. [PMID: 25561812 PMCID: PMC4277982 DOI: 10.3748/wjg.v20.i48.18427] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 08/01/2014] [Accepted: 09/16/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To determine the effect of different Roux-en-Y gastric bypass procedures in gastric carcinoma patients with type 2 diabetes mellitus.
METHODS: A retrospective analysis of the clinical data of 54 patients with gastric cancer and type 2 diabetes mellitus treated in the Department of General Surgery from January 2006 to June 2013 was conducted. The patients underwent gastrectomy using different Roux-en-Y gastric bypass procedures (traditional, n = 26; modified, n = 28). Fasting plasma glucose (FPG), two hour postprandial blood glucose (2 h PBG) and hemoglobin A1c (HbA1c) were analyzed before surgery (0 mo) and 1, 3 and 6 mo after surgery.
RESULTS: FPG and 2 h PBG levels were significantly decreased 1 mo after surgery in the traditional Roux-en-Y gastric bypass group (FPG 7.5 ± 1.3 vs 10.7 ± 1.2, P < 0.05) (2 h PBG 10.2 ± 1.8 vs 13.8 ± 3.2, P < 0.05). FPG and 2 h PBG levels were significantly decreased after surgery in the modified Roux-en-Y gastric bypass group (FPG 6.9 ± 1.2 vs 10.5 ± 1.1, 6.5 ± 1.3 vs 10.5 ± 1.1, 6.4 ± 1.2 vs 10.5 ± 1.1, P < 0.05) (2 h PBG 9.9 ± 2.2 vs 14.1 ± 2.9, 9.2 ± 2.4 vs 14.1 ± 2.9, 8.9 ± 2.6 vs 14.1 ± 2.9, P < 0.05). Compared with the levels before surgery, HbA1c levels were significantly decreased 3 and 6 mo after surgery (7.2 ± 1.1 vs 10.5 ± 1.1, 5.5 ± 1.1 vs 10.5 ± 1.1, P < 0.05). Significant differences between the two groups regarding FPG, 2 h PBG and HbA1c concentration were observed 3 and 6 mo after surgery (FPG 10.1 ± 1.5 vs 6.5 ± 1.3, 10.3 ± 1.4 vs 6.4 ± 1.2, P < 0.05) (2 h PBG 13.1 ± 2.8 vs 9.2 ± 2.4, 13.6 ± 3.1 vs 8.9 ± 2.6, P < 0.05) (HbA1c 10.1 ± 1.4 vs 7.2 ± 1.1, 10.5 ± 1.3 vs 5.5 ± 1.1, P < 0.05).
CONCLUSION: Modified Roux-en-Y gastric bypass can improve glucose metabolism in type 2 diabetic patients with gastric cancer.
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Papaetis GS. Incretin-based therapies in prediabetes: Current evidence and future perspectives. World J Diabetes 2014; 5:817-834. [PMID: 25512784 PMCID: PMC4265868 DOI: 10.4239/wjd.v5.i6.817] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Revised: 09/10/2014] [Accepted: 11/10/2014] [Indexed: 02/05/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.
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Glucagon like peptide-1 attenuates bleomycin-induced pulmonary fibrosis, involving the inactivation of NF-κB in mice. Int Immunopharmacol 2014; 22:498-504. [PMID: 25111852 DOI: 10.1016/j.intimp.2014.07.010] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 07/08/2014] [Indexed: 02/05/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality and poor prognosis. Previous studies confirmed that NF-κB plays a critical role in the pathogenesis of pulmonary fibrosis and glucagon like peptide-1 (GLP-1) has a property of anti-inflammation by inactivation of NF-κB. Furthermore, the GLP-1 receptor was detected in the lung tissues. Our aim was to investigate the potential value and mechanisms of GLP-1 on BLM-induced pulmonary fibrosis in mice. Mice with BLM-induced pulmonary fibrosis were treated with or without GLP-1 administration. 28 days after BLM infusion, the number of total cells, macrophages, neutrophils, lymphocytes, and the content of TGF-β1 in BALF were measured. Hematoxylin-eosin (HE) staining and Masson's trichrome (MT) staining were performed. The Ashcroft score and hydroxyproline content were analyzed. RT-qPCR and western blot were used to evaluate the expression of α-SMA and VCAM-1. The phosphorylation of NF-κB p65 was also assessed by western blot. DNA binding of NF-κB p65 was measured through Trans(AM) p65 transcription factor ELISA kit. GLP-1 reduced inflammatory cell infiltration and the content of TGF-β1 in BLAF in mice with BLM injection. The Ashcroft score and hydroxyproline content were decreased by GLP-1 administration. Meanwhile, BLM-induced overexpression of α-SMA and VCAM-1 were blocked by GLP-1 treatment in mice. GLP-1 also reduced the ratio of phosphor-NF-κB p65/total-NF-κB p65 and NF-κB p65 DNA binding activity in BLM-induced pulmonary fibrosis in mice. Our data found that BLM-induced lung inflammation and pulmonary fibrosis were significantly alleviated by GLP-1 treatment in mice, possibly through inactivation of NF-κB.
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Portero McLellan KC, Wyne K, Villagomez ET, Hsueh WA. Therapeutic interventions to reduce the risk of progression from prediabetes to type 2 diabetes mellitus. Ther Clin Risk Manag 2014; 10:173-88. [PMID: 24672242 PMCID: PMC3964168 DOI: 10.2147/tcrm.s39564] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Clinical trials have demonstrated that it is possible to prevent diabetes through lifestyle modification, pharmacological intervention, and surgery. This review aims to summarize the effectiveness of these various therapeutic interventions in reducing the risk of progression of prediabetes to diabetes, and address the challenges to implement a diabetes prevention program at a community level. Strategies focusing on intensive lifestyle changes are not only efficient but cost-effective and/or cost-saving. Indeed, lifestyle intervention in people at high risk for type 2 diabetes mellitus (T2DM) has been successful in achieving sustained behavioral changes and a reduction in diabetes incidence even after the counseling is stopped. Although prediabetes is associated with health and economic burdens, it has not been adequately addressed by interventions or regulatory agencies in terms of prevention or disease management. Lifestyle intervention strategies to prevent T2DM should be distinct for different populations around the globe and should emphasize sex, age, ethnicity, and cultural and geographical considerations to be feasible and to promote better compliance. The translation of diabetes prevention research at a population level, especially finding the most effective methods of preventing T2DM in various societies and cultural settings remains challenging, but must be accomplished to stop this worldwide epidemic.
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Affiliation(s)
| | - Kathleen Wyne
- Division of Diabetes, Obesity and Lipids, Department of Medicine, The Methodist Hospital Diabetes and Metabolism Institute, and the Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, USA
| | - Evangelina Trejo Villagomez
- Division of Diabetes, Obesity and Lipids, Department of Medicine, The Methodist Hospital Diabetes and Metabolism Institute, and the Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, USA
| | - Willa A Hsueh
- Division of Diabetes, Obesity and Lipids, Department of Medicine, The Methodist Hospital Diabetes and Metabolism Institute, and the Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, USA
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Nakamura Y, Tsuji M, Hasegawa H, Kimura K, Fujita K, Inoue M, Shimizu T, Gotoh H, Goto Y, Inagaki M, Oguchi K. Anti-inflammatory effects of linagliptin in hemodialysis patients with diabetes. Hemodial Int 2014; 18:433-42. [PMID: 24405885 DOI: 10.1111/hdi.12127] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammation and glycemic control are important prognosis-related factors for hemodialysis (HD) patients; moreover, inflammation affects insulin secretion. Here, we evaluated the anti-inflammatory effects of monotherapy with linagliptin-a dipeptidase-4 inhibitor-in HD patients with type 2 diabetes. We examined 21 diabetic HD patients who were not receiving oral diabetes drugs or insulin therapy and with poor glycemic control (glycated albumin [GA] level, >20%). Linagliptin (5 mg) was administered to the patients daily. The levels of prostaglandin E2 (PGE2), interleukin-6 (IL-6), high-sensitivity C-reactive protein, GA, blood glucose, and active glucagon-like peptide-1 were determined before and 6 months after treatment. Body weight and serum levels of albumin, hemoglobin, total cholesterol, and low-density lipoprotein cholesterol were also recorded before and after treatment. The levels of PGE2 and GA were significantly decreased 1 month after starting linagliptin therapy, whereas the IL-6 levels were significantly decreased 6 months after starting linagliptin therapy. After 6 months of treatment, the PGE2 levels decreased from 188 ± 50 ng/mL to 26 ± 5 ng/mL; IL-6 levels, from 1.5 ± 0.4 pg/mL to 0.6 ± 0.1 pg/mL; and GA levels, from 21.3% ± 0.6% to 18.0% ± 0.6%. Glucagon-like peptide-1 levels increased 2.5-fold during the treatment. Over the 6-month treatment period, body weight and levels of high-sensitivity C-reactive protein, blood glucose, albumin, hemoglobin, and cholesterol did not change; none of the patients exhibited hypoglycemia. The anti-inflammatory effects of linagliptin monotherapy indicate that it may serve as a useful glucose control strategy for HD patients with diabetes.
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Affiliation(s)
- Yuya Nakamura
- Saiyu Soka Hospital, Soka, Japan; Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan
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Neuroprotective effects of liraglutide for stroke model of rats. Int J Mol Sci 2013; 14:21513-24. [PMID: 24177570 PMCID: PMC3856019 DOI: 10.3390/ijms141121513] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 10/18/2013] [Accepted: 10/23/2013] [Indexed: 12/17/2022] Open
Abstract
The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson's test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF). The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation.
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Gaspari T, Welungoda I, Widdop RE, Simpson RW, Dear AE. The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE(-/-) mouse model. Diab Vasc Dis Res 2013; 10:353-60. [PMID: 23673376 DOI: 10.1177/1479164113481817] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Liraglutide, a once-daily glucagon-like peptide-1 receptor (GLP-1R) agonist, has been approved as a new treatment for type 2 diabetes and is the subject of a clinical trial programme to evaluate the effects on cardiovascular disease and safety. The current study aimed to determine the in vivo effect of liraglutide on progression of atherosclerotic vascular disease in the apolipoprotein E-deficient (ApoE(-/-)) mouse model and identify underlying mechanisms responsible. Liraglutide treatment inhibited progression of early onset, low-burden atherosclerotic disease in a partially GLP-1R-dependent manner in the ApoE(-/-) mouse model. In addition, liraglutide treatment inhibited progression of atherosclerotic plaque formation and enhanced plaque stability, again in a partially GLP-1R-dependent manner. No significant effect of liraglutide on progression of late onset, high-burden atherosclerotic disease was observed. In addition, no significant endothelial cell dysfunction was identified in ApoE(-/-) mice with early onset, low-burden atherosclerotic disease, although significant prevention of weight gain was observed in liraglutide-treated mice using this dietary protocol. Taken together, these results suggest a potential role for liraglutide in the prevention and stabilisation of atherosclerotic vascular disease together with possible protection against major cardiovascular events.
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Affiliation(s)
- Tracey Gaspari
- Department of Pharmacology, Monash University, Melbourne, VIC, Australia
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Rizzo M, Nikolic D, Banach M, Giglio RV, Patti AM, Di Bartolo V, Tamburello A, Zabbara A, Pecoraro G, Montalto G, Rizvi AA. The effects of liraglutide on glucose, inflammatory markers and lipoprotein metabolism: current knowledge and future perspective. ACTA ACUST UNITED AC 2013. [DOI: 10.2217/clp.13.8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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