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Andlib N, Prabha S, Thakur SC. Unraveling the molecular pathogenesis of Type 2 Diabetes and its impact on female infertility: A bioinformatics and systems biology approach. Comput Biol Med 2024; 180:108987. [PMID: 39116715 DOI: 10.1016/j.compbiomed.2024.108987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/25/2024] [Accepted: 08/02/2024] [Indexed: 08/10/2024]
Abstract
Type 2 diabetes mellitus (T2D) has been linked with female infertility (FI). Nevertheless, our understanding of the molecular hallmarks and underlying mechanisms remains elusive. This research article aimed to find the hub genes, pathways, transcription factors, and miRNA involved. For this study, softwares like cytoscape, string, Enrichr, FFL loop, etc., were utilized. This research article employed differentially expressed genes (DEGs) to identify multiple biological targets to understand the association between T2D and female infertility (FI). Between T2D and FI, we found 3869 differentially expressed genes. We have also analyzed different pathways like thyroid hormone signaling pathways, AGE-RAGE signaling pathways in diabetic complications and ubiquitin-mediated proteolysis through pathway analysis. Moreover, hub genes MED17, PRKCG, THRA, FOXO1, NCOA2, PLCG2, COL1A1, CXCL8, PRPF19, ANAPC5, UBE2I, XIAP and KEAP1 have been identified. Additionally, these hub genes were subjected to identify the miRNA-mRNA regulation network specific to T2D-associated female infertility. In the FFL study (Feed Forward Loop), transcription factor (SP1, NFKB1, RELA and FOX01), miRNA (has-mir-7-5p, has-let-7a-5p, hsa-mir-16-5p, hsa-mir-155-5p, has-mir-122-5p, has-let-7b-5p, has-mir-124-3p, has-mir-34a-5p, has-mir-130a-3p, has-let-7i-5p, and hsa-mir-27a-3p) and six genes (XIAP, THRA, NCOA2, MED17, FOXO1, and COL1A1) among the thirteen key genes were recognized as regulator and inhibitor. Our analysis reveals that these genes can serve as a significant biomarker for female infertility linked with Type 2 Diabetes, through the prioritization of candidate genes. This study gives us insight into the molecular and cellular mechanism of T2D-associated FI. This finding helps in developing novel therapeutic approaches and will improve efficacy and reduce side effects of the treatment. This research requires further experimental investigation of the principal targets.
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Affiliation(s)
- Nida Andlib
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Sneh Prabha
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India
| | - Sonu Chand Thakur
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India.
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Al Zoubi MS, Al Kreasha R, Aqel S, Saeed A, Al-Qudimat AR, Al-Zoubi RM. Vitamin B 12 deficiency in diabetic patients treated with metformin: A narrative review. Ir J Med Sci 2024; 193:1827-1835. [PMID: 38381379 PMCID: PMC11294377 DOI: 10.1007/s11845-024-03634-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 02/12/2024] [Indexed: 02/22/2024]
Abstract
Metformin is the most prescribed oral hypoglycemic drug and is considered by many health practitioners as the first-line treatment for non-insulin-dependent diabetes mellitus (T2DM). It is used either as a monotherapy or adjuvant to other anti-hyperglycemic agents. Most of its side effects are usually mild and self-limiting. However, several studies have shown an association between the use of metformin and low vitamin B12 levels in diabetic patients. The current review aimed to provide a literature review of the current published reports on the association, the possible mechanisms, and the related individualized risk factors that might lead to this incidence. The most accepted mechanism of the effect of metformin on vitamin B12 level is related to the absorption process where metformin antagonism of the calcium cation and interference with the calcium-dependent IF-vitamin B12 complex binding to the ileal cubilin receptor. In addition, many risk factors have been associated with the impact of metformin on vitamin B12 levels in diabetic patients such as dose and duration where longer durations showed a greater prevalence of developing vitamin B12 deficiency. Male patients showed lower levels of vitamin B12 compared to females. Black race showed a lower prevalence of vitamin B12 deficiency in metformin-treated patients. Moreover, chronic diseases including T2DM, hyperlipidemia, coronary artery disease, polycystic ovary disease (PCOD), obesity, and metformin therapy were significantly associated with increased risk of vitamin B12 deficiency.
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Affiliation(s)
- Mazhar Salim Al Zoubi
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan
| | - Rasha Al Kreasha
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan
| | - Sarah Aqel
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan
| | - Ahmad Saeed
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, 211-63, Jordan
| | - Ahmad R Al-Qudimat
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation, 3050, Doha, Qatar
| | - Raed M Al-Zoubi
- Surgical Research Section, Department of Surgery, Hamad Medical Corporation, 3050, Doha, Qatar.
- Department of Biomedical Sciences, College of Health Sciences, QU-Health, Qatar University, Doha, 2713, Qatar.
- Department of Chemistry, Jordan University of Science and Technology, P.O.Box 3030, Irbid, 22110, Jordan.
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Talab F, Zainab, Alam A, Ali M, Rehman NU, Ullah S, Halim SA, Islam MS, Khan A, Latif A, Ayaz M, Al-Ghafri A, Al-Harrasi A, Ahmad M. Polyhydroquinoline derivatives for diabetic management: synthesis, in vitro and in silico approaches. Future Med Chem 2023; 15:2195-2208. [PMID: 38085012 DOI: 10.4155/fmc-2023-0232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 10/23/2023] [Indexed: 12/20/2023] Open
Abstract
Background: Medication used to treat Type 2 diabetes by decreasing the absorption of carbohydrates in the intestine consists of α-glucosidase inhibitors. Polyhydroquinoline derivatives have attracted interest as excellent antidiabetic agents. Methods: Polyhydroquinoline derivatives (1-17) were synthesized and tested for in vitro α-glucosidase inhibitory activity. Results: All the synthesized compounds exhibited excellent to good inhibitory activity, having IC50 values from 1.23 ± 0.03 to 73.85 ± 0.61 μM, compared with the standard drug, acarbose. The binding mechanism of these derivatives with α-glucosidase was deduced by docking studies and indicated that a slight variation in the orientation of compounds, affects their binding capability. Conclusion: In order to find new antidiabetic drugs, this study has discovered prospective lead candidates.
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Affiliation(s)
- Faiz Talab
- Department of Chemistry, University of Malakand, PO Box 18800, Dir Lower, Khyber Pakhtunkhwa, Pakistan
| | - Zainab
- College of Chemistry & Materials Science, Hebei Normal University, Shijiazhuang, 050024, China
| | - Aftab Alam
- Department of Chemistry, University of Malakand, PO Box 18800, Dir Lower, Khyber Pakhtunkhwa, Pakistan
| | - Mumtaz Ali
- Department of Chemistry, University of Malakand, PO Box 18800, Dir Lower, Khyber Pakhtunkhwa, Pakistan
| | - Najeeb Ur Rehman
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - Saeed Ullah
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - Sobia Ahsan Halim
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - Mohammad Shahidul Islam
- Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh, 11451, Saudi Arabia
| | - Ajmal Khan
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - Abdul Latif
- Department of Chemistry, University of Malakand, PO Box 18800, Dir Lower, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Ayaz
- Department of Chemistry, University of Malakand, PO Box 18800, Dir Lower, Khyber Pakhtunkhwa, Pakistan
| | - Ahmed Al-Ghafri
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, Nizwa, 616, Oman
| | - Manzoor Ahmad
- Department of Chemistry, University of Malakand, PO Box 18800, Dir Lower, Khyber Pakhtunkhwa, Pakistan
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Sacks DB, Arnold M, Bakris GL, Bruns DE, Horvath AR, Lernmark Å, Metzger BE, Nathan DM, Kirkman MS. Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus. Diabetes Care 2023; 46:e151-e199. [PMID: 37471273 PMCID: PMC10516260 DOI: 10.2337/dci23-0036] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 05/11/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH An expert committee compiled evidence-based recommendations for laboratory analysis in screening, diagnosis, or monitoring of diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association for Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (HbA1c) in the blood. Glycemic control is monitored by the people with diabetes measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring (CGM) devices and also by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.
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Affiliation(s)
- David B. Sacks
- Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD
| | - Mark Arnold
- Department of Chemistry, University of Iowa, Iowa City, IA
| | - George L. Bakris
- Department of Medicine, American Heart Association Comprehensive Hypertension Center, Section of Endocrinology, Diabetes and Metabolism, University of Chicago Medicine, Chicago, IL
| | - David E. Bruns
- Department of Pathology, University of Virginia Medical School, Charlottesville, VA
| | - Andrea R. Horvath
- New South Wales Health Pathology Department of Chemical Pathology, Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skane University Hospital Malmö, Malmö, Sweden
| | - Boyd E. Metzger
- Division of Endocrinology, Northwestern University, The Feinberg School of Medicine, Chicago, IL
| | - David M. Nathan
- Massachusetts General Hospital Diabetes Center and Harvard Medical School, Boston, MA
| | - M. Sue Kirkman
- Department of Medicine, University of North Carolina, Chapel Hill, NC
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Sacks DB, Arnold M, Bakris GL, Bruns DE, Horvath AR, Lernmark Å, Metzger BE, Nathan DM, Kirkman MS. Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus. Clin Chem 2023:hvad080. [PMID: 37473453 DOI: 10.1093/clinchem/hvad080] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 05/12/2023] [Indexed: 07/22/2023]
Abstract
BACKGROUND Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH An expert committee compiled evidence-based recommendations for laboratory analysis in screening, diagnosis, or monitoring of diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association of Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (Hb A1c) in the blood. Glycemic control is monitored by the people with diabetes measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring (CGM) devices and also by laboratory analysis of Hb A1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.
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Affiliation(s)
- David B Sacks
- Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD, United States
| | - Mark Arnold
- Department of Chemistry, University of Iowa, Iowa City, IA, United States
| | - George L Bakris
- Department of Medicine, American Heart Association Comprehensive Hypertension Center, Section of Endocrinology, Diabetes and Metabolism, University of Chicago Medicine, Chicago, ILUnited States
| | - David E Bruns
- Department of Pathology, University of Virginia Medical School, Charlottesville, VA, United States
| | - Andrea R Horvath
- New South Wales Health Pathology Department of Chemical Pathology, Prince of Wales Hospital, Sydney, NSW, Australia
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skane University Hospital Malmö, Malmö, Sweden
| | - Boyd E Metzger
- Division of Endocrinology, Northwestern University, The Feinberg School of Medicine, Chicago, IL, United States
| | - David M Nathan
- Massachusetts General Hospital Diabetes Center and Harvard Medical School, Boston, MA, United States
| | - M Sue Kirkman
- Department of Medicine, University of North Carolina, Chapel Hill, NC, United States
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Al-Fawaeir S, Al-Odat I. Influence of metformin intake on serum vitamin B12 levels in patients with type 2 diabetes mellitus. PLoS One 2022; 17:e0279740. [PMID: 36584077 PMCID: PMC9803116 DOI: 10.1371/journal.pone.0279740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/14/2022] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE To describe the prevalence of vitamin B12 deficiency among Jordanian patients with type 2 diabetes mellitus treated with metformin and to compare the findings with those who did not receive metformin. DESIGN AND METHOD Total 155 patients with type 2 diabetes mellitus, aged between 48 and 82 years were enrolled in the current study. They were divided into two groups; the first (n = 120) was treated with metformin while the second (n = 35) was not. Patients' demographics (age, gender, duration of type 2 diabetes mellitus, smoking status), medication parameters (daily dosage and duration of metformin therapy), and biochemical parameters (hemoglobin level, mean corpuscular volume (MCV), serum vitamin B12, and folate level) were recorded. Definite deficiency was defined as serum vitamin B12 levels of < 150 pg/ml, whereas < 200 pg/ml indicated possible deficiency. RESULTS The mean serum ± standard deviation (SD) vitamin B12 level was significantly lower in patients who were treated with metformin (268.5 ± 35.8 vs. 389.5 ± 29.8 pg/ml, p = 0.029). The metformin group had significantly higher prevalence of definite deficiency (32% vs. 9%, p < 0.02) and possible deficiency (48% vs. 30%, p < 0.02). Within the metformin group, the mean serum ± SD vitamin B12 level was significantly lower in those on high dosage (175.2 ± 30.5 vs. 315.6 ± 37.8 pg/ml, p < 0.001). MCV (μm3) levels ± SD were higher in the metformin group (87.5 ± 2.9 vs. 83.7 ± 2.4) with no statistical significance. CONCLUSION There is a significant association between metformin intake and vitamin B12 deficiency. Serum vitamin B12 levels should be checked by physicians and serial monitoring is necessary in patients who are treated with metformin.
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Affiliation(s)
- Saad Al-Fawaeir
- Department of Medical Laboratory Science, Jadara University, Irbid, Jordan
| | - Ibrahim Al-Odat
- Department of Medical Laboratory Science, Jadara University, Irbid, Jordan
- * E-mail:
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Synthesis, biological evaluation and molecular docking study of benzimidazole derivatives as α-glucosidase inhibitors and anti-diabetes candidates. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.134774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Zhou S, Dong R, Wang J, Zhang L, Yu B, Shao X, Bai P, Zhang R, Ma Y, Yu P. Red Blood Cell Lifespan < 74 Days Can Clinically Reduce Hb1Ac Levels in Type 2 Diabetes. J Pers Med 2022; 12:1738. [PMID: 36294877 PMCID: PMC9604792 DOI: 10.3390/jpm12101738] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/10/2022] [Accepted: 10/13/2022] [Indexed: 11/24/2022] Open
Abstract
Variations in the red blood cell (RBC) lifespan can affect glycosylated hemoglobin (HbA1c) test values, but there is still a lack of evidence regarding how and to what degree the RBC lifespan influences HbA1c in the type 2 diabetes mellitus (T2DM) population owing to the restriction of traditional RBC lifespan detection means. In this study, we monitored 464 T2DM patients and 231 healthy control finger blood glucose levels at seven time points for three consecutive months. The HbA1c levels were assessed at the end of the third month as well as the RBC lifespan was measured through the CO breath test. T2DM patients were stratified into four quartile groups according to their RBC lifespans. There was no statistical significance in HbA1c among these four groups. However, the average blood glucose in the Q1 group was significantly higher than those in the other groups. Additionally, the contribution of RBC lifespan to HbA1c test value in the Q1 group was 14.07%, which was significantly higher than those in the other groups. Finally, we used multiple linear regression models to construct a mathematical formula to correct the HbA1c test value in the Q1 group, which would benefit the management of T2DM.
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Affiliation(s)
- Saijun Zhou
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China
| | - Rongna Dong
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China
| | - Junmei Wang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China
| | - Li Zhang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China
| | - Bai Yu
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China
| | - Xian Shao
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China
| | - Pufei Bai
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China
| | - Rui Zhang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China
| | - Yongjian Ma
- Guangdong Breath Test Engineering and Technology Research Center, Shenzhen University, Shenzhen 518000, China
| | - Pei Yu
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300134, China
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Kuchay MS, Misra A. Sodium-glucose cotransporter-2 inhibitors as first-line pharmacological therapy for type 2 diabetes? Diabetes Metab Syndr 2022; 16:102580. [PMID: 35921765 DOI: 10.1016/j.dsx.2022.102580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 11/16/2022]
Affiliation(s)
- Mohammad Shafi Kuchay
- Division of Endocrinology and Diabetes, Medanta the Medicity Hospital, Gurugram, 122001, Haryana, India.
| | - Anoop Misra
- Fortis CDOC Hospital for Diabetes and Allied Sciences, New Delhi, India; National Diabetes, Obesity and Cholesterol Foundation (NDOC), and Diabetes Foundation, India
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Xia SF, Maitiniyazi G, Chen Y, Wu XY, Zhang Y, Zhang XY, Li ZY, Liu Y, Qiu YY, Wang J. Web-Based TangPlan and WeChat Combination to Support Self-management for Patients With Type 2 Diabetes: Randomized Controlled Trial. JMIR Mhealth Uhealth 2022; 10:e30571. [PMID: 35353055 PMCID: PMC9008529 DOI: 10.2196/30571] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 12/20/2021] [Accepted: 02/20/2022] [Indexed: 11/25/2022] Open
Abstract
Background China has the largest number of patients with type 2 diabetes mellitus (T2DM) in the world. However, owing to insufficient knowledge of self-management in patients with diabetes, blood glucose (BG) control is poor. Most diabetes-related self-management applications fail to bring significant benefits to patients with T2DM because of the low use rate and difficult operation. Objective This study aims to examine the effectiveness of the combination of the self-designed web-based T2DM management software TangPlan and WeChat on fasting BG (FBG), glycated hemoglobin (HbA1c), body weight, blood pressure (BP), and lipid profiles in patients with T2DM over a 6-month period. Methods Participants were recruited and randomized into the TangPlan and WeChat or control groups. Participants in the control group received usual care, whereas the TangPlan and WeChat participants received self-management guidance with the help of TangPlan and WeChat from health care professionals, including BG self-monitoring; healthy eating; active physical exercise; increasing medication compliance; and health education during follow-ups, lectures, or web-based communication. They were also asked to record and send self-management data to the health care professionals via WeChat to obtain timely and effective guidance on diabetes self-management. Results In this study, 76.9% (120/156) of participants completed the 6-month follow-up visit. After the intervention, FBG (mean 6.51, SD 1.66 mmol/L; P=.048), HbA1c (mean 6.87%, SD 1.11%; P<.001), body weight (mean 66.50, SD 9.51 kg; P=.006), systolic BP (mean 127.03, SD 8.00 mm Hg; P=.005), diastolic BP (mean 75.25, SD 5.88 mm Hg; P=.03), serum low-density lipoprotein cholesterol (mean 2.50, SD 0.61 mmol/L; P=.006), and total cholesterol (mean 4.01, SD 0.83 mmol/L; P=.02) in the TangPlan and WeChat group were all significantly lower, whereas serum high-density lipoprotein cholesterol (mean 1.20, SD 0.25 mmol/L; P=.01) was remarkably higher than in those in the control group. Compared with the baseline data, significance was found in the mean change in FBG (95% CI −0.83 to −0.20; P=.002), HbA1c (95% CI −1.92 to −1.28; P<.001), body weight (95% CI −3.13 to −1.68; P<.001), BMI (95% CI −1.10 to −0.60; P<.001), systolic BP (95% CI −7.37 to −3.94; P<.001), diastolic BP (95% CI −4.52 to −2.33; P<.001), triglycerides (95% CI −0.16 to −0.03; P=.004), serum low-density lipoprotein cholesterol (95% CI −0.54 to −0.30; P<.001), and total cholesterol (95% CI −0.60 to −0.34; P<.001) in the TangPlan and WeChat group but not in the control group (P=.08-.88). Conclusions Compared with usual care for patients with T2DM, the combination of TangPlan and WeChat was effective in improving glycemic control (decrease in HbA1c and BG levels) and serum lipid profiles as well as reducing body weight in patients with T2DM after 6 months. Trial Registration Chinese Clinical Trial Registry ChiCTR2000028843; https://tinyurl.com/559kuve6
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Affiliation(s)
- Shu-Fang Xia
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | | | - Yue Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xiao-Ya Wu
- Department of Rehabilitation, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
| | - Yu Zhang
- Department of Endocrinology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xiao-Yan Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Zi-Yuan Li
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yuan Liu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yu-Yu Qiu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Jun Wang
- Department of Rehabilitation, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
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Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence. Biomolecules 2021; 11:biom11121834. [PMID: 34944478 PMCID: PMC8698925 DOI: 10.3390/biom11121834] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/26/2021] [Accepted: 12/01/2021] [Indexed: 12/20/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved.
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Huang JH, Lin YK, Lee TW, Liu HW, Chien YM, Hsueh YC, Lee TI, Chen YJ. Correlation between short- and mid-term hemoglobin A1c and glycemic control determined by continuous glucose monitoring. Diabetol Metab Syndr 2021; 13:94. [PMID: 34488880 PMCID: PMC8422722 DOI: 10.1186/s13098-021-00714-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/26/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Glucose monitoring is vital for glycemic control in patients with diabetes mellitus (DM). Continuous glucose monitoring (CGM) measures whole-day glucose levels. Hemoglobin A1c (HbA1c) is a vital outcome predictor in patients with DM. METHODS This study investigated the relationship between HbA1c and CGM, which remained unclear hitherto. Data of patients with DM (n = 91) who received CGM and HbA1c testing (1-3 months before and after CGM) were retrospectively analyzed. Diurnal and nocturnal glucose, highest CGM data (10%, 25%, and 50%), mean amplitude of glycemic excursions (MAGE), percent coefficient of variation (%CV), and continuous overlapping net glycemic action were compared with HbA1c values before and after CGM. RESULTS The CGM results were significantly correlated with HbA1c values measured 1 (r = 0.69) and 2 (r = 0.39) months after CGM and 1 month (r = 0.35) before CGM. However, glucose levels recorded in CGM did not correlate with the HbA1c values 3 months after and 2-3 months before CGM. MAGE and %CV were strongly correlated with HbA1c values 1 and 2 months after CGM, respectively. Diurnal blood glucose levels were significantly correlated with HbA1c values 1-2 months before and 1 month after CGM. The nocturnal blood glucose levels were significantly correlated with HbA1c values 1-3 months before and 1-2 months after CGM. CONCLUSIONS CGM can predict HbA1c values within 1 month after CGM in patients with DM.
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Affiliation(s)
- Jen-Hung Huang
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yung-Kuo Lin
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ting-Wei Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, 111 Xinglong Road, Section 3, Wenshan District, Taipei, 11696, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Han-Wen Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yu-Mei Chien
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yu-Chun Hsueh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Ting-I Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, 111 Xinglong Road, Section 3, Wenshan District, Taipei, 11696, Taiwan.
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
- Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
| | - Yi-Jen Chen
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
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13
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Abd-Rabou AA, Abdelaziz AM, Shaker OG, Ayeldeen G. Metformin-loaded lecithin nanoparticles induce colorectal cancer cytotoxicity via epigenetic modulation of noncoding RNAs. Mol Biol Rep 2021; 48:6805-6820. [PMID: 34468912 DOI: 10.1007/s11033-021-06680-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/23/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is major aliment around the word, with a cumulative rate of mortality. Metformin (MT) was recently approved as anticancer drug against solid tumors, such as CRC. Resistance to MT therapy remains to be a challenging matter facing the development of possible anti-cancer strategy. To circumvent this problem, MT nano-encapsulation has been introduced to sensitize resistant cancer cells. The purpose of the current study is to explore the MT's aptitude encapsulated in lecithin (LC) and chitosan (CS) nanoparticles to inhibit CRC proliferation through modulations of long noncoding RNAs (lncRNAs), micro RNAs (miRNAs), and some biochemical markers. METHODS AND RESULTS Cytotoxic screenings of the newly synthesized MT-based regimens; MT, MT-LC NPs (NP1), MT-CS NPs (NP2), and MT-LC-CS NPs (NP3) against colorectal cancerous Caco-2 and HCT116 cell lines versus normal WI-38 cells were performed. The epigenetic mechanistic effects of these proposed regimens on lncRNAs and miRNAs were investigated. Additionally, some protein levels were assessed in CRC cells upon treatments; YKL-40, PPARγ, E-cadherin (ECN), and VEGF. We resulted that NP1 recorded the highest significant cytotoxic effect on CRC cells. HCT116 cells were more sensitive to the NP1 compared to Caco-2 cells. Intriguingly, it was suggested that NP1 tackled the CRC cells through down-regulation of the H19, HOTTIP, HULC, LINC00641, miR-200, miR-92a, miR-21, YKL-40, PPARγ, and VEGF expressions, as well as up-regulation of the miR-944 and ECN expressions. CONCLUSIONS We concluded that the NP1 can potentially be cytotoxic to CRC cells in-vitro by modulating noncoding RNA.
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Affiliation(s)
- Ahmed A Abd-Rabou
- Medical Research Division, Hormones Department, National Research Center, Dokki, Giza, 12622, Egypt.
- Stem Cell Lab., Centre of Excellence for Advanced Science, National Research Center, Dokki, Giza, 12622, Egypt.
| | - Ahmed M Abdelaziz
- Ahmed Mahr Teaching Hospital (AMTH), Cairo, Egypt
- Supplementary General Sciences, Future University, Cairo, Egypt
| | - Olfat G Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ghada Ayeldeen
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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14
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Jang SK, Hong SE, Lee DH, Kim JY, Kim JY, Ye SK, Hong J, Park IC, Jin HO. Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin. BMC Cancer 2021; 21:803. [PMID: 34253170 PMCID: PMC8273940 DOI: 10.1186/s12885-021-08346-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/11/2021] [Indexed: 01/01/2023] Open
Abstract
Background Although the major anticancer effect of metformin involves AMPK-dependent or AMPK-independent mTORC1 inhibition, the mechanisms of action are still not fully understood. Methods To investigate the molecular mechanisms underlying the effect of metformin on the mTORC1 inhibition, MTT assay, RT-PCR, and western blot analysis were performed. Results Metformin induced the expression of ATF4, REDD1, and Sestrin2 concomitant with its inhibition of mTORC1 activity. Treatment with REDD1 or Sestrin2 siRNA reversed the mTORC1 inhibition induced by metformin, indicating that REDD1 and Sestrin2 are important for the inhibition of mTORC1 triggered by metformin treatment. Moreover, REDD1- and Sestrin2-mediated mTORC1 inhibition in response to metformin was independent of AMPK activation. Additionally, lapatinib enhances cell sensitivity to metformin, and knockdown of REDD1 and Sestrin2 decreased cell sensitivity to metformin and lapatinib. Conclusions ATF4-induced REDD1 and Sestrin2 expression in response to metformin plays an important role in mTORC1 inhibition independent of AMPK activation, and this signalling pathway could have therapeutic value.
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Affiliation(s)
- Se-Kyeong Jang
- Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea.,Department of Food and Microbial Technology, Seoul Women's University, 621 Hwarangro, Nowon-gu, Seoul, 01797, Republic of Korea
| | - Sung-Eun Hong
- KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Da-Hee Lee
- Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Ji-Young Kim
- KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Ji Yea Kim
- Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea
| | - Sang-Kyu Ye
- Department of Pharmacology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Jungil Hong
- Department of Food and Microbial Technology, Seoul Women's University, 621 Hwarangro, Nowon-gu, Seoul, 01797, Republic of Korea
| | - In-Chul Park
- Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea.
| | - Hyeon-Ok Jin
- KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 01812, Republic of Korea.
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15
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Liu C, Tang S, An K, Zhang S, Zhou Y, Su N, Yang R, Liao X, An Z, Li S. Knowledge, Attitude, and Practice of Metformin Extended-Release Tablets Among Clinicians in China: A Cross-Sectional Survey. Front Pharmacol 2021; 12:634561. [PMID: 34322016 PMCID: PMC8312381 DOI: 10.3389/fphar.2021.634561] [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] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/25/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Metformin extended-release (XR) is a once-daily alternative conventional immediate-release (IR) tablet for adults with type 2 diabetes. Aim: This study aimed to investigate the knowledge, attitude, and practice of the use of metformin XR tablets among clinicians. Methods: We conducted a cross-sectional online survey among endocrinologists, general practitioners, and internists, who are taking routine care of adults with type 2 diabetes in health institutes at all levels in Sichuan Province, China. We designed an online questionnaire including the demographic information, knowledge, attitude, and practice about metformin XR tablets. Results: We included 158 clinicians, 67.7% of whom were females and 63.9% were from tertiary hospitals. The median age was 39.6 years (ranging between 22 and 62 years). Only 8.2% of the clinicians correctly answered the knowledge questions, 82.3% and 62.0% of the responders assumed that metformin XR had superior efficacy and tolerability to the metformin IR, respectively. Only 46.8% of the clinicians prescribed the metformin XR based on the patient's preference for once daily frequency. Conclusion: The knowledge, attitude, and practice of metformin XR among Chinese clinicians need improving. Clinicians need credible information to support their clinical decision-making regarding metformin XR.
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Affiliation(s)
- Chang Liu
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Siqi Tang
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Kang An
- Department of General Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Shengzhao Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Yiling Zhou
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Na Su
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Rong Yang
- Department of General Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyang Liao
- Department of General Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenmei An
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- Chinese Evidence-based Medicine Centre, Cochrane China Centre and MAGIC China Centre, West China Hospital, Sichuan University, Chengdu, China
- Engineering Research Centre of Medical Information Technology, Ministry of Education, West China Hospital, Sichuan University, Chengdu, China
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James TJ, Corbett J, Cummings M, Allard S, Young JS, Towse J, Carey-Jones K, Eglin C, Hopkins B, Morgan C, Tipton M, Saynor ZL, Shepherd AI. Timing of acute passive heating on glucose tolerance and blood pressure in people with type 2 diabetes: a randomized, balanced crossover, control trial. J Appl Physiol (1985) 2021; 130:1093-1105. [PMID: 33411640 DOI: 10.1152/japplphysiol.00747.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia and progressive insulin resistance, leading to macro and microvascular dysfunction. Passive heating has potential to improve glucose homeostasis and act as an exercise mimetic. We assessed the effect of acute passive heating before or during an oral glucose tolerance test (OGTT) in people with T2DM. Twelve people with T2DM were randomly assigned to the following three conditions: 1) 3-h OGTT (control), 2) 1-h passive heating (40°C water) 30 min before an OGTT (HOT-OGTT), and 3) 1-h passive heating (40°C water) 30 min after commencing an OGTT (OGTT-HOT). Blood glucose concentration, insulin sensitivity, extracellular heat shock protein 70 (eHSP70), total energy expenditure (TEE), heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded. Passive heating did not alter blood glucose concentration [control: 1,677 (386) arbitrary units (AU), HOT-OGTT: 1,797 (340) AU, and OGTT-HOT: 1,662 (364) AU, P = 0.28], insulin sensitivity (P = 0.15), or SBP (P = 0.18) but did increase eHSP70 concentration in both heating conditions [control: 203.48 (110.81) pg·mL-1; HOT-OGTT: 402.47 (79.02) pg·mL-1; and OGTT-HOT: 310.00 (60.53) pg·mL-1, P < 0.001], increased TEE (via fat oxidation) in the OGTT-HOT condition [control: 263 (33) kcal, HOT-OGTT: 278 (40) kcal, and OGTT-HOT: 304 (38) kcal, P = 0.001], increased HR in both heating conditions (P < 0.001), and reduced DBP in the OGTT-HOT condition (P < 0.01). Passive heating in close proximity to a glucose challenge does not alter glucose tolerance but does increase eHSP70 concentration and TEE and reduce blood pressure in people with T2DM.NEW & NOTEWORTHY This is the first study to investigate the timing of acute passive heating on glucose tolerance and extracellular heat shock protein 70 concentration ([eHSP70]) in people with type 2 diabetes. The principal novel findings from this study were that both passive heating conditions: 1) did not reduce the area under the curve or peak blood glucose concentration, 2) elevated heart rate, and 3) increased [eHSP70], which was blunted by glucose ingestion, while passive heating following glucose ingestion, 4) increased total energy expenditure, and 5) reduced diastolic blood pressure.
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Affiliation(s)
- Thomas J James
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom.,Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
| | - Jo Corbett
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Michael Cummings
- Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
| | - Sharon Allard
- Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
| | - John S Young
- School of Pharmacy and Biomedical Sciences, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Jonathan Towse
- School of Pharmacy and Biomedical Sciences, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Kathryn Carey-Jones
- School of Biological Sciences, Faculty of Science and Health, University of Portsmouth, United Kingdom.,Oaks Healthcare, Cowplain Family Practice, Waterlooville, United Kingdom
| | - Clare Eglin
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Billy Hopkins
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Connor Morgan
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Michael Tipton
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom
| | - Zoe L Saynor
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom.,Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
| | - Anthony I Shepherd
- School of Sport, Health and Exercise Science, Faculty of Science and Health, University of Portsmouth, United Kingdom.,Diabetes and Endocrinology Department, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
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Drzewoski J, Hanefeld M. The Current and Potential Therapeutic Use of Metformin-The Good Old Drug. Pharmaceuticals (Basel) 2021; 14:122. [PMID: 33562458 PMCID: PMC7915435 DOI: 10.3390/ph14020122] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
Metformin, one of the oldest oral antidiabetic agents and still recommended by almost all current guidelines as the first-line treatment for type 2 diabetes mellitus (T2DM), has become the medication with steadily increasing potential therapeutic indications. A broad spectrum of experimental and clinical studies showed that metformin has a pleiotropic activity and favorable effect in different pathological conditions, including prediabetes, type 1 diabetes mellitus (T1DM) and gestational diabetes mellitus (GDM). Moreover, there are numerous studies, meta-analyses and population studies indicating that metformin is safe and well tolerated and may be associated with cardioprotective and nephroprotective effect. Recently, it has also been reported in some studies, but not all, that metformin, besides improvement of glucose homeostasis, may possibly reduce the risk of cancer development, inhibit the incidence of neurodegenerative disease and prolong the lifespan. This paper presents some arguments supporting the initiation of metformin in patients with newly diagnosed T2DM, especially those without cardiovascular risk factors or without established cardiovascular disease or advanced kidney insufficiency at the time of new guidelines favoring new drugs with pleotropic effects complimentary to glucose control. Moreover, it focuses on the potential beneficial effects of metformin in patients with T2DM and coexisting chronic diseases.
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Affiliation(s)
- Józef Drzewoski
- Central Teaching Hospital of Medical University of Lodz, 92-213 Lodz, Poland
| | - Markolf Hanefeld
- Medical Clinic III, Department of Medicine Technical University Dresden, 01307 Dresden, Germany;
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18
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Rohde C, Knudsen JS, Schmitz N, Østergaard SD, Thomsen RW. The impact of hospital-diagnosed depression or use of antidepressants on treatment initiation, adherence and HbA 1c/LDL target achievement in newly diagnosed type 2 diabetes. Diabetologia 2021; 64:361-374. [PMID: 33073329 DOI: 10.1007/s00125-020-05303-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/02/2020] [Indexed: 11/26/2022]
Abstract
AIMS/HYPOTHESIS We aimed to assess whether current antidepressant therapy or a history of hospital-diagnosed depression affects diabetes treatment initiation, adherence, and HbA1c and LDL-cholesterol target achievement. METHODS In this register-based study, we included all individuals from Central and Northern Denmark with newly diagnosed type 2 diabetes, defined as a first-ever HbA1c measurement of ≥48 mmol/mol (6.5%), between 2000 and 2016. Individuals either diagnosed with depression at a psychiatric hospital in the 2 years prior to their diabetes diagnosis or currently receiving treatment with an antidepressant were compared with individuals with type 2 diabetes, but without depression treatment or previous history of depression. Outcome measures included initiation of glucose-lowering drugs and lipid-modifying agents, adherence to these medications (medication possession ratio >80%), and HbA1c (<53 mmol/mol [7%]) and LDL-cholesterol (<2.6 mmol/l) target achievement. The assessment of association between depression or antidepressant treatment and these outcomes was conducted using regression analyses with adjustment for potential confounders. RESULTS We included a total of 87,650 individuals with first-ever HbA1c-diagnosed type 2 diabetes, of whom 0.9% (n = 784) had hospital-diagnosed depression and 11.4% (n = 9963) currently received antidepressant treatment. Compared with those without depression treatment, treatment with an antidepressant was associated with increased likelihood of glucose-lowering drug initiation (HR 1.39 [95% CI 1.34, 1.44]) and adherence (OR 1.27 [95% CI 1.18, 1.36]), lipid-modifying agent initiation (HR 1.17 [95% CI 1.11, 1.23]) and adherence (OR 1.25 [95% CI 1.09, 1.43]), and achievement of LDL (OR 1.08 [95% CI 1.03, 1.14]) but not HbA1c target (OR 0.99 [95% CI 0.93, 1.06]). The findings were similar for individuals who had hospital-diagnosed depression. CONCLUSIONS/INTERPRETATION In individuals with newly diagnosed type 2 diabetes, antidepressant treatment and depression were associated with improved diabetes treatment quality. Graphical abstract.
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Affiliation(s)
- Christopher Rohde
- Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Jakob S Knudsen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Norbert Schmitz
- Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada
| | - Søren Dinesen Østergaard
- Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Reimar W Thomsen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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19
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Investigating Health-Related Features and Their Impact on the Prediction of Diabetes Using Machine Learning. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11031173] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Diabetes Mellitus (DM) is one of the most common chronic diseases leading to severe health complications that may cause death. The disease influences individuals, community, and the government due to the continuous monitoring, lifelong commitment, and the cost of treatment. The World Health Organization (WHO) considers Saudi Arabia as one of the top 10 countries in diabetes prevalence across the world. Since most of its medical services are provided by the government, the cost of the treatment in terms of hospitals and clinical visits and lab tests represents a real burden due to the large scale of the disease. The ability to predict the diabetic status of a patient with only a handful of features can allow cost-effective, rapid, and widely-available screening of diabetes, thereby lessening the health and economic burden caused by diabetes alone. The goal of this paper is to investigate the prediction of diabetic patients and compare the role of HbA1c and FPG as input features. By using five different machine learning classifiers, and using feature elimination through feature permutation and hierarchical clustering, we established good performance for accuracy, precision, recall, and F1-score of the models on the dataset implying that our data or features are not bound to specific models. In addition, the consistent performance across all the evaluation metrics indicate that there was no trade-off or penalty among the evaluation metrics. Further analysis was performed on the data to identify the risk factors and their indirect impact on diabetes classification. Our analysis presented great agreement with the risk factors of diabetes and prediabetes stated by the American Diabetes Association (ADA) and other health institutions worldwide. We conclude that by performing analysis of the disease using selected features, important factors specific to the Saudi population can be identified, whose management can result in controlling the disease. We also provide some recommendations learned from this research.
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20
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Han Y, Cheng B, Guo Y, Wang Q, Yang N, Lin P. A Low-Carbohydrate Diet Realizes Medication Withdrawal: A Possible Opportunity for Effective Glycemic Control. Front Endocrinol (Lausanne) 2021; 12:779636. [PMID: 34970224 PMCID: PMC8713744 DOI: 10.3389/fendo.2021.779636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 11/19/2021] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Multiple studies have confirmed that diet restrictions can effectively realize glycemic control and reduce metabolic risks in patients with type 2 diabetes mellitus (T2DM). In 2018, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) stated that individuals can select a low-carbohydrate diet (LCD) according to their needs and preferences. Owing to the influence of Chinese traditional eating habits, only a small portion of patients in China have achieved their blood glucose goals. As a result, the Chinese government will incur huge expenditures. METHOD This study recruited 134 T2DM participants and randomly assigned them to the LCD group (n = 67) or the low-fat diet (LFD) group (n = 67). All of the patients had a fixed amount of exercise and were guided by clinicians. After a period of dietary washout, all of the patients received corresponding dietary education according to group. The follow-up time was 6 months. The indicators for anthropometry, glycemic control, and medication application parameters were collected and compared between the two groups. RESULTS There were 121 participants who finally entered the study. The proportions of calories from three major nutrients the participants consumed met the requirements of LCD and LFD. Compared with baseline, the pre-postdifferences of body weight, BMI, and several other indicators were significant except for dosages of insulin used in the LCD group and MES in the LFD group. After the intervention, body weight, body weight index (BMI), fasting blood glucose (FBG), postprandial 2-h blood glucose (PPG), and glycosylated hemoglobin (HbA1c) levels in the LCD group decreased significantly (p < 0.05) compared with the LFD group. The number of patients using lipid-lowering agents was significant higher in the LCD group and lower in the LFD group. However, there was no significant difference between the two groups for antihypertensive, hormone-replacement, and other agents. CONCLUSIONS The LCD diet can decrease body weight, glycemic levels, MES, and lipid-lowering agents more than the LFD diet, thus decreasing cost burden in Chinese patients with T2DM. Strict diet control and monitoring are the keys to managing diabetes.
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Affiliation(s)
- Yuxin Han
- Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bingfei Cheng
- Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanjun Guo
- Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qing Wang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Nailong Yang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Nailong Yang, ; Peng Lin,
| | - Peng Lin
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Nailong Yang, ; Peng Lin,
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21
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Chen YH, Yang SF, Yang CK, Tsai HD, Chen TH, Chou MC, Hsiao YH. Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells. Mol Med Rep 2020; 23:88. [PMID: 33236135 PMCID: PMC7716426 DOI: 10.3892/mmr.2020.11725] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/30/2020] [Indexed: 12/20/2022] Open
Abstract
Human cervical cancer is the fourth most common malignancy among women worldwide, and it is expected to result in 460,000 deaths per year by 2040. Moreover, patients with cervical cancer often display drug resistance and severe side effects; therefore, the development of effective novel chemotherapeutic agents is important. In the present study, the effects of metformin, a first-line therapeutic drug for type 2 diabetes mellitus, were evaluated in cervical cancer. Compared with the control group, metformin significantly inhibited cell viability and migration, and induced apoptosis and cell cycle arrest in human cervical cancer cell lines (CaSki and HeLa). Following metformin treatment, the protein expression levels of p-AMP-activated protein kinase (p-AMPK), which promotes cell death, and the tumor suppressor protein p-p53 were remarkably upregulated in CaSki and C33A cells compared with the control group. Furthermore, compared with the control group, metformin significantly suppressed the PI3K/AKT signaling pathway in CaSki, C33A and HeLa cells. Compound C (an AMPK inhibitor) significantly reversed the effects of metformin on CaSki, C33A and HeLa cell viability, and AMPK and p53 phosphorylation. The results of the present study suggested that metformin induced AMPK-mediated apoptosis, thus metformin may serve as a chemotherapeutic agent for human cervical cancer.
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Affiliation(s)
- Ya-Hui Chen
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Chueh-Ko Yang
- Women's Health Research Laboratory, Changhua Christian Hospital, Changhua 500, Taiwan, R.O.C
| | - Horng-Der Tsai
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 500, Taiwan, R.O.C
| | - Tze-Ho Chen
- Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 500, Taiwan, R.O.C
| | - Ming-Chih Chou
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
| | - Yi-Hsuan Hsiao
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C
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22
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Broekman KE, Hof MAJ, Touw DJ, Gietema JA, Nijman HW, Lefrandt JD, Reyners AKL, Jalving M. Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer. Invest New Drugs 2020; 38:1454-1462. [PMID: 32146550 PMCID: PMC7497683 DOI: 10.1007/s10637-020-00920-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 02/28/2020] [Indexed: 12/24/2022]
Abstract
Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.
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Affiliation(s)
- K Esther Broekman
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Marieke A J Hof
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Daan J Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jourik A Gietema
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Hans W Nijman
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Joop D Lefrandt
- Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - An K L Reyners
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands
| | - Mathilde Jalving
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.
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Petersen I, Nicolaisen SK, Ricciardi F, Sharma M, Thomsen RW, Baio G, Pedersen L. Impact of Being Eligible for Type 2 Diabetes Treatment on All-Cause Mortality and Cardiovascular Events: Regression Discontinuity Design Study. Clin Epidemiol 2020; 12:569-577. [PMID: 32606982 PMCID: PMC7294562 DOI: 10.2147/clep.s251704] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 04/30/2020] [Indexed: 11/23/2022] Open
Abstract
Background Individuals with type 2 diabetes (T2D) have a twofold increased risk for cardiovascular events (CVE), and CVE is responsible for nearly 80% of the mortality. Current treatment guidelines state that individuals should immediately initiate antidiabetic treatment and cardiovascular risk-factor management from T2D diagnosis. However, the evidence base is sparse, and randomized trials are unlikely to be conducted. We examined the impact of being eligible for T2D treatment, as determined by the threshold of HbA1c ≥6.5% (≥48 mmol/mol), on all-cause mortality and CVE. We hypothesised that individuals who were just above this threshold had a lower risk of CVE and all-cause mortality than individuals just below. Methods and Findings We used the regression discontinuity design (RDD), a quasi-experimental design, comparing rates of all-cause mortality and CVE in people just below and just above the eligibility for treatment threshold. We included Danish healthcare records from 43,070 individuals aged 40–80 years with no previous T2D record and the first record of HbA1c in the range of 6.0–7.0% (42–53 mmol/mol) between 2006 and 2014. In total, 36,360 individuals had the first record of HbA1c between 6.0% and 6.4% (42–47 mmol/mol), and 6710 individuals had a first record between 6.5% and 7.0% (48–53 mmol/mol). Individuals with a measurement just above 6.5% (48 mmol/mol) had a 21% lower rate of death or CVE, compared to those just below (hazard ratio: 0.79 (95% CI 0.69–0.90)). Few individuals received early metformin treatment. However, the chance of metformin treatment initiation within 3 months was substantially higher for individuals with an HbA1c measurement above (14%) than below (1%) the threshold. Conclusion Individuals with first record of HbA1c measure just above treatment threshold experienced a 21% lower rate of death or CVE than those just below. Lifestyle modifications and cardiovascular risk-factor management may contribute to this reduced rate.
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Affiliation(s)
- Irene Petersen
- Department of Primary Care and Population Health, University College London, London, UK.,Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
| | | | - Federico Ricciardi
- Department of Statistical Science, University College London, London, UK
| | - Manuj Sharma
- Department of Primary Care and Population Health, University College London, London, UK
| | - Reimar W Thomsen
- Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
| | - Gianluca Baio
- Department of Statistical Science, University College London, London, UK
| | - Lars Pedersen
- Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
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Tavaf Z, Dangolani SK, Yousefi R, Panahi F, Shahsavani MB, Khalafi-Nezhad A. Synthesis of new curcumin derivatives as influential antidiabetic α-glucosidase and α-amylase inhibitors with anti-oxidant activity. Carbohydr Res 2020; 494:108069. [PMID: 32563890 DOI: 10.1016/j.carres.2020.108069] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/29/2020] [Accepted: 06/08/2020] [Indexed: 12/13/2022]
Abstract
In this study, a new class of curcumin derivatives was synthesized using a multicomponent reaction containing curcumin, aldehydes, and malononitrile. This new protocol afforded a novel class of 4H-pyran heterocycles incorporating curcumin moiety. The products were obtained in the presence of p-toluenesulfonic acid (PTSA) as a catalyst in ethanol solvent in good to excellent yields. The synthetic compounds indicated a notable inhibitory activity against α-glucosidase (α-Gls) and revealed a weak inhibitory property against α-amylase (α-Amy). Also, these synthetic compounds indicated significant antioxidant activity. The new curcumin derivatives were also discovered to display no significant effect against the growth of two bacterial microflora in the human intestine. A molecular docking study was done to realize the binding interaction of the synthetic curcumin derivatives with the α-Gls enzyme. The results of our study introduced new synthetic curcumin derivatives as potential antidiabetic drugs.
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Affiliation(s)
- Zohreh Tavaf
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz 71454, Iran
| | - Soheila Khajeh Dangolani
- Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran; Department of Chemistry, Payame Noor University, 19395-3697, Tehran, Iran
| | - Reza Yousefi
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz 71454, Iran.
| | - Farhad Panahi
- Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran.
| | - Mohammad Bagher Shahsavani
- Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz 71454, Iran
| | - Ali Khalafi-Nezhad
- Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran
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Davies MJ, Bianchi C, Del Prato S. Use of incretin-based medications: what do current international recommendations suggest with respect to GLP-1 receptor agonists and DPP-4 inhibitors? Metabolism 2020; 107:154242. [PMID: 32315698 DOI: 10.1016/j.metabol.2020.154242] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 12/25/2022]
Abstract
In recent years guidelines for the treatment of type 2 diabetes (T2DM) have evolved substantially. Initially limited to a few glucose lowering agents, early guidelines predicated strict glycemic control as a main goal in the attempt to reduce the risk of long-term diabetic complications. Nowadays, guidelines are not limited to such a goal but include cardiovascular (and renal) protection. This rapid evolution was made possible by the introduction of new glucose lowering agents, which have been extensively tested in randomized clinical studies including large cardiovascular outcome trials (CVOTs). In this review we will specifically consider the use of incretin-based medications in T2DM as recommended in the recent ADA/EASD consensus, and other international guidelines, with special consideration of their glucose-lowering efficacy, their cardiovascular (and renal) benefit, their effect on body weight and risk of hypoglycemia, as well as the economic implications for their use.
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Affiliation(s)
- Melanie J Davies
- Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK; Diabetes Research Centre, University of Leicester, UK
| | - Cristina Bianchi
- Department of Clinical & Experimental Medicine, Section of Diabetes & Metabolic Diseases, University of Pisa, Pisa, Italy
| | - Stefano Del Prato
- Department of Clinical & Experimental Medicine, Section of Diabetes & Metabolic Diseases, University of Pisa, Pisa, Italy.
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Rahim F, Zaman K, Taha M, Ullah H, Ghufran M, Wadood A, Rehman W, Uddin N, Shah SAA, Sajid M, Nawaz F, Khan KM. Synthesis, in vitro alpha-glucosidase inhibitory potential of benzimidazole bearing bis-Schiff bases and their molecular docking study. Bioorg Chem 2020; 94:103394. [DOI: 10.1016/j.bioorg.2019.103394] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 09/29/2019] [Accepted: 10/22/2019] [Indexed: 02/06/2023]
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Schernthaner G, Schernthaner GH. The right place for metformin today. Diabetes Res Clin Pract 2020; 159:107946. [PMID: 31778746 DOI: 10.1016/j.diabres.2019.107946] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 11/22/2019] [Indexed: 02/06/2023]
Abstract
Metformin is the most widely used glucose lowering drug worldwide in the treatment of patients with type 2 diabetes, since we have experience with this drug for more than 60 years about the efficacy and safety. Metformin is very effective in HbA1c lowering associated with some weight loss, but does not increase risk for hypoglycemia. At the moment all guidelines in the world recommend to use metformin in monotherapy in patients with newly diagnosed diabetes or in combination with other antidiabetic drugs with documented CV (and renal) benefit in cardiovascular outcome trials (CVOT). Although a randomized placebo controlled CVOT with metformin is lacking, many observational studies in patients with coronary heart disease, heart failure and chronic kidney disease have demonstrated consistent beneficial effects. A recent metanalysis of 26 observational studies including 815 839 patients showed that metformin use was associated with a significantly lower rate of all-cause mortality (HR: 0.74; 95% CI: 0.68-0.81). Whether this very consistent reduction of all-cause mortality is related to the incidence/outcome of several cancers has still to be investigated. In the future early combination therapy of metformin e.g. with SGLT-2 inhibitors should be more often used.
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Affiliation(s)
- Guntram Schernthaner
- Rudolfstiftung Hospital & Medical University of Vienna, Department of Medicine II, Vienna, Austria; Medical University of Vienna, Department of Medicine II, Vienna, Austria
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28
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Alomar MJ, Al-Ansari KR, Hassan NA. Comparison of awareness of diabetes mellitus type II with treatment's outcome in term of direct cost in a hospital in Saudi Arabia. World J Diabetes 2019; 10:463-472. [PMID: 31523382 PMCID: PMC6715573 DOI: 10.4239/wjd.v10.i8.463] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/08/2015] [Accepted: 07/20/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Saudi Arabia is among the top 10 countries with the highest prevalence of diabetes. Cost of prevention and the indirect cost must be calculated to increase the awareness of society and to emphasize disease prevention and limit further complications. AIM To understand the importance of awareness and the impact on the expenditure of diabetes mellitus and treatments outcomes. METHODS A prospective descriptive and comparative survey was carried out among patients with diabetes mellitus in Saudi Arabia. RESULTS One hundred and one participants were included in the study of which 40% were female and one third were above the age of 50. The mean of the first HbA1c reading was 6.95, and the median was 7. The mean of the second reading of HbA1c was 7.26, and the median was 7. The mean body mass index was 32.1, and the median was 30.9. The average yearly cost of the medication was 995.14 SR. Comparing participants who think that a healthy low-sugar diet can affect blood sugar with those who do not, showed a statistically significant difference when cost was considered (P value = 0.03). Also, when comparing the group of participants who know when to take their oral hyperglycemic medicine and their yearly direct cost and those who do not know when to take it, by using independent sample T test, showed significant statistical difference (P value = 0.046). CONCLUSION It is essential for the governments to invest in ways to prevent and help in the early detection of such an expensive disease by performing national screening and education programs. Many pharmaco-economic studies can be done to help the decision-maker in our hospitals think about strategies to help the patient to be physically fit by offering gymnasium or places to walk or contract.
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Affiliation(s)
- Muaed Jamal Alomar
- Clinical Pharmacy Department, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Khadeja Rashed Al-Ansari
- Clinical Pharmacy Department, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Najeeb A Hassan
- Clinical Pharmacy Department, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
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Regassa LD, Gete YK, Mekonnen FA. Time to acute kidney injury and its predictors among newly diagnosed Type 2 diabetic patients at government hospitals in Harari Region, East Ethiopia. PLoS One 2019; 14:e0215967. [PMID: 31048925 PMCID: PMC6497261 DOI: 10.1371/journal.pone.0215967] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 04/11/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Incidence of Acute Kidney Injury (AKI) among Type 2 diabetic patients is significantly increasing. But, earlier studies has focused on the admitted patients which may hide the true nature of the Acute Kidney Injury among Type 2 Diabetic (T2D) patients. So, this study was conducted to determine the time to Acute Kidney Injury and its predictors among Type 2 Diabetic patients in Harari Region, East Ethiopia. METHODS We conducted a retrospective cohort study among type 2 diabetic patients who had been receiving treatment at government hospitals of Harari region, Ethiopia from 2013 to 2017. We extracted data from patients' medical records. We estimated incidence rate and compared survival curves between different exposure groups using Kaplan-Meier and log-rank test. Weibull regression model was fitted to the data to identify the predictor variables. Variables with p-value <0.05 were considered statistically significant. RESULTS Overall, 14.5% (95%CI: 11.7-17.9) of the study population developed acute kidney injury, with median survival time of 57 months. The significant predictors were physical activity [Adjusted Time Ratio (ATR):95%CI; 0.6 (0.49-0.75)], congestive heart failure [ATR:95%CI; 0.84 (0.71-0.99)], chronic kidney disease [ATR:95%CI; 0.77(0.65-0.91)], hypertension [ATR:95%CI; 0.78(0.65-0.91)], obesity [ATR:95%CI; 0.84(0.74-0.96)], diabetic nephropathy [ATR:95%CI; 0.80(0.65-0.98)], diuretics & beta blockers [ATR:95%CI; 0.85(0.74-0.97)], and delay of follow-up [ATR:95%CI; 0.97(0.96-0.98)]. CONCLUSIONS Incidence of acute kidney injury was high in our study area. Hence, identification and controlling of comorbidities along with regular monitoring of kidney function are needed to prevent or delay the risk of acute kidney injury in type 2 diabetic patients.
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Affiliation(s)
- Lemma Demissie Regassa
- Department of Epidemiology and Biostatistics, Collage of Health and Medical Sciences, Haramaya University, Haramaya, Ethiopia
| | - Yigzaw Kebede Gete
- Department of Epidemiology and Biostatistics, Institute of Public Health, Collage of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Fantahun Ayenew Mekonnen
- Department of Epidemiology and Biostatistics, Institute of Public Health, Collage of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Mao XB, Cheng YH, Xu YY. miR-204-5p promotes diabetic retinopathy development via downregulation of microtubule-associated protein 1 light chain 3. Exp Ther Med 2019; 17:2945-2952. [PMID: 30936964 PMCID: PMC6434256 DOI: 10.3892/etm.2019.7327] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 12/12/2018] [Indexed: 12/14/2022] Open
Abstract
Diabetic retinopathy (DR) is a chronic and progressive complication of diabetes mellitus. DR impairs sight due to neuronal and vascular dysfunction in the retina. It is critical to investigate the pathogenesis of DR to develop effective treatment. In the present study, a streptozotocin (STZ)-induced diabetic rat model was constructed and the expression of microRNA (miR)-204-5p and vascular endothelial growth factor (VEGF) were determined. Immunohistochemistry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were employed to detect the effects of miR-204-5p on the expression of microtubule-associated protein 1 light chain 3 (LC3B). RT-qPCR analysis demonstrated that miR-204-5p and VEGF were significantly upregulated in the retina tissue of diabetic rats compared with the control group (P<0.01). Immunohistochemistry and western blotting revealed that the protein expression levels of LC3B-II and the ratio of LC3B-II/LC3B-I were significantly suppressed in the diabetes group compared with the control (P<0.01). In retinal tissues, anti-miR-204-5p treatment significantly enhanced the protein expression levels of LC3B-II and the ratio of LC3B-II/LC3B-I and these levels were significantly reduced in response to miR-204-5p mimic treatment compared with the negative miR control (P<0.01). In rat retinal endothelial cells isolated from diabetic rats, anti-miR-204-5p treatment increased the number of autophagic vacuoles, and significantly promoted LC3B-II expression and the LC3B-II/LC3B-I ratio compared with the negative control (P<0.01). The results of the present study revealed that miR-204-5p downregulated the expression of LC3B-II to inhibit autophagy in DR. Therefore, miR-204-5p may be considered as a novel effective therapeutic target during the development of DR.
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Affiliation(s)
- Xin-Bang Mao
- Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yan-Hua Cheng
- Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yan-Ying Xu
- Department of Ophthalmology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
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Zhou X, Zhang R, Zou Z, Shen X, Xie T, Xu C, Dong J, Liao L. Hypoglycaemic effects of glimepiride in sulfonylurea receptor 1 deficient rat. Br J Pharmacol 2018; 176:478-490. [PMID: 30471094 DOI: 10.1111/bph.14553] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/30/2018] [Accepted: 11/02/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND PURPOSE Sulfonylureas (SUs) have been suggested to have an insulin-independent blood glucose-decreasing activity due to an extrapancreatic effect. However, a lack of adequate in vivo evidence makes this statement controversial. Here, we aimed to evaluate whether glimepiride has extrapancreatic blood glucose-lowering activity in vivo. EXPERIMENTAL APPROACH Sulfonylurea receptor 1 deficient (SUR1-/- ) rats were created by means of transcription activator-like effector nucleases (TALEN)-mediated gene targeting technology. Type 2 diabetic models were established by feeding a high-fat diet and administering a low-dose of streptozotocin. These rats were then randomly divided into four groups: glimepiride, gliclazide, metformin and saline. All rats were treated for 2 weeks. KEY RESULTS Glimepiride decreased blood glucose levels and increased insulin sensitivity without elevating insulin levels. Gliclazide showed similar effects as glimepiride. Both agents were weaker than metformin. Further mechanistic investigations revealed that glimepiride increased hepatic glycogen synthesis and decreased gluconeogenesis, which were accompanied by the activation of Akt in the liver. Moreover, glimepiride increased both total and membrane glucose transporter 4 (GLUT4) levels in muscle and fat, which might be attributed to insulin receptor-independent IRS1/Akt activation. CONCLUSION AND IMPLICATIONS Glimepiride possesses an extrapancreatic blood glucose-lowering effect in vivo, which might be attributed to its direct effect on insulin-sensitive tissues. Therefore, the combination of glimepiride with multiple insulin injections should not be excluded per se.
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Affiliation(s)
- Xiaojun Zhou
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Rui Zhang
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Zhiwei Zou
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China
| | - Xue Shen
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tianyue Xie
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chunmei Xu
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Jianjun Dong
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China
| | - Lin Liao
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
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Alharbi TJ, Tourkmani AM, Abdelhay O, Alkhashan HI, Al-Asmari AK, Bin Rsheed AM, Abuhaimed SN, Mohammed N, AlRasheed AN, AlHarbi NG. The association of metformin use with vitamin B12 deficiency and peripheral neuropathy in Saudi individuals with type 2 diabetes mellitus. PLoS One 2018; 13:e0204420. [PMID: 30321183 PMCID: PMC6188756 DOI: 10.1371/journal.pone.0204420] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Accepted: 09/09/2018] [Indexed: 12/17/2022] Open
Abstract
Aims To compare the prevalence of vitamin B12 deficiency and peripheral neuropathy between two groups of type 2 diabetes mellitus (T2DM) patients treated with or without metformin, and to determine factors associated with vitamin B12 deficiency therapy and dietary intake of vitamin B12. Methods In this retrospective study, we recruited 412 individuals with T2DM: 319 taking metformin, and 93 non-metformin users. Demographics, dietary assessment for vitamin B12 intakes, and medical history were collected. Participants were assessed for peripheral neuropathy. Blood specimens were collected and checked for serum vitamin B12 levels. The differences between the two groups were analyzed using an independent t-test for continuous data, and the Chi-squared or Fisher's exact test was used for categorical data. The relationship of vitamin B12 deficiency with demographics and clinical characteristics was modeled using logistic regression. Results The prevalence of B12 deficiency was 7.8% overall, but 9.4% and 2.2% in metformin users and non-metformin users, respectively. The odds ratio for serum vitamin B12 deficiency in metformin users was 4.72 (95% CI, 1.11–20.15, P = 0.036). There were no significant differences in a test of peripheral neuropathy between the metformin users and non-metformin users (P > 0.05). Low levels of vitamin B12 occurred when metformin was taken at a dose of more than 2,000 mg/day (AOR, 21.67; 95% CI, 2.87–163.47) or for more than 4 years (AOR, 6.35; 95% CI, 1.47–24.47). Conclusion Individuals with T2DM treated with metformin, particularly those who use metformin at large dosages (> 2,000 mg/day) and for a longer duration (> 4 years), should be regularly screened for vitamin B12 deficiency and metformin is associated with B12 deficiency, but this is not associated with peripheral neuropathy.
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Affiliation(s)
- Turki J. Alharbi
- Family and Community Medicine Department, Prince Sultan Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Ayla M. Tourkmani
- Family and Community Medicine Department, Prince Sultan Medical City, Riyadh, Kingdom of Saudi Arabia
- * E-mail:
| | - Osama Abdelhay
- Family and Community Medicine Department, Prince Sultan Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Hesham I. Alkhashan
- Family and Community Medicine Department, Prince Sultan Medical City, Riyadh, Kingdom of Saudi Arabia
| | | | - Abdulaziz M. Bin Rsheed
- Family and Community Medicine Department, Prince Sultan Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Sarah N. Abuhaimed
- Family and Community Medicine Department, Prince Sultan Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Najeebuddin Mohammed
- Family and Community Medicine Department, Prince Sultan Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Abdulrhman N. AlRasheed
- Family and Community Medicine Department, Prince Sultan Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Nouf G. AlHarbi
- Family and Community Medicine Department, Prince Sultan Medical City, Riyadh, Kingdom of Saudi Arabia
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Blind E, Janssen H, Dunder K, de Graeff PA. The European Medicines Agency's approval of new medicines for type 2 diabetes. Diabetes Obes Metab 2018; 20:2059-2063. [PMID: 29740935 PMCID: PMC6667915 DOI: 10.1111/dom.13349] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 04/30/2018] [Accepted: 05/02/2018] [Indexed: 12/11/2022]
Abstract
Since 2005, more than 40 new medicines for the treatment of type 2 diabetes have been introduced on the market. These consist of 15 new active substances establishing three new classes of non-insulin products, and several new or modified insulin products and combinations. The approval of these products in Europe is regulated via the centralized procedure at the European Medicines Agency. Demonstration of benefit with regard to improved glucose control remains the principal outcome required from confirmatory studies to demonstrate efficacy. For the majority of these new medicines approved since 2005, cardiovascular outcome trials have now been completed, and have invariably supported the cardiovascular safety of these products. In some of these trials additional important benefits have been observed, for instance, a reduction in major adverse cardiovascular events and improvement of renal outcome. The existing regulatory framework and the continuous adaption of regulatory requirements to emerging developments will continue to guide the approval of new products in the future.
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Armagan B, Sari A, Erden A, Kilic L, Erdat EC, Kilickap S, Kiraz S, Bilgen SA, Karadag O, Akdogan A, Ertenli I, Kalyoncu U. Starting of biological disease modifying antirheumatic drugs may be postponed in rheumatoid arthritis patients with multimorbidity: Single center real life results. Medicine (Baltimore) 2018; 97:e9930. [PMID: 29595700 PMCID: PMC5895384 DOI: 10.1097/md.0000000000009930] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The objective of this study was to assess the frequency of comorbidities and multimorbidities in rheumatoid arthritis (RA) patients under biologic therapy and their effects on biological disease modifying antirheumatic drugs (DMARDs) choice, timing, and response.Hacettepe University Biologic Registry (HUR-BIO) is single center biological DMARD registry. Cardiovascular, infectious, cancer, and other comorbidities were recorded with face to face interviews. Multimorbidity is defined as >1 comorbidity. Disease duration, initial date of biological DMARDs, initial and overall biological DMARD choice were recorded. Disease activity score-28 (DAS-28) responses were compared to comorbidity presence and multimorbidity.Total of 998 RA patients were enrolled into the study. The mean age was 53.1 (12.5) and mean disease duration (standard deviation [SD]) was 11.7 (7.5) years. At least 1 comorbidity was detected in 689 (69.1%) patients, 375 (37.9%) patients had multimorbidity. Patients had mean 1.36 ± 1.32 comorbidity. The median durations of first biological DMARDs prescription were 60 (3-552) months after RA diagnosis. For multimorbidity patients, the median first biological prescription duration was longer than the duration for patients without multimorbidity (72 [3-552] vs 60 [3-396] months, P < .001). The physicians prescribe tumor necrosis factor inhibitor (TNFi) biological drugs less frequently than other biological DMARDs in patients with at least 1 comorbidity (66.2% vs 74.5%, P = .007) or multimorbidity (34.6% vs 43.5%, P = .006). Patients with comorbidities and multimorbidity achieved DAS-28 remission less frequently than patients without comorbidity (31.6% vs 42.6%, P = .012 and 27.2% vs 39.7%, P = .001, respectively).In real life, physicians may postpone to prescribe biological DMARDs and less frequently choose TNFi biological drugs in patients with multimorbidity. Furthermore, comorbidity may have a negative effect on the treatment response.
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Affiliation(s)
| | | | | | | | | | - Saadettin Kilickap
- Division of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey
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Kawazu S, Kanazawa Y, Iwamoto Y, Katayama S, Origasa H, Kuzuya T. Effect of antihyperglycemic drug monotherapy to prevent the progression of mild hyperglycemia in early type 2 diabetic patients: the Japan Early Diabetes Intervention Study (JEDIS). Diabetol Int 2017; 8:350-365. [PMID: 30603341 PMCID: PMC6224919 DOI: 10.1007/s13340-017-0319-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 03/27/2017] [Indexed: 11/25/2022]
Abstract
To effectively prevent the worsening of hyperglycemia in type 2 diabetes mellitus, it is of interest to see the clinical efficacy of early introduction of pharmacotherapy in addition to lifestyle intervention which is not always easy to continue throughout life. This is a randomized unblinded comparative clinical study on suppressive effects of lifestyle intervention alone and additional monotherapies for mild hyperglycemia at an early stage of treatment-naïve type 2 diabetic patients, whose fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) are less than 140 mg/dl and 7.4%, respectively. The control group (group N = arm N) received conventional lifestyle intervention assisted by routine facilities, while the pharmacological intervention group (group D composed of 4 arms) was additionally treated by monotherapy with one of four kinds of oral antihyperglycemic agents i.e., sulfonylurea (SU), α-glucosidase inhibitor, biguanide and dipeptidyl peptidase-4 inhibitor. The participants were scheduled to follow up for 3 years to maintain glycemic control below primary endpoint which was defined as the first occurrence of FPG ≥140 mg/dl and HbA1c ≥7.4% simultaneously even by increasing doses of oral drug in group D, if necessary. The outcomes of occurrences of primary endpoint were not different between group N and group D composed of 4 arms during 3 years by Kaplan-Meyer plots (p = 0.405). On the other hand, ΔFPG (Δ: incremental change from baseline) and ΔHbA1c in group D significantly decreased when compared to those of group N during 3 years (p < 0.05 and p < 0.01 respectively). Significant reductions of ΔBMI were seen similarly in both groups throughout the study (p < 0.05), but did not differ between two groups. Among these 5 arms, significant decreases of ΔHbA1c were observed in three monotherapy arms of group D compared to arm N for 3 years (p < 0.05 or p < 0.01), except for arm SU in which ΔBMI and ΔHbA1c tended to increase at the latter half of the study. The final achievement rates of target HbA1c less than 7.4, 7.0 and 6.5% in all the participants tended to be higher in group D than in group N (p < 0.047 for 7.4%, but not significant for others). In conclusion, the early introduction of pharmacological monotherapy in addition to lifestyle intervention seem to suppress mild hyperglycemia with small doses of antihyperglycemic agents for 3 years, except for the use of SU drug. Although a larger scale of trial will be necessary to conclude, the early treatment with suitable monotherapy could be effective to bring and keep "safe level of glycemia".
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Affiliation(s)
- Shoji Kawazu
- The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6 Nihonbashi, Bakuro-cho, Chuo-ku, Tokyo, 103-0002 Japan
| | | | - Yasuhiko Iwamoto
- The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6 Nihonbashi, Bakuro-cho, Chuo-ku, Tokyo, 103-0002 Japan
| | | | - Hideki Origasa
- Department of Biostatistics and Clinical Epidemiology, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan
| | | | - The JEDIS (Japan Early Diabetes Intervention Study) Research Group
- The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6 Nihonbashi, Bakuro-cho, Chuo-ku, Tokyo, 103-0002 Japan
- Jichi Medical University, Tochigi, Japan
- Saitama Medical University, Saitama, Japan
- Department of Biostatistics and Clinical Epidemiology, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan
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Cao MM, Lu X, Liu GD, Su Y, Li YB, Zhou J. Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1. Exp Ther Med 2017; 15:576-584. [PMID: 29387206 DOI: 10.3892/etm.2017.5400] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 08/24/2017] [Indexed: 12/13/2022] Open
Abstract
The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health problem and novel therapeutic strategies are required to prevent and treat T2DM. It has been demonstrated that resveratrol (RSV) may prevent T2DM by targeting Sirtuin type 1 (SIRT1), indicating that SIRT1 may be a novel therapeutic target for T2DM prevention. In the present study, a T2DM rat model was established by administering a high fat diet and streptozotocin (STZ) injections. Measurements of blood glucose and insulin confirmed successful establishment of the T2DM model. RSV was used to treat rats with STZ-induced T2DM and the results indicated that RSV reversed the STZ-induced downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α, SIRT1 and forkhead box protein O 3a. Furthermore, RSV modulated the activity of superoxide dismutase and malondialdehyde, which are associated with oxidative stress. In vitro, cells from the insulinoma cell line clone 1E were pretreated with palmitic acid (PA) to simulate a high fat environment. The results of reverse transcription-quantitative polymerase chain reaction indicated that PA suppressed the expression of SIRT1 in a dose- and time-dependent manner. Furthermore, PA modulated the expression of mitochondrial biogenesis-associated, lipid metabolism-associated and β-cell-associated genes, whereas RSV treatment ameliorated the PA-induced changes in the expression of these genes via SIRT1. The results of the present study suggest that RSV participates in the prevention of T2DM by regulating the expression of mitochondrial genes associated with biogenesis, lipid metabolism and β-cells via SIRT1. The results of the current study provide an insight into the mechanisms by which SIRT1 inhibits T2DM and may be used as a basis for future studies.
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Affiliation(s)
- Ming-Ming Cao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xi Lu
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Guo-Dong Liu
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Ying Su
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yan-Bo Li
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jin Zhou
- Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Arshad R, Khanam S, Shaikh F, Karim N. Feto-maternal outcomes and Glycemic control in Metformin versus insulin treated Gestational Diabetics. Pak J Med Sci 2017; 33:1182-1187. [PMID: 29142561 PMCID: PMC5673730 DOI: 10.12669/pjms.335.13286] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 06/29/2017] [Accepted: 10/03/2017] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To evaluate and compare feto-maternal outcomes and glycemic control in metformin versus insulin treated gestational diabetics. METHODS The study was conducted in 2010- 2012 as a part of M. Phil at Civil hospital, Lyari General Hospital and Mamji Hospital in Karachi. After written informed consent, 71 GDM diagnosed females with WHO criteria were enrolled. They were divided into two groups. Group-A, 32 females were given oral metformin 500 mg TDS while Group-B, 39 females were given insulin 0.8-0.9 mg/kg/day in two divided doses subcutaneously. Patients were followed till term. Feto-maternal outcomes were evaluated in 25 patients in each group who completed the study. RESULTS When groups were compared, newborns in Group-B were significantly more in weight (p=0.01). Significant numbers of babies were delivered after 38 weeks of pregnancy in Group-B (P=0.021). There were two intrauterine deaths and significantly higher HbA1C at term in Group-B. (P=0.03). FBS at term was non-significant (p=0.079) and there was more number of cesarean sections due to feto-maternal disproportion in Group-B (28% vs.2%). Results analyzed for glycemic control before and after the treatment revealed that FBS was statistically less in Group-A (p=0.00) whereas for Group-B the value of FBS and HbA1C was statistically high. (p=0.002 & 0.04 respectively). CONCLUSION Metformin has produced better effects on feto-maternal outcomes and glycemic control in comparison to Insulin in GDM.
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Affiliation(s)
- Rabia Arshad
- Dr. Rabia Arshad, MBBS, M. Phil, Assistant Professor, Department of Pharmacology, Altamash Institute of Dental Medicines, Karachi, Pakistan
| | - Samia Khanam
- Dr. Samia Khanam, MBBS, M. Phil, Assistant Professor and Head, Department of Pathology, Altamash Institute of Dental Medicines, Karachi, Pakistan
| | - Fuad Shaikh
- Dr. Fuad Shaikh, MBBS, M.Phil, Associate Professor, Department of Pharmacology, Dow University of Health Sciences, Karachi, Pakistan
| | - Nasim Karim
- Dr. Nasim Karim, MBBS, M. Phil, Ph D, Post Doc (USA), Head of Pharmacology Department, Bahria University Medical and Dental College, Sailors Street, Adjacent PNS Shifa, Defence Phase-II, Karachi, Pakistan
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A phase Ib study of everolimus combined with metformin for patients with advanced cancer. Invest New Drugs 2017; 36:53-61. [PMID: 28616837 PMCID: PMC5805805 DOI: 10.1007/s10637-017-0478-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 05/30/2017] [Indexed: 12/13/2022]
Abstract
Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4–78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.
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Stanislaus S, Hecht R, Yie J, Hager T, Hall M, Spahr C, Wang W, Weiszmann J, Li Y, Deng L, Winters D, Smith S, Zhou L, Li Y, Véniant MM, Xu J. A Novel Fc-FGF21 With Improved Resistance to Proteolysis, Increased Affinity Toward β-Klotho, and Enhanced Efficacy in Mice and Cynomolgus Monkeys. Endocrinology 2017; 158:1314-1327. [PMID: 28324011 DOI: 10.1210/en.2016-1917] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Accepted: 01/20/2017] [Indexed: 01/10/2023]
Abstract
Fibroblast growth factor (FGF) 21 is a natural hormone that modulates glucose, lipid, and energy metabolism. Previously, we engineered an Fc fusion FGF21 variant with two mutations, Fc-FGF21(RG), to extend the half-life and reduce aggregation and in vivo degradation of FGF21. We now describe a new variant developed to reduce the extreme C-terminal degradation and improve the binding affinity to β-Klotho. We demonstrate, by introducing one additional mutation located at the C terminus of FGF21 (A180E), that the new molecule, Fc-FGF21(RGE), has gained many improved attributes. Compared with Fc-FGF21(RG), Fc-FGF21(RGE) has similar in vitro potency, preserves β-Klotho dependency, and maintains FGF receptor selectivity and cross-species reactivity. In vivo, Fc-FGF21(RGE) showed reduced susceptibility to extreme C-terminal degradation and increased plasma levels of the bioactive intact molecule. The circulating half-life of intact Fc-FGF21(RGE) increased twofold compared with that of Fc-FGF21(RG) in mice and cynomolgus monkeys. Additionally, Fc-FGF21(RGE) exhibited threefold to fivefold enhanced binding affinity to coreceptor β-Klotho across mouse, cynomolgus monkey, and human species. In obese and diabetic mouse and cynomolgus monkey models, Fc-FGF21(RGE) demonstrated greater efficacies to Fc-FGF21(RG), resulting in larger and more sustained improvements in multiple metabolic parameters. No increased immunogenicity was observed with Fc-FGF21(RGE). The superior biophysical, pharmacokinetic, and pharmacodynamic properties, as well as the positive metabolic effects across species, suggest that further clinical development of Fc-FGF21(RGE) as a metabolic therapy for diabetic and/or obese patients may be warranted.
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Affiliation(s)
- Shanaka Stanislaus
- Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California 91320
| | - Randy Hecht
- Department of Biologics, Amgen Inc., Thousand Oaks, California 91320
| | - Junming Yie
- Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California 91320
| | - Todd Hager
- Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California 91320
| | - Michael Hall
- Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California 91320
| | - Chris Spahr
- Department of Biologics, Amgen Inc., Thousand Oaks, California 91320
| | - Wei Wang
- Department of Biologics, Amgen Inc., Thousand Oaks, California 91320
| | - Jennifer Weiszmann
- Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California 91320
- Amgen Inc., South San Francisco, California 94080
| | - Yang Li
- Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California 91320
- Amgen Inc., South San Francisco, California 94080
| | - Liying Deng
- Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California 91320
| | - Dwight Winters
- Department of Biologics, Amgen Inc., Thousand Oaks, California 91320
| | - Stephen Smith
- Department of Biologics, Amgen Inc., Thousand Oaks, California 91320
| | - Lei Zhou
- Department of Medical Science, Amgen Inc., Thousand Oaks, California 91320
| | - Yuesheng Li
- Department of Biologics, Amgen Inc., Thousand Oaks, California 91320
| | - Murielle M Véniant
- Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California 91320
| | - Jing Xu
- Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, California 91320
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Metformin Use Is Associated with Reduced Incidence and Improved Survival of Endometrial Cancer: A Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5905384. [PMID: 28409158 PMCID: PMC5376924 DOI: 10.1155/2017/5905384] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 12/31/2016] [Accepted: 01/24/2017] [Indexed: 12/30/2022]
Abstract
Studies have suggested that metformin can potentially decrease the incidence of cancer and improve survival outcomes. However, the association between metformin use and the incidence and survival of endometrial cancer (EC) remains controversial. So, a meta-analysis was performed. An electronic search was conducted using PubMed, EMBASE, and Web of Science. The outcome measures were relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CIs) comparing the EC incidence and survival in patients treated with and without metformin. Eleven studies involving 766,926 participants were included in this study. In the pooled analysis of five studies which evaluated the association of metformin use with the incidence of EC, we found that metformin use was associated with a 13% reduction in EC risk among patients with diabetes (RR = 0.87, 95% CI: 0.80–0.95; p = 0.006). In the pooled analysis of six retrospective cohort studies evaluating the effect of metformin on the survival of EC patients, we found that, relative to nonuse, metformin use significantly improved the survival of EC patients (HR = 0.63, 95% CI: 0.45–0.87; p = 0.006). This study showed that metformin use was significantly associated with a decreased incidence of EC in diabetes and a favorable survival outcome of EC patients.
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Mirijello A, Vallone C, De Cosmo S, Landolfi R, Addolorato G. Chronic diarrhea in a patient with severe vitamin B12 deficiency: a rare clinical manifestation. Scand J Gastroenterol 2016; 51:763-4. [PMID: 26794081 DOI: 10.3109/00365521.2015.1136353] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Antonio Mirijello
- a Department of Medical Sciences , Catholic University School of Medicine , Rome , Italy ;,b Department of Medical Sciences , IRCCS Casa Sollievo Della Sofferenza , San Giovanni Rotondo , Italy
| | - Carla Vallone
- a Department of Medical Sciences , Catholic University School of Medicine , Rome , Italy
| | - Salvatore De Cosmo
- a Department of Medical Sciences , Catholic University School of Medicine , Rome , Italy
| | - Raffaele Landolfi
- a Department of Medical Sciences , Catholic University School of Medicine , Rome , Italy
| | - Giovanni Addolorato
- b Department of Medical Sciences , IRCCS Casa Sollievo Della Sofferenza , San Giovanni Rotondo , Italy
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Affiliation(s)
- Ian W Campbell
- Consultant Physician, Victoria Hospital, Hayfield Road, Kirkcaldy, Fife, KY2 5AH, UK, . nhs.uk
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Abstract
Type 2 diabetes mellitus is epidemic in most developed and many developing countries. The associated morbidity, mortality and high costs of care, make type 2 diabetes an important global public health challenge and target for prevention. Patients at high risk for type 2 diabetes can be diagnosed by fasting glucose levels or responses to an oral glucose tolerance test (OGTT). Such patients are also at increased risk for cardiovascular disease (CVD). Since obesity and physical inactivity are important risk factors for type 2 diabetes, lifestyle interventions, emphasising modest weight loss and increases in physical activity, should be recommended for most patients with pre-diabetes. Such interventions are safe and effective and also reduce risk factors for CVD. Several oral antidiabetic agents have been shown to be effective at delaying onset of type 2 diabetes. Thiazolidinediones (TZDs) reduced incident diabetes by ~60%, whilst metformin, acarbose and orlistat are only about half as effective as the TZDs. Pharmacological interventions may be appropriate for patients at particular risk for developing diabetes, but the benefits of treatment need to be balanced against the safety and tolerability of the intervention. If pharmacological treatment is warranted, metformin should be considered first because of its favourable overall safety, tolerability, efficacy, and cost profile.
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Affiliation(s)
- Richard E Pratley
- Diabetes and Metabolism Translational Medicine Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Vermont College of Medicine,
| | - Glenn Matfin
- Division of Endocrinology and Diabetes, Department of Medicine, New York University School of Medicine, New York, USA
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Feher MD, Al-Mrayat M, Brake J, Leong KS. Tolerability of prolonged-release metformin (Glucophage® SR) in individuals intolerant to standard metformin — results from four UK centres. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/14746514070070050501] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Advances in drug formulation have improved the tolerability of many commonly used agents. Metformin is recommended as initial drug therapy for type 2 diabetes and has proven long-term efficacy and safety. However, gastrointestinal (GI) side-effects of standard, immediate-release (IR) metformin often reduce medication adherence and limit dose titration. A prolonged-release metformin formulation may improve tolerability over its IR counterpart. We report the results of two prospective and two retrospective clinic-based evaluations of the tolerability of metformin in a total of 95 patients intolerant to standard IR metformin assessed over three to six months following a switch from IR to prolonged-release metformin (Glucophage® SR). Between 62% and 100% of patients from the centres tolerated the prolonged-release formulation. Glycaemia following the switch was improved or unchanged. Prolonged-release metformin represents a useful option for patients intolerant of standard IR metformin due to GI side-effects. This improved tolerance of prolonged-release metformin may improve medication adherence and thereby enhance treatment outcomes.
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Affiliation(s)
- Michael D Feher
- Beta Cell Diabetes Centre, Chelsea and Westminster Hospital, London, UK,
| | | | - Julie Brake
- Royal Liverpool University Hospital, Liverpool, UK
| | - King Sun Leong
- Department of Diabetes and Endocrinology, Clatterbridge General Hospital, Wirral NHS Trust, Bebington, UK
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Tai H, Wang MY, Zhao YP, Li LB, Dong QY, Liu XG, Kuang JS. The effect of alogliptin on pulmonary function in obese patients with type 2 diabetes inadequately controlled by metformin monotherapy. Medicine (Baltimore) 2016; 95:e4541. [PMID: 27537577 PMCID: PMC5370803 DOI: 10.1097/md.0000000000004541] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND To observe the effect of alogliptin combined with metformin on pulmonary function in obese patients with type 2 diabetes inadequately controlled by metformin monotherapy (500 mg, bid po, for at least 3 months), and evaluate its efficacy and safety. METHODS After a 2-week screening period, adult patients (aged 36-72 years) entered a 4-week run-in/stabilization period. Then, patients were randomly assigned to either the intervention group (n = 55) or the control group (n = 50) for 26 weeks. The patients in the control group were given metformin (1000 mg, bid po) and the patients in the intervention group were given metformin (500 mg, bid po) combined with alogliptin (25 mg, qd po). All the patients received counseling about diet and exercise from a nutritionist during run-in and treatment periods.The primary endpoints were the between-group differences in the changes in pulmonary function parameters (vital capacity [VC]%, forced vital capacity [FVC]%, forced expiratory volume in 1 second (FEV1)%, peak expiratory force [PEF]%, maximal voluntary ventilation [MVV]%, total lung capacity [TLC%], forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC%], diffusing capacity for carbon monoxide of lung [DLCO]%, and diffusing capacity for carbon monoxide of lung/unit volume [DLCO/VA%]) between pretherapy and posttreatment. The secondary endpoints were changes from baseline to week 26 in glycosylated hemoglobinA1c (HbA1c), FPG, 2hPG, homeostasis model assessment insulin resistance (HOMA-IR), waist circumference (WC), and BMI. The tertiary endpoints were the changes from baseline to week 26 in blood-fat (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides [TG]). The quartus endpoints were the changes from baseline to week 26 in systolic blood pressure (SBP) and diastolic blood pressure (DBP). The 5th endpoints were the changes from baseline to week 26 in oxidative/antioxidative parameters (reactive oxygen species [ROS], malondialdehyde [MDA], superioxide dismutase [SOD], and glutathione peroxidase [GSH-Px]). In addition, safety endpoints were assessed (AEs, clinical laboratory tests, vital signs, and electrocardiographic readings). RESULTS Eighty-one patients completed our clinical trial: intervention group (n = 44) and control group (n = 37). At week 26, pulmonary function parameters (VC%, FVC%, FEV1%, PEF%, MVV%, TLC%, FEV1/FVC%, DLCO%, and DLCO/VA%) had increased significantly from pretherapy values in both groups (P < 0.05), and the pulmonary function tests were significantly greater (P < 0.05) in intervention group than in controls posttherapy. Pulmonary function (FVC%, FEV1%, PEF%, TLC%, FEV1/FVC%, DLCO%, and DLCO/VA%) was lower in the group with HbA1c levels ≥8.0 at 26 weeks, but VC%, FEV1%, MVV%, and TLC% were not significantly lower (P > 0.05). Pulmonary function parameters were positively correlated with GSH-Px and SOD and negatively correlated with ROS and MDA. Mean declines in HbA1c, FPG, 2hPG, HOMA-IR, and blood-fat (TC, HDL-C, LDL-C, and TG) were significantly greater (P < 0.05) in intervention group compared with the controls, but mean declines in BMI, WC, and BP (SBP, DBP) did not differ significantly between the 2 groups (P > 0.05). SOD and GSH-Px increased more (P < 0.05) in the intervention group, compared with the controls; ROS and MDA declined more (P < 0.05) in intervention group, as compared with the control group. The most common AEs were gastrointestinal events, headaches, skin-related AEs (mostly pruritic events), and hypoglycemia. The incidences of AEs did not differ significantly (P > 0.05) between the 2 groups except for the headache and skin-related adverse events (the incidence of headache was higher in the intervention group than in controls; P < 0.05). No patient died during the study. CONCLUSION In patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin monotherapy, the addition of alogliptin contributed to clinically significant increases in pulmonary function through regulating glycemia and improving the imbalance of the oxidative-related substances in the serum, without increasing the incidence of hypoglycemia, dyslipidemia, dysarteriotony, and any notable increase in body weight.
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Affiliation(s)
- He Tai
- Department of Endocrinology and Metabolic, Liaoning Provincial Corps Hospital of Chinese People's Armed Police Forces
| | - Ming-Yue Wang
- Department of Endocrinology and Metabolic, Liaoning Provincial Corps Hospital of Chinese People's Armed Police Forces
| | - Yue-Ping Zhao
- Department of Endocrinology and Metabolic, Liaoning Provincial Corps Hospital of Chinese People's Armed Police Forces
| | - Ling-Bing Li
- Department of Endocrinology and Metabolic, Liaoning Provincial Corps Hospital of Chinese People's Armed Police Forces, Shenyang
| | - Qian-Yan Dong
- Department of Endocrinology and Metabolic, Shenyang the Fourth Hospital of People, Shenyang, Liaoning, China
| | - Xin-Guang Liu
- Department of Endocrinology and Metabolic, Shenyang the Fourth Hospital of People, Shenyang, Liaoning, China
| | - Jin-Song Kuang
- Department of Endocrinology and Metabolic, Shenyang the Fourth Hospital of People, Shenyang, Liaoning, China
- Correspondence: Jin-Song Kuang, Department of Endocrinology and Metabolic, Shenyang the Fourth Hospital of People, No.20 Huanghe Road, Shenyang, Liaoning 110031, China (e-mail: )
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Fogelman Y, Goldfracht M, Karkabi K. Managing Diabetes Mellitus: A Survey of Attitudes and Practices Among Family Physicians. J Community Health 2016; 40:1002-7. [PMID: 25877332 PMCID: PMC4556738 DOI: 10.1007/s10900-015-0024-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Due to the increasing prevalence of diabetes and the shortage of endocrinologists, family physicians have an important role in diabetes management. The purpose of this study was to examine the sources of knowledge, attitudes and practices of family physicians regarding the management of type 2 diabetes. Attendees at continuous medical education (CME) programs in Israel were requested to respond anonymously to written questions about their sources of knowledge about diabetes, the methods of diabetes management they advise their patients, their knowledge of diabetes medication treatments, and their attitudes toward people with type 2 diabetes. Questionnaires were completed by 362 family physicians (79% response rate). Of them, 329 (91%) reported that they usually manage their patients' diabetes care, including that of patients with concomitant risk factors. Their most common recommendations for diabetes control were: to increase physical activity, decrease total calorie intake, consult with a dietitian and undergo weight loss counseling. Almost all physicians (97%) reported providing lifestyle change counseling. Sixty percent reported lacking knowledge about nutritional issues. Only 58% answered correctly regarding the effect of the anti-diabetic drug, GLP1 analog. Board certified family physicians and their residents exhibited more knowledge about diabetes practice than did non-board certified family physicians. The great majority of family physicians surveyed usually manage their patients' diabetes themselves, and do not refer them to diabetes specialists. The implementation of strategies that will enhance the competencies and confidence of family physicians in diabetes management are important for achieving successful treatment.
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Affiliation(s)
- Yacov Fogelman
- Department of Family Practice, Leumit HMO and Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, P.O. Box 121, 23800, Givat Elah, Israel,
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Mashitisho MLI, Mashitisho BG. Early insulin therapy in patients with type 2 diabetes mellitus. JOURNAL OF ENDOCRINOLOGY, METABOLISM AND DIABETES OF SOUTH AFRICA 2016. [DOI: 10.1080/16089677.2016.1160539] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers. Cancer Chemother Pharmacol 2016; 77:973-7. [PMID: 27014780 DOI: 10.1007/s00280-016-3009-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 03/10/2016] [Indexed: 12/11/2022]
Abstract
PURPOSE Mammalian target of rapamycin (mTOR) inhibitors like temsirolimus may result in undesirable AKT upregulation. Metformin inhibits mTOR through different mechanisms and may enhance temsirolimus's antitumor activity. We conducted an open-label phase I dose escalation trial of this drug combination in patients with advanced/refractory cancers. METHODS Temsirolimus, 25 mg weekly, was combined with an escalating daily dose of metformin (level 1: 500; level 2: 1000; level 3: 1500; level 4: 2000 mg) by utilizing a standard 3 + 3 trial design. Treatment was administered in 28-day cycles following initial 2-week metformin titration during the first cycle. RESULTS Twenty-one patients (median age, 56 years) with sarcoma (n = 8), colorectal (n = 3), endometrial (n = 4), uterine carcinosarcoma (n = 2), ovarian (n = 2), and other (n = 2) cancers were enrolled. Patients had received median of four prior systemic treatments. Two dose-limiting toxicities were observed (grade 3 mucositis, grade 3 renal failure); both patients continued treatment after dose modification. Fifty-six percent patients had stable disease as best response; clinical benefit rate was 22 %. Patients continued treatment for median of 11 weeks. CONCLUSIONS Combination temsirolimus/metformin was well tolerated with modestly promising effectiveness among this heavily pretreated patient cohort. We recommend a dose of temsirolimus 25 mg weekly and metformin 2000 mg daily for phase II study.
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Ji M, Xia L, Cao J, Zou D. Sitagliptin/Metformin Versus Insulin Glargine Combined With Metformin in Obese Subjects With Newly Diagnosed Type 2 Diabetes. Medicine (Baltimore) 2016; 95:e2961. [PMID: 26986104 PMCID: PMC4839885 DOI: 10.1097/md.0000000000002961] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
To compare the therapeutic effects of different regimens in Chinese obese type 2 diabetic mellitus (T2DM) patients. From October 2013 to July 2014, a total of 166 T2DM outpatients who attended the Shanghai Changhai Hospital and the Yijishan Hospital of Wannan Medical College were randomly assigned into an experimental sitagliptin/metformin combined with low caloric diet group (n = 115) and an insulin glargine combined with metformin control group (n = 51). Inclusion criteria were body mass index (BMI) ≥ 25 kg/m and diagnosed with T2DM with glycosylated hemoglobin (glycated hemoglobin A1C [HbA1c]) >9%. Main outcome parameters were fasting plasma glucose, postprandial plasma glucose, BMI, HbA1c, fasting C-peptide, 2-h postprandial C-peptide, triglyceride (TG), total cholesterol (TC), high-density cholesterol (HDL-C), and low-density cholesterol (LDL-C), which were determined by the 75 g steamed-bun meal tolerance test before and 4, 8, 12, and 24 weeks after the treatment started. Treatment costs and life quality were also assessed. BMI, HbA1C, TG, TC, and LDL were significantly more reduced (P < 0.000) and HbA1c significantly better improved in the experimental group than in the control group (<6.5% in 24 [20.87%] vs 2 [3.92%], P < 0.001; <7% in 65 [56.52%] vs 12 [23.53%], P < 0.001). Quality of life scores in the experimental group increased more than in the control group (P < 0.001). The costs for the experimental group medication were less than for other regimens. For obese T2DM patients diagnosed with a glycosylated hemoglobin level >9%, oral sitagliptin/metformin combined with a low caloric diet effectively and economically maintained glycemic control and significantly improved life quality.
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Affiliation(s)
- Ming Ji
- From the Department of Endocrinology,Shanghai Changhai Hospital,No.168 Changhai Road,Shanghai 200433,China (MJ, JC, DZ) and Department of Endocrinology, Yijishan Hospital of Wannan Medical College,Wuhu,Anhui,241000,China (LX, DZ), China
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Moioli A, Maresca B, Manzione A, Napoletano AM, Coclite D, Pirozzi N, Punzo G, Menè P. Metformin associated lactic acidosis (MALA): clinical profiling and management. J Nephrol 2016; 29:783-789. [PMID: 26800971 DOI: 10.1007/s40620-016-0267-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Accepted: 01/09/2016] [Indexed: 12/20/2022]
Abstract
Metformin (MF) accumulation during acute kidney injury is associated with high anion gap lactic acidosis type B (MF-associated lactic acidosis, MALA), a serious medical condition leading to high mortality. Despite dose adjustment for renal failure, diabetic patients with chronic kidney disease (CKD) stage III-IV are at risk for rapid decline in renal function by whatever reason, so that MF toxicity might arise if the drug is not timely withdrawn. Sixteen consecutive patients were admitted to our Hospital's Emergency Department with clinical findings consistent with MALA. Fifteen had prior history of CKD, 60 % of them with GFR between 30 and 60 ml/min. Of these, 5 required mechanical ventilation and cardiovascular support; 3 promptly recovered renal function after rehydration, whereas 10 (62 %) required continuous veno-venous renal replacement treatment. SOFA and SAPS II scores were significantly related to the degree of lactic acidosis. In addition, lactate levels were relevant to therapeutic choices, since they were higher in dialyzed patients than in those on conservative treatment (11.92 mmol/l vs 5.7 mmol/l, p = 0.03). The overall death rate has been 31 %, with poorer prognosis for worse acidemia, as serum pH was significantly lower in non-survivors (pH 6.96 vs 7.16, p > 0.04). Our own data and a review of the literature suggest that aged, hemodynamically frail patients, with several comorbidities and CKD, are at greater risk of MALA, despite MF dosage adjustment. Moreover, renal replacement therapy rather than simple acidosis correction by administration of alkali seems the treatment of choice, based on eventual renal recovery and overall outcome.
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Affiliation(s)
- Alessandra Moioli
- Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy.,Chair and Division of Nephrology, Sant'Andrea University Hospital, Rome, Italy
| | - Barbara Maresca
- Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy.,Chair and Division of Nephrology, Sant'Andrea University Hospital, Rome, Italy
| | - Andrea Manzione
- Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy.,Chair and Division of Nephrology, Sant'Andrea University Hospital, Rome, Italy
| | | | | | - Nicola Pirozzi
- Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy.,Chair and Division of Nephrology, Sant'Andrea University Hospital, Rome, Italy
| | - Giorgio Punzo
- Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy.,Chair and Division of Nephrology, Sant'Andrea University Hospital, Rome, Italy
| | - Paolo Menè
- Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy. .,Chair and Division of Nephrology, Sant'Andrea University Hospital, Rome, Italy. .,UOC Nefrologia, A.O. Sant'Andrea, Via di Grottarossa 1035-1039, 00189, Rome, Italy.
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