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Kilmister EJ, Koh SP, Weth FR, Gray C, Tan ST. Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment. Biomedicines 2022; 10:biomedicines10112988. [PMID: 36428556 PMCID: PMC9687343 DOI: 10.3390/biomedicines10112988] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/13/2022] [Accepted: 11/15/2022] [Indexed: 11/24/2022] Open
Abstract
Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)-a small population of highly tumorigenic cancer cells with pluripotency and self-renewal properties, at the apex of a cellular hierarchy. CSCs drive metastasis and treatment resistance and are sustained by a dynamic tumor microenvironment (TME). Numerous pathways mediate communication between CSCs and/or the surrounding TME. These include a paracrine renin-angiotensin system and its convergent signaling pathways, the immune system, and other signaling pathways including the Notch, Wnt/β-catenin, and Sonic Hedgehog pathways. Appreciation of the mechanisms underlying metastasis and treatment resistance, and the pathways that regulate CSCs and the TME, is essential for developing a durable treatment for cancer. Pre-clinical and clinical studies exploring single-point modulation of the pathways regulating CSCs and the surrounding TME, have yielded partial and sometimes negative results. This may be explained by the presence of uninhibited alternative signaling pathways. An effective treatment of cancer may require a multi-target strategy with multi-step inhibition of signaling pathways that regulate CSCs and the TME, in lieu of the long-standing pursuit of a 'silver-bullet' single-target approach.
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Affiliation(s)
| | - Sabrina P. Koh
- Gillies McIndoe Research Institute, Wellington 6242, New Zealand
| | - Freya R. Weth
- Gillies McIndoe Research Institute, Wellington 6242, New Zealand
| | - Clint Gray
- Gillies McIndoe Research Institute, Wellington 6242, New Zealand
| | - Swee T. Tan
- Gillies McIndoe Research Institute, Wellington 6242, New Zealand
- Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Lower Hutt 5010, New Zealand
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3010, Australia
- Correspondence:
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Mao D, Lau ESH, Wu H, Yang A, Shi M, Fan B, Tam CHT, Chow E, Kong APS, Ma RCW, Luk A, Chan JCN. Risk associations of long-term HbA1c variability and obesity on cancer events and cancer-specific death in 15,286 patients with diabetes - A prospective cohort study. THE LANCET REGIONAL HEALTH. WESTERN PACIFIC 2022; 18:100315. [PMID: 35024653 PMCID: PMC8669375 DOI: 10.1016/j.lanwpc.2021.100315] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/05/2021] [Accepted: 10/11/2021] [Indexed: 02/07/2023]
Abstract
Background Obesity, cancer and diabetes frequently coexist. The association of glycaemic variability (GV) and obesity with cancer events had not been explored in diabetes. Methods In the prospective Hong Kong Diabetes Register cohort (1995-2019), we used cox proportional hazards models to examine the risk associations of GV with all-site cancer (primary outcome) and cause-specific death (secondary outcome). We also explored the joint association of obesity and GV with these outcomes and site-specific cancer. We expressed GV using HbA1c variability score (HVS) defined as percentage of HbA1c values varying by 0.5% compared with values in preceding visit. Findings We included 15,286 patients (type 2 diabetes: n=15,054, type 1 diabetes: n=232) with ≥10 years of diabetes and ≥3 years of observation (51.7% men, age (mean±SD): 61.04±10.73 years, HbA1c: 7.54±1.63%, body mass index [BMI]: 25.65±3.92 kg/m2, all-site cancer events: n=928, cancer death events: n=404). There were non-linear relationships between HVS and outcomes but there was linearity within the high and low HVS groups stratified by the median (IQR) value of HVS (42.31 [27.27, 56.28]). In the high HVS group, the adjusted hazard ratios (aHR) of each SD of HVS was 1.15 (95% CI: 1.04, 1.26) for all-site cancer (n=874). The respective aHRs for breast (n=77), liver (n=117) and colorectal (n=184) cancer were 1.44 (1.07, 1.94), 1.37 (1.08, 1.74), and 1.09 (0.90, 1.32). In the high GV group, the respective aHRs were 1.21 (1.06, 1.39), 1.27 (1.15, 1.40), and 1.15 (1.09, 1.22) for cancer, vascular, and noncancer nonvascular death. When stratified by obesity (BMI ≥25 kg/m2), the high HVS & obese group had the highest aHRs of 1.42 (1.16, 1.73), 2.44 (1.24, 4.82), and 2.63 (1.45, 4.74) respectively for all-site, breast, and liver cancer versus the low GV & non-obese group. The respective aHRs were 1.45 (1.07, 1.96), 1.47 (1.12, 1.93), and 1.35 (1.16, 1.57) for cancer, vascular, and noncancer nonvascular death. Interpretation Obesity and high GV were associated with increased risk of all-site, breast, liver cancer, and cancer-specific death in T2D. Funding The Chinese University of Hong Kong Diabetes Research Fund
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Key Words
- ALT, alanine aminotransferase
- BMI, body mass index
- BP, blood pressure
- CI, confidence interval
- CVD, cardiovascular disease
- EMR, electronic medical record
- GV, glycaemic variability
- HA, Hospital Authority
- HDLC, high-density lipoprotein cholesterol
- HKDR, Hong Kong Diabetes Register
- HR, hazard ratio
- HVS, HbA1c variability score
- IQR, inter‐quartile range
- LDLC, low-density lipoprotein cholesterol
- LLD, lipid lowering drug
- MD, median
- Mn, mean
- OGLDs, oral glucose lowering drugs
- RAS, renin angiotensin system
- SD, standard deviation
- SDIM, SD independent of mean
- T2D, type 2 diabetes
- TC, total cholesterol
- TG, triglyceride
- aHR, adjusted hazard ratio
- cancer and all cause death
- diabetes
- glycaemic variability
- obesity
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Affiliation(s)
- Dandan Mao
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China
| | - Eric S H Lau
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China
| | - Hongjiang Wu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China
| | - Aimin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong
| | - Mai Shi
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China
| | - Baoqi Fan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China
| | - Claudia H T Tam
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China
| | - Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong.,Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong
| | - Alice P S Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Ronald C W Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Andrea Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong.,Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
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Wu B, Ye Y, Xie S, Li Y, Sun X, Lv M, Yang L, Cui N, Chen Q, Jensen LD, Cui D, Huang G, Zuo J, Zhang S, Liu W, Yang Y. Megakaryocytes Mediate Hyperglycemia-Induced Tumor Metastasis. Cancer Res 2021; 81:5506-5522. [PMID: 34535458 DOI: 10.1158/0008-5472.can-21-1180] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/19/2021] [Accepted: 09/15/2021] [Indexed: 11/16/2022]
Abstract
High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKCα pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a platelet-adoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKCα pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. SIGNIFICANCE: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75.
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Affiliation(s)
- Biying Wu
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ying Ye
- Department of Oral Implantology, School and Hospital of Stomatology, Tongji University; Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Sisi Xie
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yintao Li
- Phase I Clinical Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China
| | - Xiaoting Sun
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengyuan Lv
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ling Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Nan Cui
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Qiying Chen
- Department of Cardiology, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Lasse D Jensen
- Department of Medicine, Health and Caring Science, Division of Diagnostics and Specialist Medicine, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden
| | - Dongmei Cui
- Shenzhen Eye Hospital, Shenzhen Key Laboratory of Ophthalmology, Affiliated Shenzhen Eye Hospital of Jinan University, Shenzhen, China
| | - Guichun Huang
- Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Ji Zuo
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Shaochong Zhang
- Shenzhen Eye Hospital, Shenzhen Key Laboratory of Ophthalmology, Affiliated Shenzhen Eye Hospital of Jinan University, Shenzhen, China
| | - Wen Liu
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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Mao D, Cao H, Shi M, Wang CC, Kwong J, Li JJX, Hou Y, Ming X, Lee HM, Tian XY, Wong CK, Chow E, Kong APS, Lui VWY, Chan PKS, Chan JCN. Increased co-expression of PSMA2 and GLP-1 receptor in cervical cancer models in type 2 diabetes attenuated by Exendin-4: A translational case-control study. EBioMedicine 2021; 65:103242. [PMID: 33684886 PMCID: PMC7938253 DOI: 10.1016/j.ebiom.2021.103242] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) increases the risk of many types of cancer. Dysregulation of proteasome-related protein degradation leads to tumorigenesis, while Exendin-4, a glucagon-like peptide 1 receptor (GLP-1R) agonist, possesses anti-cancer effects. METHODS We explored the co-expression of proteasome alpha 2 subunit (PSMA2) and GLP-1R in the Cancer Genome Atlas (TCGA) database and human cervical cancer specimens, supplemented by in vivo and in vitro studies using multiple cervical cancer cell lines. FINDINGS PSMA2 expression was increased in 12 cancer types in TCGA database and cervical cancer specimens from patients with T2D (T2D vs non-T2D: 3.22 (95% confidence interval CI: 1.38, 5.05) vs 1.00 (0.66, 1.34) fold change, P = 0.01). psma2-shRNA decreased cell proliferation in vitro, and tumour volume and Ki67 expression in vivo. Exendin-4 decreased psma2 expression, tumour volume and Ki67 expression in vivo. There was no change in GLP-1R expression in 12 cancer types in TCGA database. However, GLP-1R expression (T2D vs non-T2D: 5.49 (3.0, 8.1) vs 1.00 (0.5, 1.5) fold change, P < 0.001) was increased and positively correlated with PSMA2 expression in T2D-related (r = 0.68) but not in non-T2D-related cervical cancer specimens. This correlation was corroborated by in vitro experiments where silencing glp-1r decreased psma2 expression. Exendin-4 attenuated phospho-p65 and -IκB expression in the NF-κB pathway. INTERPRETATION PSMA2 and GLP-1R expression in T2D-related cervical cancer specimens was increased and positively correlated, suggesting hyperglycaemia might promote cancer growth by increasing PSMA2 expression which could be attenuated by Exendin-4. FUNDING This project was supported by Postdoctoral Fellowship Scheme, Direct Grant, Diabetes Research and Education Fund from the Chinese University of Hong Kong (CUHK).
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Affiliation(s)
- Dandan Mao
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Huanyi Cao
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Mai Shi
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Chi Chiu Wang
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Joseph Kwong
- Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Joshua Jing Xi Li
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Yong Hou
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Xing Ming
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Heung Man Lee
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Xiao Yu Tian
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Chun Kwok Wong
- Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Alice Pik Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Vivian Wai Yan Lui
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Paul Kay Sheung Chan
- Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Juliana Chung Ngor Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.
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Yip TCF, Wong GLH, Chan HLY, Tse YK, Liang LY, Hui VWK, Lee HW, Lui GCY, Kong APS, Wong VWS. Elevated testosterone increases risk of hepatocellular carcinoma in men with chronic hepatitis B and diabetes mellitus. J Gastroenterol Hepatol 2020; 35:2210-2219. [PMID: 32343449 DOI: 10.1111/jgh.15079] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 03/31/2020] [Accepted: 04/27/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM Male sex is a risk factor for hepatocellular carcinoma (HCC). Diabetes mellitus (DM) is associated with a doubled risk of HCC in patients with chronic hepatitis B (CHB). We examined the relationship between serum total testosterone and HCC risk in male CHB patients with DM. METHODS We performed a retrospective cohort study of male CHB patients with DM between 2000 and 2017 using a territory-wide electronic health-care database in Hong Kong. DM was defined by use of anti-diabetic medications, hemoglobin A1c ≥ 6.5%, and/or fasting glucose ≥ 7 mmol/L in two measurements or ≥ 11.1 mmol/L in one measurement. RESULTS Of 928 male CHB patients with DM, 83 (8.9%) developed HCC at a median (interquartile range) of 10.7 (6.1-14.6) years. Higher testosterone was associated with an elevated risk of HCC (adjusted hazard ratio [aHR] per 1 SD increase 1.23, 95% confidence interval [CI] 1.03-1.46, P = 0.024). The upper tertile of testosterone (aHR 1.86, 95% CI 1.02-3.39, P = 0.043), but not middle tertile (aHR 0.84, 95% CI 0.41-1.69 P = 0.620), was associated with a higher risk of HCC than the lower tertile. The cumulative incidence (95% CI) of HCC at 5, 10, and 15 years was 4.4% (2.5-7.2%), 12.4% (8.7-16.7%), and 19.1% (14.2-24.5%), respectively, in patients in the upper tertile of testosterone. By subgroup analysis, the association between testosterone and HCC was stronger in patients aged ≥ 50 years and those not receiving antiviral therapy. CONCLUSION Higher serum testosterone is associated with a higher incidence of HCC in male CHB patients with DM.
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Affiliation(s)
- Terry Cheuk-Fung Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Yee-Kit Tse
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Lilian Yan Liang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Vicki Wing-Ki Hui
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Hye Won Lee
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, China
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Crigna AT, Samec M, Koklesova L, Liskova A, Giordano FA, Kubatka P, Golubnitschaja O. Cell-free nucleic acid patterns in disease prediction and monitoring-hype or hope? EPMA J 2020; 11:603-627. [PMID: 33144898 PMCID: PMC7594983 DOI: 10.1007/s13167-020-00226-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023]
Abstract
Interest in the use of cell-free nucleic acids (CFNAs) as clinical non-invasive biomarker panels for prediction and prevention of multiple diseases has greatly increased over the last decade. Indeed, circulating CFNAs are attributable to many physiological and pathological processes such as imbalanced stress conditions, physical activities, extensive apoptosis of different origin, systemic hypoxic-ischemic events and tumour progression, amongst others. This article highlights the involvement of circulating CFNAs in local and systemic processes dealing with the question, whether specific patterns of CFNAs in blood, their detection, quantity and quality (such as their methylation status) might be instrumental to predict a disease development/progression and could be further utilised for accompanying diagnostics, targeted prevention, creation of individualised therapy algorithms, therapy monitoring and prognosis. Presented considerations conform with principles of 3P medicine and serve for improving individual outcomes and cost efficacy of medical services provided to the population.
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Affiliation(s)
- Adriana Torres Crigna
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Marek Samec
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Lenka Koklesova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Alena Liskova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Frank A. Giordano
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive, Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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Yaribeygi H, Maleki M, Sathyapalan T, Jamialahmadi T, Sahebkar A. Incretin-based therapies and renin-angiotensin system: Looking for new therapeutic potentials in the diabetic milieu. Life Sci 2020; 256:117916. [PMID: 32534034 DOI: 10.1016/j.lfs.2020.117916] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 05/27/2020] [Accepted: 06/04/2020] [Indexed: 02/08/2023]
Abstract
Incretin-based therapies include pharmacologic agents such as glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors which exert potent anti-hyperglycemic effects in the diabetic milieu. They are also shown to have extra-pancreatic effects. Renin-angiotensin system is part of the endocrine system which is widely distributed in the body and is closely involved in water and electrolyte homeostasis as well as renal and cardiovascular functions. Hence the renin-angiotensin system is the main target for treating patients with various renal and cardiovascular disorders. There is growing evidence that incretins have modulatory effects on renin-angiotensin system activity; thereby, can be promising therapeutic agents for the management of renal and cardiovascular disorders. But the exact molecular interactions between incretins and renin-angiotensin system are not clearly understood. In this current study, we have reviewed the possible molecular mechanisms by which incretins modulate renin-angiotensin system activity.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Mina Maleki
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull
| | - Tannaz Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran.
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Yip TCF, Wong VWS, Chan HLY, Tse YK, Hui VWK, Liang LY, Lee HW, Lui GCY, Kong APS, Wong GLH. Thiazolidinediones reduce the risk of hepatocellular carcinoma and hepatic events in diabetic patients with chronic hepatitis B. J Viral Hepat 2020; 27:904-914. [PMID: 32340077 DOI: 10.1111/jvh.13307] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/27/2020] [Accepted: 04/05/2020] [Indexed: 12/22/2022]
Abstract
Thiazolidinediones (TZDs) improve glycaemic control and ameliorate liver steatosis, inflammation and fibrosis in patients with fatty liver disease. We aimed to study the impact of TZD and glycaemic control on the risk of hepatocellular carcinoma (HCC) and hepatic events in diabetic patients with chronic hepatitis B (CHB). We performed a retrospective cohort study on diabetic patients with CHB in 2000-2017 using a territory-wide electronic healthcare database in Hong Kong. Diabetes mellitus was identified by use of any antidiabetic medication, haemoglobin A1c (HbA1c ) ≥6.5%, fasting glucose ≥7 mmol/L in two measurements or ≥11.1 mmol/L in one measurement and/or diagnosis codes. Use of antidiabetic medications was modelled as time-dependent covariates. Of 28 999 diabetic patients with CHB, 3963 (13.7%) developed liver-related events (a composite endpoint of HCC and hepatic events) at a median (interquartile range) follow-up of 7.1 (3.7-11.8) years; 1153 patients received TZD during follow-up. After adjusted for important confounders, TZD use was associated with a reduced risk of liver-related events (adjusted hazard ratio [aHR] 0.46, 95% confidence interval [CI] 0.24-0.88; P = .019). Similar trends were observed in HCC (aHR 0.57) and hepatic events (aHR 0.35) separately. Compared to HbA1c of 6.5% at baseline, patients with HbA1c ≥7% had an increased risk of liver-related events; the risk further increased in 5795 (20.0%) patients with HbA1c ≥9% at baseline (aHR 1.14, 95% CI 1.04-1.26; P = .006). TZD use is associated with a lower risk of liver-related events in diabetic patients with CHB. Liver-related events are more common in patients with high HbA1c levels.
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Affiliation(s)
- Terry Cheuk-Fung Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yee-Kit Tse
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vicki Wing-Ki Hui
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lilian Yan Liang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hye Won Lee
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
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9
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Cheuk-Fung Yip T, Wai-Sun Wong V, Lik-Yuen Chan H, Tse YK, Pik-Shan Kong A, Long-Yan Lam K, Chung-Yan Lui G, Lai-Hung Wong G. Effects of Diabetes and Glycemic Control on Risk of Hepatocellular Carcinoma After Seroclearance of Hepatitis B Surface Antigen. Clin Gastroenterol Hepatol 2018; 16:765-773.e2. [PMID: 29246694 DOI: 10.1016/j.cgh.2017.12.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 12/03/2017] [Accepted: 12/04/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Diabetes is associated with a 2-fold increase in risk of hepatocellular carcinoma (HCC) among patients with chronic hepatitis B virus (HBV) infection. However, we know little about the effect of diabetes on HCC risk after seroclearance of hepatitis B surface antigen (HBsAg). We evaluated the effect of diabetes and glycemic control on HCC development after HBsAg seroclearance in a population-wide study in Hong Kong. METHODS We performed a retrospective study of 4568 patients with chronic HBV infection who cleared HBsAg from January 2000 through August 2016, using the Clinical Data Analysis and Reporting System of the Hospital Authority, Hong Kong. We collected and analyzed data on patient demographics, comorbidities, medications, laboratory test results, and subsequent development of HCC. The presence of diabetes was defined by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code, with level of hemoglobin A1c (HbA1c) above 6.5%, fasting glucose level of 7 mmol/L or more, or treatment with any antidiabetic agent. RESULTS We identified 1560 patients with diabetes; 29 patients (1.9%) developed HCC after a median follow-up time of 3.4 years (interquartile range, 1.5-5.0 years). Diabetes was associated with increased risk of HCC after adjustment of age, sex, presence of cirrhosis, and the use of medications (adjusted hazard ratio, 1.85; 95% CI, 1.04-3.28; P = .036). Among patients with diabetes, time-weighted average level of HbA1c was an independent risk factor for HCC, after adjustment for age at clearance, use of statins, and other important covariates (adjusted hazard ratio: 1.51; 95% CI, 1.20-1.91; P < .001). A time-weighted average level of HbA1c of 7% or more was associated with a higher 5-year cumulative incidence of HCC (4.0%) than a time-weighted average HbA1c level below 7% (1.8%; log-rank test P = .035). CONCLUSIONS In a population-based analysis of patients with chronic HBV infection in Hong Kong, we found diabetes to be an independent risk factor for HCC after HBsAg seroclearance. However, glycemia control appears to reduce the risk of HCC.
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Affiliation(s)
- Terry Cheuk-Fung Yip
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
| | - Yee-Kit Tse
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Kelvin Long-Yan Lam
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China.
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10
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Ng IHY, Cheung KKT, Yau TTL, Chow E, Ozaki R, Chan JCN. Evolution of Diabetes Care in Hong Kong: From the Hong Kong Diabetes Register to JADE-PEARL Program to RAMP and PEP Program. Endocrinol Metab (Seoul) 2018; 33:17-32. [PMID: 29589385 PMCID: PMC5874192 DOI: 10.3803/enm.2018.33.1.17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 02/26/2018] [Accepted: 02/28/2018] [Indexed: 12/14/2022] Open
Abstract
The rapid increase in diabetes prevalence globally has contributed to large increases in health care expenditure on diabetic complications, posing a major health burden to countries worldwide. Asians are commonly observed to have poorer β-cell function and greater insulin resistance compared to the Caucasian population, which is attributed by their lower lean body mass and central obesity. This "double phenotype" as well as the rising prevalence of young onset diabetes in Asia has placed Asians with diabetes at high risk of cardiovascular and renal complications, with cancer emerging as an important cause of morbidity and mortality. The experience from Hong Kong had demonstrated that a multifaceted approach, involving team-based integrated care, information technological advances, and patient empowerment programs were able to reduce the incidence of diabetic complications, hospitalizations, and mortality. System change and public policies to enhance implementation of such programs may provide solutions to combat the burgeoning health problem of diabetes at a societal level.
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Affiliation(s)
- Ivy H Y Ng
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- Department of Medicine and Geriatrics, United Christian Hospital, Kwun Tong, Hong Kong
| | - Kitty K T Cheung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Tiffany T L Yau
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Elaine Chow
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Risa Ozaki
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
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11
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Chen Y, Du L, Li L, Ma J, Geng X, Yao X, Liu G, Sun X. Cancer risk of sulfonylureas in patients with type 2 diabetes mellitus: A systematic review. J Diabetes 2017; 9:482-494. [PMID: 27273872 DOI: 10.1111/1753-0407.12435] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 05/03/2016] [Accepted: 05/24/2016] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Increasing evidence suggests that oral hypoglycemic agents used in type 2 diabetes mellitus (T2DM) may affect cancer risk. Sulfonylureas (SUs) are the most frequently used antidiabetic medications for T2DM. Whether using SUs has any effect on cancer has received considerable attention. The aim of this study was to assess the effects of SUs on cancer risk in T2DM patients. METHODS Published studies were identified in PubMed, EMBASE, and the Cochrane Register of Clinical Studies, and ClinicalTrials.gov was searched for additional information to identify randomized controlled trials (RCTs), cohort studies, and case-control studies. The abstracts and full text were screened, data collected, and the risk of bias assessed for each individual study. RESULTS Seventy-seven studies (33 RCTs, 27 cohort studies, and 17 case-control studies) were analyzed. The RCTs did not report a difference in the risk of malignant tumor between SU-treated T2DM patients and controls (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.78-1.18); cohort studies showed that cancer risk was higher in patients using SUs than metformin (relative risk 1.60 [95%CI 1.37-1.87]; adjusted hazard ratio 1.13 [95%CI 1.06-1.19]), and case-control studies suggested a trend for increased cancer risk in those using SUs compared with non-SU users (adjusted OR 1.13; 95%CI 0.93-1.37). CONCLUSIONS The available evidence clearly shows that SUs can significantly increase the risk of cancer compared with metformin. Although the evidence suggests the possibility that SU users may have a higher risk of cancer than those using alternative medications in addition to metformin, it remains inadequate to enable definitive conclusions to be drawn.
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Affiliation(s)
- Yuehong Chen
- Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Liang Du
- Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ling Li
- Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jun Ma
- The Second People's Hospital, Mudanjiang, China
| | - Xingyuan Geng
- Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xun Yao
- Department of Teaching Affairs, West China Medical School, Sichuan University, Chengdu, China
| | - Guanjian Liu
- Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Sun
- Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
- Centre for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada
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12
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Lee SC, Chan JCN. Evidence for DNA damage as a biological link between diabetes and cancer. Chin Med J (Engl) 2016; 128:1543-8. [PMID: 26021514 PMCID: PMC4733759 DOI: 10.4103/0366-6999.157693] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective: This review examines the evidence that: Diabetes is a state of DNA damage; pathophysiological factors in diabetes can cause DNA damage; DNA damage can cause mutations; and DNA mutation is linked to carcinogenesis. Data Sources: We retrieved information from the PubMed database up to January, 2014, using various search terms and their combinations including DNA damage, diabetes, cancer, high glucose, hyperglycemia, free fatty acids, palmitic acid, advanced glycation end products, mutation and carcinogenesis. Study Selection: We included data from peer-reviewed journals and a textbook printed in English on relationships between DNA damage and diabetes as well as pathophysiological factors in diabetes. Publications on relationships among DNA damage, mutagenesis, and carcinogenesis, were also reviewed. We organized this information into a conceptual framework to explain the possible causal relationship between DNA damage and carcinogenesis in diabetes. Results: There are a large amount of data supporting the view that DNA mutation is a typical feature in carcinogenesis. Patients with type 2 diabetes have increased production of reactive oxygen species, reduced levels of antioxidant capacity, and increased levels of DNA damage. The pathophysiological factors and metabolic milieu in diabetes can cause DNA damage such as DNA strand break and base modification (i.e., oxidation). Emerging experimental data suggest that signal pathways (i.e., Akt/tuberin) link diabetes to DNA damage. This collective evidence indicates that diabetes is a pathophysiological state of oxidative stress and DNA damage which can lead to various types of mutation to cause aberration in cells and thereby increased cancer risk. Conclusions: This review highlights the interrelationships amongst diabetes, DNA damage, DNA mutation and carcinogenesis, which suggests that DNA damage can be a biological link between diabetes and cancer.
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Affiliation(s)
- Shao Chin Lee
- Department of Biological Sciences, School of Life Sciences, Shanxi University, Taiyuan, Shanxi 030006, China
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13
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Abstract
Hypoglycemia is one of the major barriers in optimizing glycemic control. In type 2 diabetes, hypoglycemia is associated with multiple morbidities (eg, myocardial ischemia, cardiac arrhythmia, stroke, dementia, psychosocial dysfunction, obesity, microvascular complications, cancer, and diseases of respiratory, digestive, and dermatological systems). Risk factors associated with hypoglycemia in patients with type 2 diabetes include old age, long disease duration, low body mass index, high baseline glycated hemoglobin (HbA1c), treatment with insulin and sulphonylurea, renal dysfunction, albuminuria, reduced level of low density lipoprotein cholesterol, low triglyceride and depression. There are considerable overlaps between phenotypes associated with severe hypoglycemia and all-site cancer suggesting that hypoglycemia may be a marker of vulnerability. In patients with severe hypoglycemia, comprehensive assessment is recommended to detect silent conditions, such as renal dysfunction, cancer, depression as well as review of treatment strategies including drug use to prevent morbidities and mortality.
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Affiliation(s)
- Alice P S Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, SAR, China,
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14
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Yang XL, Huo XX, Chan JCN. Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes. World J Methodol 2015; 5:122-126. [PMID: 26413484 PMCID: PMC4572024 DOI: 10.5662/wjm.v5.i3.122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 06/12/2015] [Accepted: 08/14/2015] [Indexed: 02/06/2023] Open
Abstract
There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.
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Abstract
On the basis of data obtained from a prospective cohort of Chinese patients with type 2 diabetes mellitus (T2DM), we discuss cancer subphenotypes (risk factors) in patients with T2DM, which can lead to drug-cancer subphenotype interactions. These subphenotypes include HDL cholesterol levels <1.0 mmol/l, co-occurrence of LDL cholesterol levels <2.8 mmol/l and triglyceride levels <1.7 mmol/l, and co-occurrence of LDL cholesterol levels <2.8 mmol/l and albuminuria. The increased risk of cancer associated with low levels of HDL cholesterol, low LDL cholesterol levels plus low triglyceride levels, and low levels of LDL cholesterol plus albuminuria can be reduced by treatment with metformin, renin-angiotensin system (RAS) inhibitors and statins, respectively. Mechanistic studies support the hypothesis that dysregulation of the 5'-AMP-activated protein kinase pathway and crosstalk between the RAS and insulin-like growth factor 1-cholesterol pathways create a cancer-promoting milieu in patients with T2DM. These findings highlight that in Chinese individuals, multiple pathways are implicated in the link between T2DM and cancer, which can generate multiple subphenotypes as well as drug-subphenotype interactions.
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Affiliation(s)
- Xilin Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Heung M Lee
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR, China
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, New Territories, Hong Kong SAR, China
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16
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Dose-related neuropathic and anti-neuropathic effects of simvastatin in vincristine-induced neuropathic pain in rats. Food Chem Toxicol 2015; 80:32-40. [DOI: 10.1016/j.fct.2015.02.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 02/19/2015] [Accepted: 02/20/2015] [Indexed: 12/18/2022]
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17
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Abstract
China has a large burden of diabetes: in 2013, one in four people with diabetes worldwide were in China, where 11·6% of adults had diabetes and 50·1% had prediabetes. Many were undiagnosed, untreated, or uncontrolled. This epidemic is the result of rapid societal transition that has led to an obesogenic environment against a backdrop of traditional lifestyle and periods of famine, which together puts Chinese people at high risk of diabetes and multiple morbidities. Societal determinants including social disparity and psychosocial stress interact with factors such as low-grade infection, environmental pollution, care fragmentation, health illiteracy, suboptimal self-care, and insufficient community support to give rise to diverse subphenotypes and consequences, notably renal dysfunction and cancer. In the China National Plan for Non-Communicable Disease Prevention and Treatment (2012-15), the Chinese Government proposed use of public measures, multisectoral collaborations, and social mobilisation to create a health-enabling environment and to reform the health-care system. While awaiting results from these long-term strategies, we advocate the use of a targeted and proactive approach to identify people at high risk of diabetes for prevention, and of private-public-community partnerships that make integrated care more accessible and sustainable, focusing on registry, empowerment, and community support. The multifaceted nature of the societal and personal challenge of diabetes requires a multidimensional solution for prevention in order to reduce the growing disease burden.
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Affiliation(s)
- Juliana C N Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; Li Ka Shing Institute of Health Sciences, Hong Kong Institute of Diabetes and Obesity, and International Diabetes Federation Centre of Education, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
| | - Yuying Zhang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Guang Ning
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, Shanghai Clinical Center for Endocrine and Metabolic Disease, National Clinical Research Center for Metabolic Diseases, E-Institute of Shanghai Universities, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Kubota Y, Iso H, Ikehara S, Tamakoshi A. Relationship between sleep duration and cause-specific mortality in diabetic men and women based on self-reports. Sleep Biol Rhythms 2014. [DOI: 10.1111/sbr.12091] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Yasuhiko Kubota
- Public Health; Department of Social and Environmental Medicine; Osaka University Graduate School of Medicine; Osaka Japan
| | - Hiroyasu Iso
- Public Health; Department of Social and Environmental Medicine; Osaka University Graduate School of Medicine; Osaka Japan
| | - Satoyo Ikehara
- Public Health; Department of Social and Environmental Medicine; Osaka University Graduate School of Medicine; Osaka Japan
| | - Akiko Tamakoshi
- Department of Public Health; Hokkaido University Graduate School of Medicine; Hokkaido Japan
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Yang X, Chan JC. Metformin and the risk of cancer in type 2 diabetes: methodological challenges and perspectives. ANNALS OF TRANSLATIONAL MEDICINE 2014; 2:52. [PMID: 25333027 DOI: 10.3978/j.issn.2305-5839.2014.06.07] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 06/10/2014] [Indexed: 12/22/2022]
Affiliation(s)
- Xilin Yang
- 1 Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China ; 2 Department of Medicine and Therapeutics, 3 Hong Kong Institute of Diabetes and Obesity, 4 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
| | - Juliana Cn Chan
- 1 Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China ; 2 Department of Medicine and Therapeutics, 3 Hong Kong Institute of Diabetes and Obesity, 4 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
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