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Pliszka M, Szablewski L. Associations between Diabetes Mellitus and Selected Cancers. Int J Mol Sci 2024; 25:7476. [PMID: 39000583 PMCID: PMC11242587 DOI: 10.3390/ijms25137476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.
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Affiliation(s)
- Monika Pliszka
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
| | - Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
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2
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Frkic RL, Pederick JL, Horsfall AJ, Jovcevski B, Crame EE, Kowalczyk W, Pukala TL, Chang MR, Zheng J, Blayo AL, Abell AD, Kamenecka TM, Harbort JS, Harmer JR, Griffin PR, Bruning JB. PPARγ Corepression Involves Alternate Ligand Conformation and Inflation of H12 Ensembles. ACS Chem Biol 2023; 18:1115-1123. [PMID: 37146157 DOI: 10.1021/acschembio.2c00917] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Inverse agonists of peroxisome proliferator activated receptor γ (PPARγ) have emerged as safer alternatives to full agonists for their reduced side effects while still maintaining impressive insulin-sensitizing properties. To shed light on their molecular mechanism, we characterized the interaction of the PPARγ ligand binding domain with SR10221. X-ray crystallography revealed a novel binding mode of SR10221 in the presence of a transcriptionally repressing corepressor peptide, resulting in much greater destabilization of the activation helix, H12, than without corepressor peptide. Electron paramagnetic resonance provided in-solution complementary protein dynamic data, which revealed that for SR10221-bound PPARγ, H12 adopts a plethora of conformations in the presence of corepressor peptide. Together, this provides the first direct evidence for corepressor-driven ligand conformation for PPARγ and will allow the development of safer and more effective insulin sensitizers suitable for clinical use.
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Affiliation(s)
- Rebecca L Frkic
- The Institute for Photonics and Advanced Sensing and School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Jordan L Pederick
- The Institute for Photonics and Advanced Sensing and School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Aimee J Horsfall
- ARC Centre of Excellence for Nanoscale Biophotonics, The Institute for Photonics and Advanced Sensing, and School of Physical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Blagojce Jovcevski
- Department of Chemistry, School of Physical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Elise E Crame
- Discipline of Physiology, School of Biomedicine, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | | | - Tara L Pukala
- Department of Chemistry, School of Physical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Mi Ra Chang
- Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
- Department of Molecular Therapeutics, UF Scripps Biomolecular Research, University of Florida, Jupiter, Florida 33458, United States
| | - Jie Zheng
- Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
- Department of Molecular Therapeutics, UF Scripps Biomolecular Research, University of Florida, Jupiter, Florida 33458, United States
| | - Anne-Laure Blayo
- Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
- Department of Molecular Therapeutics, UF Scripps Biomolecular Research, University of Florida, Jupiter, Florida 33458, United States
| | - Andrew D Abell
- ARC Centre of Excellence for Nanoscale Biophotonics, The Institute for Photonics and Advanced Sensing, and School of Physical Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Theodore M Kamenecka
- Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
- Department of Molecular Therapeutics, UF Scripps Biomolecular Research, University of Florida, Jupiter, Florida 33458, United States
| | - Joshua S Harbort
- Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Jeffrey R Harmer
- Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Patrick R Griffin
- Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
- Department of Molecular Therapeutics, UF Scripps Biomolecular Research, University of Florida, Jupiter, Florida 33458, United States
| | - John B Bruning
- The Institute for Photonics and Advanced Sensing and School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia
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Olatunde A, Nigam M, Singh RK, Panwar AS, Lasisi A, Alhumaydhi FA, Jyoti Kumar V, Mishra AP, Sharifi-Rad J. Cancer and diabetes: the interlinking metabolic pathways and repurposing actions of antidiabetic drugs. Cancer Cell Int 2021; 21:499. [PMID: 34535145 PMCID: PMC8447515 DOI: 10.1186/s12935-021-02202-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 09/06/2021] [Indexed: 12/18/2022] Open
Abstract
Cancers are regarded as one of the main causes of death and result in high health burden worldwide. The management of cancer include chemotherapy, surgery and radiotherapy. The chemotherapy, which involves the use of chemical agents with cytotoxic actions is utilised as a single treatment or combined treatment. However, these managements of cancer such as chemotherapy poses some setbacks such as cytotoxicity on normal cells and the problem of anticancer drug resistance. Therefore, the use of other therapeutic agents such as antidiabetic drugs is one of the alternative interventions used in addressing some of the limitations in the use of anticancer agents. Antidiabetic drugs such as sulfonylureas, biguanides and thiazolidinediones showed beneficial and repurposing actions in the management of cancer, thus, the activities of these drugs against cancer is attributed to some of the metabolic links between the two disorders and these includes hyperglycaemia, hyperinsulinemia, inflammation, and oxidative stress as well as obesity. Furthermore, some studies showed that the use of antidiabetic drugs could serve as risk factors for the development of cancerous cells particularly pancreatic cancer. However, the beneficial role of these chemical agents overweighs their detrimental actions in cancer management. Hence, the present review indicates the metabolic links between cancer and diabetes and the mechanistic actions of antidiabetic drugs in the management of cancers.
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Affiliation(s)
- Ahmed Olatunde
- Department of Biochemistry, Abubakar Tafawa Balewa University, Bauchi, 740272, Nigeria
| | - Manisha Nigam
- Department of Biochemistry, School of Life Sciences, Hemvati Nandan Bahuguna Garhwal University, Srinagar, Garhwal, Uttarakhand, 246174, India.
| | - Rahul Kunwar Singh
- Department of Microbiology, School of Life Sciences, Hemvati Nandan Bahuguna Garhwal University, Srinagar, Garhwal, Uttarakhand, 246174, India
| | - Abhaya Shikhar Panwar
- Department of Biochemistry, School of Life Sciences, Hemvati Nandan Bahuguna Garhwal University, Srinagar, Garhwal, Uttarakhand, 246174, India
| | - Abdulwahab Lasisi
- Maidstone and Tunbridge Wells NHS Trust, Hermitage Lane, Maidstone, Kent, ME169QQ, UK
| | - Fahad A Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Vijay Jyoti Kumar
- Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University, Garhwal, Srinagar, Uttarakhand, 246174, India
| | - Abhay Prakash Mishra
- Department of Pharmacology, School of Clinical Medicine, Faculty of Health Science, University of Free State, 205, Nelson Mandela Drive, Park West, Bloemfontein, 9300, South Africa
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Frkic RL, Richter K, Bruning JB. The therapeutic potential of inhibiting PPARγ phosphorylation to treat type 2 diabetes. J Biol Chem 2021; 297:101030. [PMID: 34339734 PMCID: PMC8387755 DOI: 10.1016/j.jbc.2021.101030] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 11/30/2022] Open
Abstract
A promising approach for treating type 2 diabetes mellitus (T2DM) is to target the Peroxisome Proliferator-Activated Receptor γ (PPARγ) transcription factor, which regulates the expression of proteins critical for T2DM. Mechanisms involved in PPARγ signaling are poorly understood, yet globally increasing T2DM prevalence demands improvements in drug design. Synthetic, nonactivating PPARγ ligands can abolish the phosphorylation of PPARγ at Ser273, a posttranslational modification correlated with obesity and insulin resistance. It is not understood how these ligands prevent phosphorylation, and the lack of experimental mechanistic information can be attributed to previous ambiguity in the field as well as to limitations in experimental approaches; in silico modeling currently provides the only insight into how ligands block Ser273 phosphorylation. The future availability of experimental evidence is critical for clarifying the mechanism by which ligands prevent phosphorylation and should be the priority of future T2DM-focused research. Following this, the properties of ligands that enable them to block phosphorylation can be improved upon to generate ligands tailored for blocking phosphorylation and therefore restoring insulin sensitivity. This would represent a significant step forward for treating T2DM. This review summarizes current knowledge of the roles of PPARγ in T2DM as well as the effects of synthetic ligands on the modulation of these roles. We hypothesize potential factors that contribute to the reduction in recent developments and summarize what has currently been done to shed light on this critical field of research.
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Affiliation(s)
- Rebecca L Frkic
- The Institute for Photonics and Advanced Sensing, and School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Katharina Richter
- Richter Lab, Department of Surgery, Basil Hetzel Institute for Translational Health Research, The University of Adelaide, Adelaide, South Australia, Australia
| | - John B Bruning
- The Institute for Photonics and Advanced Sensing, and School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
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Schulten HJ, Bakhashab S. Meta-Analysis of Microarray Expression Studies on Metformin in Cancer Cell Lines. Int J Mol Sci 2019; 20:3173. [PMID: 31261735 PMCID: PMC6650866 DOI: 10.3390/ijms20133173] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/08/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
Several studies have demonstrated that metformin (MTF) acts with variable efficiency as an anticancer agent. The pleiotropic anticancer effects of MTF on cancer cells have not been fully explored yet. By interrogating the Gene Expression Omnibus (GEO) for microarray expression data, we identified eight eligible submissions, representing five different studies, that employed various conditions including different cell lines, MTF concentrations, treatment durations, and cellular components. A compilation of the data sets of 13 different conditions contained 443 repeatedly up- and 387 repeatedly down-regulated genes; the majority of these 830 differentially expressed genes (DEGs) were associated with higher MTF concentrations and longer MTF treatment. The most frequently upregulated genes include DNA damage inducible transcript 4 (DDIT4), chromodomain helicase DNA binding protein 2 (CHD2), endoplasmic reticulum to nucleus signaling 1 (ERN1), and growth differentiation factor 15 (GDF15). The most commonly downregulated genes include arrestin domain containing 4 (ARRDC4), and thioredoxin interacting protein (TXNIP). The most significantly (p-value < 0.05, Fisher's exact test) overrepresented protein class was entitled, nucleic acid binding. Cholesterol biosynthesis and other metabolic pathways were specifically affected by downregulated pathway molecules. In addition, cell cycle pathways were significantly related to the data set. Generated networks were significantly related to, e.g., carbohydrate and lipid metabolism, cancer, cell cycle, and DNA replication, recombination, and repair. A second compilation comprised genes that were at least under one condition up- and in at least another condition down-regulated. Herein, the most frequently deregulated genes include nuclear paraspeckle assembly transcript 1 (NEAT1) and insulin induced gene 1 (INSIG1). The most significantly overrepresented protein classes in this compilation were entitled, nucleic acid binding, ubiquitin-protein ligase, and mRNA processing factor. In conclusion, this study provides a comprehensive list of deregulated genes and biofunctions related to in vitro MTF application and individual responses to different conditions. Biofunctions affected by MTF include, e.g., cholesterol synthesis and other metabolic pathways, cell cycle, and DNA replication, recombination, and repair. These findings can assist in defining the conditions in which MTF exerts additive or synergistic effects in cancer treatment.
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Affiliation(s)
- Hans-Juergen Schulten
- Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.
| | - Sherin Bakhashab
- Biochemistry Department, King Abdulaziz University, P.O. Box 80218, Jeddah 21589, Saudi Arabia
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK
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Wierzba W, Śliwczynski A, Karnafel W, Dziemidok P, Pinkas J. Comparison of the incidence of new malignancies in diabetic patients in urban and rural populations in Poland in the years 2008-2014 based on the database of the National Health Fund. Arch Med Sci 2019; 15:330-336. [PMID: 30899284 PMCID: PMC6425219 DOI: 10.5114/aoms.2017.68409] [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: 02/12/2017] [Accepted: 05/08/2017] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Many epidemiological studies show a correlation between the risk of cancer and type 2 diabetes mellitus in various populations. MATERIAL AND METHODS The material was obtained from the database of the National Health Fund. This publication presents a comparison of the incidence of new malignancies in rural and urban populations of diabetic patients in Poland based on the database of the National Health Fund for the period between 1.05.2008 and 30.09.2014. RESULTS Comparison of the mean incidence of selected malignancies in diabetic patients in the population analysed indicated significant differences between the incidence rate in the urban and rural populations (p < 0.001). The mean incidence of gastric cancer, colorectal cancer, kidney cancer, brain tumours and leukaemia in both sexes was significantly higher in rural areas compared to urban. The mean incidence of oesophageal cancer and pancreatic cancer in females was significantly higher among in the urban population compared to the rural areas (p < 0.001). No differences in the incidence rate of these neoplasms were observed in men (p > 0.05). CONCLUSIONS The incidence of gastric cancer, colorectal cancer, laryngeal cancer, lung cancer, testicular cancer, kidney cancer, lung cancer, lymphocytic leukaemia and myeloid leukaemia is higher in diabetic males in rural areas than the incidence in the urban population. The incidence of the malignancies liver cancer, malignant skin melanoma, malignant skin, prostate cancer, urinary bladder cancer and multiple myeloma in male diabetic patients living in urban areas is higher than the incidence in rural areas.
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Affiliation(s)
- Waldemar Wierzba
- Department of Public Health, University of Humanities and Economics, Lodz, Poland
| | - Andrzej Śliwczynski
- Division of Quality Services, Procedures and Medical Standards, Medical University of Lodz, Lodz, Poland
| | - Waldemar Karnafel
- Department of Diabetology, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Dziemidok
- Department of Diabetology, Institute of Rural Health, Lublin, Poland
| | - Jaroslaw Pinkas
- Department of Health Care, Center of Postgraduate Medical Education, Warsaw, Poland
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7
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Association of adiponectin gene polymorphism with type 2 diabetes and metabolic syndrome. TRANSLATIONAL METABOLIC SYNDROME RESEARCH 2018. [DOI: 10.1016/j.tmsr.2018.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Effect of Metformin Use on Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma. Clin Genitourin Cancer 2017; 15:221-229. [DOI: 10.1016/j.clgc.2016.06.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 06/17/2016] [Accepted: 06/19/2016] [Indexed: 01/05/2023]
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Differences in prevalence of diabetes mellitus type 2 and impaired fasting glucose between urban and rural areas according to PURE Poland substudy. Int J Diabetes Dev Ctries 2016. [DOI: 10.1007/s13410-016-0523-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Papanagnou P, Stivarou T, Tsironi M. Unexploited Antineoplastic Effects of Commercially Available Anti-Diabetic Drugs. Pharmaceuticals (Basel) 2016; 9:ph9020024. [PMID: 27164115 PMCID: PMC4932542 DOI: 10.3390/ph9020024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 04/23/2016] [Accepted: 04/28/2016] [Indexed: 02/07/2023] Open
Abstract
The development of efficacious antitumor compounds with minimal toxicity is a hot research topic. Numerous cancer cell targeted agents are evaluated daily in laboratories for their antitumorigenicity at the pre-clinical level, but the process of their introduction into the market is costly and time-consuming. More importantly, even if these new antitumor agents manage to gain approval, clinicians have no former experience with them. Accruing evidence supports the idea that several medications already used to treat pathologies other than cancer display pleiotropic effects, exhibiting multi-level anti-cancer activity and chemosensitizing properties. This review aims to present the anticancer properties of marketed drugs (i.e., metformin and pioglitazone) used for the management of diabetes mellitus (DM) type II. Mode of action, pre-clinical in vitro and in vivo or clinical data as well as clinical applicability are discussed here. Given the precious multi-year clinical experience with these non-antineoplastic drugs their repurposing in oncology is a challenging alternative that would aid towards the development of therapeutic schemes with less toxicity than those of conventional chemotherapeutic agents. More importantly, harnessing the antitumor function of these agents would save precious time from bench to bedside to aid the fight in the arena of cancer.
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Affiliation(s)
- Panagiota Papanagnou
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Orthias Artemidos and Plateon St, Sparti GR-23100, Greece.
| | - Theodora Stivarou
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Orthias Artemidos and Plateon St, Sparti GR-23100, Greece.
| | - Maria Tsironi
- Department of Nursing, Faculty of Human Movement and Quality of Life Sciences, University of Peloponnese, Orthias Artemidos and Plateon St, Sparti GR-23100, Greece.
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Haseen SD, Khanam A, Sultan N, Idrees F, Akhtar N, Imtiaz F. Elevated fasting blood glucose is associated with increased risk of breast cancer: outcome of case-control study conducted in Karachi, Pakistan. Asian Pac J Cancer Prev 2015; 16:675-8. [PMID: 25684506 DOI: 10.7314/apjcp.2015.16.2.675] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND There are several validated risk factors for breast cancer. However the legitimacy of elevated fasting blood glucose (FBG) is not well established. This study was designed to assess this parameter as a risk factor for breast cancer among pre- and post-menopausal women. MATERIALS AND METHODS This case-control study was conducted at Department of Biochemistry, University of Karachi from June 2010 to August 2014. Simple random sampling technique was used to collect data of study subjects comprising 175 diagnosed breast cancer patients with positive histopathology from Breast Clinic, surgical unit-1, Civil Hospital, Karachi and 175 healthy controls from various screening programs. Blood samples were analyzed for FBG and serum insulin. RESULTS FBG, HOMA-IR, systolic and diastolic blood pressure were significantly raised in breast cancer cases when compared to control subjects. Cases and controls were further categorized in to two groups using cutoff value of 110 mg/dl to distinguish subjects into normal fasting glucose (<110 mg/dl) and having impaired fasting glucose (≥110-≤125 mg/dl) or diabetes (≥126 mg/dl). Odds ratios were found to be 1.57, 2.15 and 1.17 in overall, pre-menopausal and post-menopausal groups, respectively. (all p<0.05). CONCLUSIONS A statistically significant risk of breast cancer exists in women having elevated fasting blood glucose levels, corresponding to prediabetes and diabetes, among pre and postmenopausal ages, with comparatively greater effects in the premenopausal group.
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Affiliation(s)
- Syed Danish Haseen
- Dept. of Biochemistry, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan E-mail :
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Hsu CY, Sulake RS, Huang PK, Shih HY, Sie HW, Lai YK, Chen C, Weng CF. Synthetic (+)-antroquinonol exhibits dual actions against insulin resistance by triggering AMP kinase and inhibiting dipeptidyl peptidase IV activities. Br J Pharmacol 2015; 172:38-49. [PMID: 24977411 DOI: 10.1111/bph.12828] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 06/03/2014] [Accepted: 06/19/2014] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND PURPOSE The fungal product (+)-antroquinonol activates AMP kinase (AMPK) activity in cancer cell lines. The present study was conducted to examine whether chemically synthesized (+)-antroquinonol exhibited beneficial metabolic effects in insulin-resistant states by activating AMPK and inhibiting dipeptidyl peptidase IV (DPP IV) activity. EXPERIMENTAL APPROACH Effects of (+)-antroquinonol on DPP IV activity were measured with a DPPIV Assay Kit and effects on GLP-1-induced PKA were measured in AR42J cells. Translocation of the glucose transporter 4, GLUT4, induced either by insulin-dependent PI3K/AKT signalling or by insulin-independent AMPK activation, was assayed in differentiated myotubes. Glucose uptake and GLUT4 translocation were assayed in L6 myocytes. Mice with diet-induced obesity were used to assess effects of acute and chronic treatment with (+)-antroquinonol on glycaemic control in vivo. KEY RESULTS The results showed that of (+)-antroquinonol (100 μM ) inhibited the DPP IV activity as effectively as the clinically used inhibitor, sitagliptin. The phosphorylation of AMPK Thr(172) in differentiated myotubes was significantly increased by (+)-antroquinonol. In cells simultaneously treated with S961 (insulin receptor antagonist), insulin and (+)-antroquinonol, the combination of (+)-antroquinonol plus insulin still increased both GLUT4 translocation and glucose uptake. Further, (+)-antroquinonol and sitagliptin reduced blood glucose, when given acutely or chronically to DIO mice. CONCLUSIONS AND IMPLICATIONS Chemically synthesized (+)-antroquinonol exhibits dual effects to ameliorate insulin resistance, by increasing AMPK activity and GLUT4 translocation, along with inhibiting DPP IV activity.
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Affiliation(s)
- C Y Hsu
- Institute of Biotechnology, National Dong-Hwa University, Hualien, Taiwan; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
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Proline-rich AKT substrate of 40-kDa (PRAS40) in the pathophysiology of cancer. Biochem Biophys Res Commun 2015; 463:161-6. [PMID: 26003731 DOI: 10.1016/j.bbrc.2015.05.041] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 05/07/2015] [Indexed: 12/18/2022]
Abstract
Dysregulation of PI3K-AKT-mTOR pathway has been reported in various pathologies, such as cancer and insulin resistance. The proline-rich AKT substrate of 40-kDa (PRAS40), also known as AKT substrate 1 (AKT1S1), lies at the crossroads of these cascades and inhibits the activity of the mTOR complex 1 (mTORC1) kinase. This review discusses the role of PRAS40 and possible feedback mechanisms, and alterations in AKT/PRAS40/mTOR signaling that have been implicated in the pathogenesis of tumor progression. Additionally, we probed new datasets extracted from Oncomine, a cancer microarray database containing datasets derived from patient samples, to further understand the role of PRAS40 (AKT1S1). These data strongly supports the hypothesis that PRAS40 may serve as a potential therapeutic target for various cancers.
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14
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Kosti A, Harry Chen HI, Mohan S, Liang S, Chen Y, Habib SL. Microarray profile of human kidney from diabetes, renal cell carcinoma and renal cell carcinoma with diabetes. Genes Cancer 2015; 6:62-70. [PMID: 25821562 PMCID: PMC4362485 DOI: 10.18632/genesandcancer.51] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 02/13/2015] [Indexed: 11/25/2022] Open
Abstract
Recent study from our laboratory showed that patients with diabetes are at a higher risk of developing kidney cancer. In the current study, we have screened whole human DNA genome from healthy control, patients with diabetes or renal cell carcinoma (RCC) or RCC+diabetes. We found that 883 genes gain/163 genes loss of copy number in RCC+diabetes group, 669 genes gain/307 genes loss in RCC group and 458 genes gain/38 genes loss of copy number in diabetes group, after removing gain/loss genes obtained from healthy control group. Data analyzed for functional annotation enrichment pathways showed that control group had the highest number (280) of enriched pathways, 191 in diabetes+RCC group, 148 in RCC group, and 81 in diabetes group. The overlap GO pathways between RCC+diabetes and RCC groups showed that nine were enriched, between RCC+diabetes and diabetes groups was four and between diabetes and RCC groups was eight GO pathways. Overall, we observed majority of DNA alterations in patients from RCC+diabetes group. Interestingly, insulin receptor (INSR) is highly expressed and had gains in copy number in RCC+diabetes and diabetes groups. The changes in INSR copy number may use as a biomarker for predicting RCC development in diabetic patients.
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Affiliation(s)
- Adam Kosti
- Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, Texas
| | - Hung-I Harry Chen
- Department of Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas
| | - Sumathy Mohan
- Department of Pathology, University of Texas Health Science Center, San Antonio, Texas
| | - Sitai Liang
- Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, Texas
| | - Yidong Chen
- Department of Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas ; Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas
| | - Samy L Habib
- Geriatric Research, Education and Clinical Center, South Texas Veterans Healthcare System, University of Texas Health Science Center, San Antonio, Texas ; Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, Texas
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The association between type 2 diabetes mellitus and women cancer: the epidemiological evidences and putative mechanisms. BIOMED RESEARCH INTERNATIONAL 2015; 2015:920618. [PMID: 25866823 PMCID: PMC4383430 DOI: 10.1155/2015/920618] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 09/12/2014] [Accepted: 10/08/2014] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes mellitus (T2DM), a chronic disease increasing rapidly worldwide, is well established as an important risk factor for various types of cancer. Although many factors impact the development of T2DM and cancer including sex, age, ethnicity, obesity, diet, physical activity levels, and environmental exposure, many epidemiological and experimental studies are gradually contributing to knowledge regarding the interrelationship between DM and cancer. The insulin resistance, hyperinsulinemia, and chronic inflammation associated with diabetes mellitus are all associated strongly with cancer. The changes in bioavailable ovarian steroid hormone that occur in diabetes mellitus (the increasing levels of estrogen and androgen and the decreasing level of progesterone) are also considered potentially carcinogenic conditions for the breast, endometrium, and ovaries in women. In addition, the interaction among insulin, insulin-like growth factors (IGFs), and ovarian steroid hormones, such as estrogen and progesterone, could act synergistically during cancer development. Here, we review the cancer-related mechanisms in T2DM, the epidemiological evidence linking T2DM and cancers in women, and the role of antidiabetic medication in these cancers.
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Hyperactivation of Akt/mTOR and deficiency in tuberin increased the oxidative DNA damage in kidney cancer patients with diabetes. Oncotarget 2015; 5:2542-50. [PMID: 24797175 PMCID: PMC4058025 DOI: 10.18632/oncotarget.1833] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Recent study from our laboratory showed that patients with diabetes are at a higher risk of developing kidney cancer. In the current study, we have explored one of the mechanisms by which diabetes accelerates tumorigenesis in the kidney. Kidney cancer tissue from patients with diabetes showed a higher activity of Akt and decreased in total protein of tuberin compared to kidney cancer patient without diabetes or diabetes alone. In addition, a significant increase in phospho-Akt/tuberin expression was associated with an increase in Ki67 expression and activation of mTOR in kidney tumor with or without diabetes compared to diabetes alone. In addition, decrease in tuberin expression resulted in a significant decrease in protein expression of OGG1 and increased in oxidative DNA damage, 8-oxodG in kidney tissues from patients with cancer or cancer+diabetes. Importantly, these data showed that the majority of the staining of Akt/tuberin/p70S6K phosphorylation was more prominently in the tubular cells. In addition, accumulation of oxidative DNA damage is localized only in the nucleus of tubular cells within the cortex region. These data suggest that Akt/tuberin/mTOR pathway plays an important role in the regulation DNA damage and repair pathways that may predispose diabetic kidneys to pathogenesis of renal cell carcinoma.
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Zhao W, Guan J, Horswell R, Li W, Wang Y, Wu X, Hu G. HDL cholesterol and cancer risk among patients with type 2 diabetes. Diabetes Care 2014; 37:3196-203. [PMID: 25216507 PMCID: PMC4237978 DOI: 10.2337/dc14-0523] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To investigate the relationship between HDL cholesterol (HDL-C) and cancer risk among type 2 diabetic patients. RESEARCH DESIGN AND METHODS We performed a retrospective cohort study of 14,169 men and 23,176 women with type 2 diabetes. Cox proportional hazards regression models were used to estimate the association of various levels of HDL cholesterol (HDL-C) with cancer risk. RESULTS During a mean follow-up period of 6.4 years, 3,711 type 2 diabetic patients had a cancer diagnosis. A significant inverse association between HDL-C and the risk of cancer was found among men and women. The multivariable-adjusted hazard ratios (HRs) of cancer at various levels of HDL-C at baseline (<30, 30-39.9, 40-49.9, 50-59.9, 60-69.9, 70-79.9, and ≥80 mg/dL) were 1.00, 0.87, 0.95, 1.01, 0.61, 0.45, and 0.37, respectively, in men (Ptrend = 0.027) and 1.00, 0.98, 0.88, 0.85, 0.84, 0.86, and 0.84, respectively, in women (Ptrend = 0.025). When stratified by race, BMI, smoking status, or medication use, the inverse association was still present. With an updated mean of HDL-C used in the analysis, the inverse association of HDL-C with cancer risk did not change. The inverse association substantially attenuated after excluding patients who died of or were diagnosed with cancer during the first 2 years of follow-up. CONCLUSIONS The study suggests an inverse association of HDL-C with cancer risk among men and women with type 2 diabetes, whereas the effect of HDL-C was partially mediated by reverse causation.
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Affiliation(s)
- Wenhui Zhao
- Pennington Biomedical Research Center, Baton Rouge, LA Department of Endocrinology, China Japan Friendship Hospital, Beijing, China
| | - Jing Guan
- Pennington Biomedical Research Center, Baton Rouge, LA Beijing University of Traditional Chinese Medicine, Beijing, China
| | | | - Weiqin Li
- Pennington Biomedical Research Center, Baton Rouge, LA Tianjin Women's and Children's Health Center, Tianjin, China
| | - Yujie Wang
- Pennington Biomedical Research Center, Baton Rouge, LA
| | - Xiaocheng Wu
- Louisiana Tumor Registry, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA
| | - Gang Hu
- Pennington Biomedical Research Center, Baton Rouge, LA
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Otunctemur A, Ozbek E, Sahin S, Dursun M, Besiroglu H, Koklu I, Erkoc M, Danis E, Bozkurt M, Gurbuz A. Diabetes Mellitus as a Risk Factor for High Grade Renal Cell Carcinoma. Asian Pac J Cancer Prev 2014; 15:3993-6. [DOI: 10.7314/apjcp.2014.15.9.3993] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Ko EM, Walter P, Clark L, Jackson A, Franasiak J, Bolac C, Havrilesky L, Secord AA, Moore DT, Gehrig PA, Bae-Jump VL. The complex triad of obesity, diabetes and race in Type I and II endometrial cancers: Prevalence and prognostic significance. Gynecol Oncol 2014; 133:28-32. [DOI: 10.1016/j.ygyno.2014.01.032] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 01/15/2014] [Accepted: 01/18/2014] [Indexed: 01/27/2023]
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Cummings BP, Bettaieb A, Graham JL, Stanhope K, Haj FG, Havel PJ. Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats. J Endocrinol 2014; 221:133-44. [PMID: 24627447 PMCID: PMC4457365 DOI: 10.1530/joe-13-0601] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset.
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Affiliation(s)
- Bethany P Cummings
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, T7 022A Veterinary Research Tower (Box 17), Ithaca, New York 14850, USA Department of Molecular Biosciences, School of Veterinary Medicine Department of Nutrition, University of California Davis, Davis, California, USA Department of Internal Medicine, University of California, Davis, Sacramento, California, USA
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Toaiari M, Davì MV, Dalle Carbonare L, Boninsegna L, Castellani C, Falconi M, Francia G. Presentation, diagnostic features and glucose handling in a monocentric series of insulinomas. J Endocrinol Invest 2013; 36:753-8. [PMID: 23608735 DOI: 10.3275/8942] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND New aspects have emerged in the clinical and diagnostic scenarios of insulinoma: current guidelines have lowered the diagnostic insulin threshold to 3 μU/ml in the presence of hypoglycemia (<55 mg/dl); post-prandial hypoglycemia has been reported as the only presenting symptom; preexisting diabetes mellitus (DM) was recognized in some patients. AIM To evaluate clinical features, diagnostic criteria and glucose metabolic profile in a monocentric series of patients affected by insulinomas including two subgroups: sporadic and multiple endocrine neoplasia type-1 syndrome (MEN-1). SUBJECTS AND METHODS Clinical, pathological and biochemical data regarding 33 patients were analyzed. RESULTS following the current guidelines the 72-h fasting test was initially positive in all cases but one. In this case the test, initially negative, became positive after a 2-yr follow-up. Nadir insulin level was ≥ 3 μU/ml but <6 μU/ml in 3 patients and ≥ 6 μU/ml in the remaining 30 cases. At presentation, 27 patients (82%) reported only fasting symptoms, 3 (9%) only post-prandial and 3 (9%) both. Seven cases (21%) had previously been affected by type 2 DM or impaired glucose metabolism. CONCLUSIONS In our series the new cut-off of insulin increased the sensitivity of the 72-h fasting test from 87% to 97%. The absence of hypoglycemia during the test cannot definitively rule out the diagnosis and the test should be repeated in every highly suspicious case. Post-prandial hypoglycemia can be the only presenting symptom. DM may be associated with the occurrence of insulinoma. So that a possible diagnosis of insulinoma must not be ignored if previous impaired glucose handling is evident.
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Affiliation(s)
- M Toaiari
- Department of Internal Medicine D, "G.B. Rossi" University Hospital, Verona, Italy
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22
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Ha YS, Kim WT, Yun SJ, Lee SC, Kim WJ, Park YH, Kang SH, Hong SH, Byun SS, Kim YJ. Multi-Institutional Analysis of Localized Renal Cell Carcinoma that Demonstrates the Impact of Diabetic Status on Prognosis After Nephrectomy. Ann Surg Oncol 2013; 20:3662-8. [DOI: 10.1245/s10434-013-3147-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Indexed: 12/14/2022]
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Cummings BP. Leptin therapy in type 2 diabetes. Diabetes Obes Metab 2013; 15:607-12. [PMID: 23216672 DOI: 10.1111/dom.12048] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Revised: 12/03/2012] [Accepted: 12/03/2012] [Indexed: 02/06/2023]
Abstract
There is a pressing need for new effective therapeutic strategies for addressing the epidemic of type 2 diabetes. Leptin has been shown to reduce hyperglycaemia in rodent models of type 1 diabetes and has recently been shown to normalize fasting plasma glucose concentrations in a rodent model of polygenic obesity and type 2 diabetes. Overall, these findings suggest that leptin may be an effective therapeutic option for both type 1 and type 2 diabetes. However, short-term human clinical studies in overweight and obese patients with recently diagnosed type 2 diabetes have reported minimal efficacy of leptin administration to lower blood glucose levels. Herein, the role of leptin in the maintenance of glucose homeostasis and the potential use of leptin in the treatment of type 2 diabetes are discussed.
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Affiliation(s)
- B P Cummings
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, USA.
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Gupta C, Tikoo K. High glucose and insulin differentially modulates proliferation in MCF-7 and MDA-MB-231 cells. J Mol Endocrinol 2013; 51:119-29. [PMID: 23690508 DOI: 10.1530/jme-13-0062] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Various preclinical and clinical studies have linked diabetes and breast cancer, but little is known regarding the molecular mechanism involved. This study aimed to investigate the effect of high glucose and insulin in breast cancer cells (MCF-7: non-invasive, hormone dependent, and MDA-MB-231: invasive, hormone independent). In contrast to MCF-7 cells, high glucose augmented proliferation of MDA-MB-231 cells as observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and bromodeoxyuridine assays. The high-glucose condition led to increased expression of cyclin D1, de-phosphorylation of p38, and increased phosphorylation of ERK in MDA-MB-231 cells but not in MCF-7 cells. Interestingly, we observed increased phosphorylation of GSK-3β, NF-κB, and ERα only in MCF-7 cells, highlighting their role as potential targets in prevention of progression of breast cancer under a high-glucose and insulin condition. Furthermore, insulin treatment under a high-glucose condition resulted in increased histone H3 phosphorylation and de-acetylation only in MDA-MB-231 cells. Taken together, we provide the first evidence that high glucose and insulin promotes proliferation of MDA-MB-231 cells by differential alteration of GSK-3β, NF-κB, and ERα expression and histone H3 modifications, which may directly or indirectly modulate the expression of genes involved in its proliferation.
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Affiliation(s)
- Chanchal Gupta
- Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research NIPER, Sector 67, S.A.S. Nagar, Mohali, Punjab-160062, India
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25
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Coppari R, Bjørbæk C. Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 2012; 11:692-708. [PMID: 22935803 PMCID: PMC4019022 DOI: 10.1038/nrd3757] [Citation(s) in RCA: 204] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Since the discovery of leptin in 1994, we now have a better understanding of the cellular and molecular mechanisms underlying its biological effects. In addition to its established anti-obesity effects, leptin exerts antidiabetic actions that are independent of its regulation of body weight and food intake. In particular, leptin can correct diabetes in animal models of type 1 and type 2 diabetes. In addition, long-term leptin replacement therapy improves glycaemic control, insulin sensitivity and plasma triglycerides in patients with severe insulin resistance due to lipodystrophy. These results have spurred enthusiasm for the use of leptin therapy to treat diabetes. Here, we review the current understanding of the glucoregulatory functions of leptin, emphasizing its central mechanisms of action and lessons learned from clinical studies, and discuss possible therapeutic applications of leptin in the treatment of type 1 and type 2 diabetes.
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Affiliation(s)
- Roberto Coppari
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas TX, 75390, USA
- Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- The Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, 92697, USA
| | - Christian Bjørbæk
- Department of Medicine, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston MA, 02215, USA
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26
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Habib SL, Prihoda TJ, Luna M, Werner SA. Diabetes and risk of renal cell carcinoma. J Cancer 2011; 3:42-8. [PMID: 22232697 PMCID: PMC3253431 DOI: 10.7150/jca.3718] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Accepted: 12/20/2011] [Indexed: 01/30/2023] Open
Abstract
Background and objectives: There is evidence that the incidence of solid tumors is markedly increased in patients with diabetes mellitus. In the current study, we investigate the association between diabetes and renal cancer. Patients and Methods: A single-center retrospective analysis of 473 patients who underwent nephrectomy for renal cell carcinoma (RCC) was performed. Diabetic RCC patients were screened for age, gender, ethnicity, HgA1C, glucose levels and renal function. Results: Of the 473 cases with RCC, we identified 120 patients (25.4%) with a history of diabetes. The incidence of diabetes in RCC patients was higher in female than male subjects and in Hispanic compared to White and Other ethnic backgrounds. At diagnosis, the majority of diabetic RCC patients were 50-59 years of age. In diabetic RCC cases, clear cell type histology (92.0%), nuclear grade 2 (56.1%) and tumor size range from 1-5 cm (65.7%) were the most common in each category. Conclusion: Our findings indicate that diabetic RCC patients have a predominance of localized, small clear cell RCC. In addition, females with a history of RCC have a higher frequency of diabetes compared to males. This is the first report of clinical and histopathological features of RCC associated with diabetes.
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Affiliation(s)
- Samy L Habib
- 1. Geriatric Research, Education, and, Clinical Center, South Texas, Veterans Healthcare System, San Antonio, Texas 78229, USA
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27
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Aljada A, Mousa SA. Metformin and neoplasia: implications and indications. Pharmacol Ther 2011; 133:108-15. [PMID: 21924289 DOI: 10.1016/j.pharmthera.2011.09.004] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Accepted: 08/20/2011] [Indexed: 01/08/2023]
Abstract
Metformin has been shown to exert anti-neoplastic and chemopreventive activities in epidemiological and animal studies. This review article discusses the epidemiological studies and examines the possible mechanisms by which metformin exerts its anti-carcinogenic activities in breast, colon, ovarian, lung, and prostate cancers. We performed a systematic review of the clinical studies examining the anti-neoplastic activities of metformin and the potential mechanisms associated with these activities. Several observational and biological studies revealed a significant association between metformin and reduction in cancer incidence. The mechanisms by which metformin exerts these effects are unknown. This action may be mediated through activation of AMP-activated protein kinase (AMPK), inhibition of the mammalian target of rapamycin (mTOR) pathway, and inhibition of insulin like growth factors (IGFs), and many others. Further laboratory investigation and large, prospective population clinical trials are required to elucidate metformin anti-neoplastic and chemo-preventive actions.
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Affiliation(s)
- Ahmad Aljada
- Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudia Arabia.
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Abstract
Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts multiple functions in determination of cell fate, tissue metabolism, and host immunity. Two synthetic PPARγ ligands (rosiglitazone and pioglitazone) were approved for the therapy of type-2 diabetes mellitus and are expected to serve as novel cures for inflammatory diseases and cancer. However, PPARγ and its ligands exhibit a janus-face behaviour as tumor modulators in various systems, resulting in either tumor suppression or tumor promotion. This may be in part due to signaling crosstalk to the mitogen-activated protein kinase (MAPK) cascades. The genomic activity of PPARγ is modulated, in addition to ligand binding, by phosphorylation of a serine residue by MAPKs, such as extracellular signal-regulated protein kinases-1/2 (ERK-1/2), or by nucleocytoplasmic compartmentalization through the ERK activators MAPK kinases-1/2 (MEK-1/2). PPARγ ligands themselves activate the ERK cascade through nongenomic and often PPARγ-independent signaling. In the current review, we discuss the molecular mechanisms and physiological implications of the crosstalk of PPARγ with MEK-ERK signaling and its potential as a novel drug target for cancer therapy in patients.
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Cancer risk in type 2 diabetes mellitus: metabolic links and therapeutic considerations. J Nutr Metab 2011; 2011:708183. [PMID: 21773024 PMCID: PMC3136221 DOI: 10.1155/2011/708183] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Revised: 02/10/2011] [Accepted: 03/24/2011] [Indexed: 12/14/2022] Open
Abstract
Type 2 diabetes mellitus (DM2) is increasing in incidence, creating worldwide public health concerns and impacting morbidity and mortality rates. An increasing number of studies have demonstrated shared associations between DM2 and malignancy, including key clinical, biochemical, and metabolic commonalities. This paper will attempt to explore the relationship between the various types of cancer and diabetes, the common metabolic pathways underlying cancer development, and the potential impact of various antidiabetes therapies on cancer risk.
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Bao B, Wang Z, Li Y, Kong D, Ali S, Banerjee S, Ahmad A, Sarkar FH. The complexities of obesity and diabetes with the development and progression of pancreatic cancer. BIOCHIMICA ET BIOPHYSICA ACTA 2011; 1815:135-46. [PMID: 21129444 PMCID: PMC3056906 DOI: 10.1016/j.bbcan.2010.11.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Revised: 11/19/2010] [Accepted: 11/20/2010] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer (PC) is one of the most lethal malignant diseases with the worst prognosis. It is ranked as the fourth leading cause of cancer-related deaths in the United States. Many risk factors have been associated with PC. Interestingly, large numbers of epidemiological studies suggest that obesity and diabetes, especially type-2 diabetes, are positively associated with increased risk of PC. Similarly, these chronic diseases (obesity, diabetes, and cancer) are also a major public health concern. In the U.S. population, 50 percent are overweight, 30 percent are medically obese, and 10 percent have diabetes mellitus (DM). Therefore, obesity and DM have been considered as potential risk factors for cancers; however, the focus of this article is restricted to PC. Although the mechanisms responsible for the development of these chronic diseases leading to the development of PC are not fully understood, the biological importance of the activation of insulin, insulin like growth factor-1 (IGF-1) and its receptor (IGF-1R) signaling pathways in insulin resistance mechanism and subsequent induction of compensatory hyperinsulinemia has been proposed. Therefore, targeting insulin/IGF-1 signaling with anti-diabetic drugs for lowering blood insulin levels and reversal of insulin resistance could be useful strategy for the prevention and/or treatment of PC. A large number of studies have demonstrated that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers, suggesting that these agents might be useful anti-tumor agents for the treatment of PC. In this review article, we will discuss the potential roles of metformin and TZD anti-diabetic drugs as anti-tumor agents in the context of PC and will further discuss the complexities and the possible roles of microRNAs (miRNAs) in the pathogenesis of obesity, diabetes, and PC.
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Affiliation(s)
- Bin Bao
- Department of Pathology, Wayne State University, Detroit, Michigan
| | - Zhiwei Wang
- Department of Pathology, Wayne State University, Detroit, Michigan
| | - Yiwei Li
- Department of Pathology, Wayne State University, Detroit, Michigan
| | - Dejuan Kong
- Department of Pathology, Wayne State University, Detroit, Michigan
| | - Shadan Ali
- Division of Hematology/Oncology Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Sanjeev Banerjee
- Department of Pathology, Wayne State University, Detroit, Michigan
| | - Aamir Ahmad
- Department of Pathology, Wayne State University, Detroit, Michigan
| | - Fazlul H. Sarkar
- Department of Pathology, Wayne State University, Detroit, Michigan
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Abstract
Data available from in-vitro and in-vivo studies suggest oncostatic properties of peroral antidiabetics, thiazolidinediones, in many types of cancer. This study is the first report on the chemopreventive effect of pioglitazone in mammary carcinogenesis in rats. Mammary carcinogenesis was induced by N-methyl-N-nitrosourea administered in two intraperitoneal doses per 50 mg/kg bodyweight on the 43rd and 50th postnatal days. Pioglitazone was administered in the diet at concentrations of 10 and 100 ppm, respectively, 12 days before the first carcinogen dose until the termination of the experiment. During the experiment, the animals were weighed weekly and palpated for the presence of mammary tumors, and the incidence, latency, tumor frequency, and tumor volume were recorded. The experiment was terminated 17 weeks after the first carcinogen dose; basic tumor growth parameters and metabolic and hormonal variables were evaluated. Pioglitazone at higher concentration decreased incidence and frequency per group from the 11th week of experiment when compared with the control group and a group receiving a lower dose. Pioglitazone at a higher dose decreased the final incidence by 38%, frequency per group by 63%, and extended latency period by 32% when compared with the control group. Our data suggest that pioglitazone and other glitazones should be further investigated for oncopreventive effects.
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Ansari NA, Rasheed Z. Non-enzymatic glycation of proteins: From diabetes to cancer. BIOCHEMISTRY (MOSCOW) SUPPLEMENT SERIES B: BIOMEDICAL CHEMISTRY 2009; 3:335-342. [DOI: 10.1134/s1990750809040027] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/07/2024]
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Sadikot S, Sosale A, Nigam A, Ahmed J, Singh S, Zargar A, Misra A, PrasannaKumar K, Wangnoo S, Makker B, Bajaj S, Singh J, Dhruv U, Jali M, Sinha N, Sai K, SadasivRao Y, Murthy S, Reddy A. No “Barge in” on “Glargine”! Diabetes Metab Syndr 2009. [DOI: 10.1016/j.dsx.2009.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Tanaka T, Yasui Y, Ishigamori-Suzuki R, Oyama T. Citrus compounds inhibit inflammation- and obesity-related colon carcinogenesis in mice. Nutr Cancer 2009; 60 Suppl 1:70-80. [PMID: 19003583 DOI: 10.1080/01635580802381253] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Dietary polyphenols are important potential chemopreventive natural agents. Other agents, such as citrus compounds, are also candidates for cancer chemopreventives. They act on multiple key elements in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, and obesity. This short review article provides our findings of preclinical studies on potential chemopreventive activities of dietary citrus compounds, auraptene, collinin, and citrus unshiu segment membrane (CUSM), using clitis- and obesity-related colon tumorigenesis models. Dietary feeding with auraptene and collinin at dose levels of 0.01% and 0.05% significantly lowered the incidence (50-60% reduction) and multiplicity (67-80% reduction) of colonic adenocarcinomas induced by azoxymetahene [AOM, single intraperitoneal injection of 10 mg/kg body weight (bw)] and dextran sodium sulfate (1% in drinking water). Anti-inflammatory potency of aurapene and collinin may contribute to the effects. Administration with CUSM at 3 doses in diet significantly inhibited development of aberrant crypts foci induced by 5 weekly subcutaneous injections of AOM (15 mg/kg bw) in male db/db mice: 53% inhibition by 0.02% CUSM, 54% inhibition by 0.1% CUSM, and 59% inhibition by 0.5% CUSM. CUSM treatment also decreased serum level of triglycerides. Our findings suggest that certain citrus materials are capable of inhibiting clitis- and obesity-related colon carcinogenesis.
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Affiliation(s)
- Takuji Tanaka
- Kanazawa Medical University, Daigaku, Uchinada, Ishikawa, Japan.
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Metabolic Syndrome and Its Associations with Surgery. POLISH JOURNAL OF SURGERY 2009. [DOI: 10.2478/v10035-009-0071-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Sennoune SR, Martinez-Zaguilan R. Plasmalemmal vacuolar H+-ATPases in angiogenesis, diabetes and cancer. J Bioenerg Biomembr 2008; 39:427-33. [PMID: 18058006 DOI: 10.1007/s10863-007-9108-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Angiogenesis, i.e., new blood vessel formation, is required in normal and pathological states. A dysfunction in the microvascular endothelium occurs in diabetes, leading to decreased blood flow and limb amputation. In cancer, angiogenesis is increased to allow for growth, invasion, and metastasis of tumor cells. Better understanding of the molecular events that cause or are associated with either of these diseases is needed to develop therapies. The tumor and angiogenic cells micro-environment is acidic and not permissive for growth. We have shown that to survive this environment, highly metastatic and angiogenic cells employ vacuolar H+-ATPase at their plasma membranes (pmV-ATPases) to maintain an alkaline pHcyt. However, in lowly metastatic and in microvascular endothelial cells from diabetic model, the density of pmV-ATPase and the cell invasiveness are decreased. Therefore, the overexpression of the pmV-ATPase is important for cell invasion, and essential for tumor progression, angiogenesis and metastasis. Both, cancer and diabetes are heterogenous diseases that involve many different proteins and signaling pathways. Changes in pHcyt have been associated with the regulation of a myriad of proteins, signaling molecules and pathways affecting many if not all cellular functions. Since changes in pHcyt are pleiotropic, we hypothesize that alteration in a single protein, pmV-ATPase, that can regulate pHcyt may explain the dysfunction of many proteins and cellular pathways in diabetes and cancer. Our long term goal is to determine the molecular mechanisms by which pmV-ATPase expression regulates tumor angiogenesis and metastasis. Such knowledge would be useful to identify targets for cancer therapy.
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Affiliation(s)
- Souad R Sennoune
- Department of Cellular Physiology and Molecular Biophysics, Health Sciences Center, Texas Tech University, 3601 4th Street, Lubbock, TX 79430-6551, USA.
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Oba S, Nagata C, Nakamura K, Takatsuka N, Shimizu H. Self-reported diabetes mellitus and risk of mortality from all causes, cardiovascular disease, and cancer in Takayama: a population-based prospective cohort study in Japan. J Epidemiol 2008; 18:197-203. [PMID: 18753735 PMCID: PMC4771590 DOI: 10.2188/jea.je2008004] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Diabetes mellitus has been reported to be a major risk factor for cardiovascular disease (CVD), and higher risk of CVD among women than that among men has been observed in many studies. Further, the association of diabetes with increasing risk of cancer has also been reported. Well-designed studies conducted among men and women in the general Japanese population remain scarce. METHODS Our cohort consisted of 13355 men and 15724 women residing in Takayama, Japan, in 1992. At the baseline, the subjects reported diabetes in a questionnaire. Any deaths occurring in the cohort until 1999 were noted by using data from the Office of the National Vital Statistics. The risk of mortality was separately assessed for men and women by using a Cox proportional hazard model after adjusting for age; smoking status; body mass index (BMI); physical activity; years of education; history of hypertension; and intake of total energy, vegetables, fat, and alcohol. RESULTS Diabetes significantly increased the risk of mortality from all causes [hazard ratio (HR): 1.35, 95% confidence interval (CI): 1.11-1.64] and from coronary heart disease (CHD) (HR: 2.96, 95% CI: 1.59-5.50) among men, and that from all causes (HR: 1.74, 95% CI: 1.34-2.26) and cancer (HR: 1.88, 95% CI: 1.16-3.05) among women. Diabetes was not significantly associated with mortality from CHD among women. CONCLUSION The findings suggest that diabetes increases the risk of mortality from CVD among men and that from cancer among women. The absence of increased risk of mortality from CHD among women may suggest a particular pattern in the Japanese population.
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Affiliation(s)
- Shino Oba
- Department of Prevention for Lifestyle-related Diseases, Gifu University Graduate School of Medicine, Gifu, Japan.
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Harish K, Dharmalingam M, Himanshu M. Study Protocol: insulin and its role in cancer. BMC Endocr Disord 2007; 7:10. [PMID: 17953765 PMCID: PMC2151943 DOI: 10.1186/1472-6823-7-10] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2007] [Accepted: 10/22/2007] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Studies have shown that metabolic syndrome and its consequent biochemical derangements in the various phases of diabetes may contribute to carcinogenesis. A part of this carcinogenic effect could be attributed to hyperinsulinism. High levels of insulin decrease the production of IGF-1 binding proteins and hence increase levels of free IGF-1. It is well established that bioactivity of free insulin growth factor 1 (IGF-1) increases tumor turnover rate. The objective is to investigate the role of insulin resistance/sensitivity in carcinogenesis by studying the relation between insulin resistance/sensitivity and IGF-1 levels in cancer patients. We postulate that hyperinsulinaemia which prevails during initial phases of insulin resistance (condition prior to overt diabetes) increases bioactivity of free IGF-1, which may contribute to process of carcinogenesis. METHODS/DESIGN Based on our pilot study results and power analysis of the same, we have designed a two group case-control study. 800 proven untreated cancer patients (solid epithelial cell tumors) under age of 50 shall be recruited with 200 healthy subjects serving as controls. Insulin resistance/sensitivity and free IGF-1 levels shall be determined in all subjects. Association between the two parameters shall be tested using suitable statistical methods. DISCUSSION Well controlled studies in humans are essential to study the link between insulin resistance, hyperinsulinaemia, IGF-1 and carcinogenesis. This study could provide insights to the role of insulin, insulin resistance, IGF-1 in carcinogenesis although a precise role and the extent of influence cannot be determined. In future, cancer prevention and treatment strategies could revolve around insulin and insulin resistance.
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Affiliation(s)
- K Harish
- Department of Surgical Oncology, M. S. Ramaiah Medical College & Hospital, Bangalore 560054, India
| | - M Dharmalingam
- Department of Endocrinology, M. S. Ramaiah Medical College & Hospital, Bangalore 560054, India
| | - M Himanshu
- Department of Endocrinology, M. S. Ramaiah Medical College & Hospital, Bangalore 560054, India
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Travier N, Jeffreys M, Brewer N, Wright CS, Cunningham CW, Hornell J, Pearce N. Association between glycosylated hemoglobin and cancer risk: a New Zealand linkage study. Ann Oncol 2007; 18:1414-9. [PMID: 17693655 DOI: 10.1093/annonc/mdm135] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The purpose of this study was to examine the relationship between glycosylated hemoglobin (HbA(1c)) level and subsequent cancer risk. MATERIAL AND METHODS HbA(1c) measurements were made on blood samples of participants in a hepatitis B (HB) screening program (1999-2001). Cancer incidence was determined by linkage to cancer registrations and hospitalization records to the end of 2004. Participants previously diagnosed with diabetes or cancer were excluded. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using Cox regression. RESULTS Among the 46 575 participants (70% Māori, 12% Pacific, 5% Asian and 12% Other), 634 cancer cases were observed. For all cancers combined, a significant increased risk was found in persons with moderately elevated HbA(1c) levels (6%-6.9%) (HR 1.40, 95% CI: 1.11-1.76), with a smaller increased risk in persons with highly elevated levels (> or =7%) (HR 1.09, 95% CI: 0.80-1.48) as compared with persons having low HbA(1c) levels (<6%). The HRs for respiratory cancers were 2.27 (95% CI: 1.34-3.86) for the moderate HbA(1c) category and 1.58 (95% CI: 0.77-3.26) for the upper HbA(1c) category. For endometrial cancers, the HRs were 4.05 (95% CI: 1.10-14.88) and 5.07 (95% CI: 1.20-21.31), respectively. For other cancer sites, no significantly increased risks were found. CONCLUSIONS These findings are consistent with other evidence that abnormal glucose metabolism may be associated with an increased risk of some cancers.
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Affiliation(s)
- N Travier
- Centre for Public Health Research, Massey University, Wellington, New Zealand.
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Voskuil DW, Monninkhof EM, Elias SG, Vlems FA, van Leeuwen FE. Physical activity and endometrial cancer risk, a systematic review of current evidence. Cancer Epidemiol Biomarkers Prev 2007; 16:639-48. [PMID: 17416752 DOI: 10.1158/1055-9965.epi-06-0742] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE To assess the epidemiologic evidence for the association between physical activity and endometrial cancer risk, taking into account the methodologic quality of each study. DESIGN Systematic review, best evidence synthesis. DATA SOURCES Studies were identified through a systematic review of literature available on PubMed through December 2006. REVIEW METHODS We included cohort and case-control studies that assessed total and/or leisure time and/or occupational activities in relation to the incidence of endometrial cancer. The methodologic quality of the studies was assessed with a comprehensive scoring system. RESULTS The included cohort (n = 7) and case-control (n = 13) studies consistently show that physical activity is associated with a decreased risk of endometrial cancer. The best evidence synthesis showed that the majority (80%) of 10 high-quality studies found risk reductions of >20%. Pooling of seven high-quality cohort studies that measured total, leisure time, or occupational activity showed a significantly decreased risk of endometrial cancer (summary estimate: OR, 0.77; 95% CI, 0.70-0.85) for the most active women. Case control studies with relatively unfavorable quality scores reported divergent risk estimates, between 2-fold decreased and 2-fold increased risk. Effect modification by body mass index or menopausal status was not consistently observed. Evidence for an effect of physical activity during childhood or adolescence was limited. CONCLUSIONS Physical activity seems to be associated with a reduction in the risk of endometrial cancer, which is independent of body weight. Further studies, preferably prospective cohort studies, are needed to determine the magnitude of the risk reduction and to assess which aspects of physical activity contribute most strongly to the reduced risk and in which period of life physical activity is most effective.
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Affiliation(s)
- Dorien W Voskuil
- Department of Epidemiology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands
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Stattin P, Björ O, Ferrari P, Lukanova A, Lenner P, Lindahl B, Hallmans G, Kaaks R. Prospective study of hyperglycemia and cancer risk. Diabetes Care 2007; 30:561-7. [PMID: 17327321 DOI: 10.2337/dc06-0922] [Citation(s) in RCA: 263] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To investigate whether hyperglycemia is associated with increased cancer risk. RESEARCH DESIGN AND METHODS In the Västerbotten Intervention Project of northern Sweden, fasting and postload plasma glucose concentrations were available for 33,293 women and 31,304 men and 2,478 incident cases of cancer were identified. Relative risk (RR) of cancer for levels of fasting and postload glucose was calculated with the use of Poisson models, with adjustment for age, year of recruitment, fasting time, and smoking status. Repeated measurements 10 years after baseline in almost 10,000 subjects were used to correct RRs for random error in glucose measurements. RESULTS Total cancer risk in women increased with rising plasma levels of fasting and postload glucose, up to an RR for the top versus bottom quartile of 1.26 (95% CI 1.09-1.47) (P(trend) <0.001) and 1.31 (1.12-1.52) (P(trend) = 0.001), respectively. Correction for random error in glucose measurements increased these risks up to 1.75 (1.32-2.36) and 1.63 (1.26-2.18), respectively. For men, corresponding uncorrected RR was 1.08 (0.92-1.27) (P(trend) = 0.25) and 0.98 (0.83-1.16) (P(trend) = 0.99), respectively. Risk of cancer of the pancreas, endometrium, urinary tract, and of malignant melanoma was statistically significantly associated with high fasting glucose with RRs of 2.49 (1.23-5.45) (P(trend) = 0.006), 1.86 (1.09-3.31) (P(trend) = 0.02), 1.69 (0.95-3.16) (P(trend) = 0.049), and 2.16 (1.14-4.35) (P(trend) = 0.01), respectively. Adjustment for BMI had no material effect on risk estimates. CONCLUSIONS The association of hyperglycemia with total cancer risk in women and in women and men combined for several cancer sites, independently of obesity, provides further evidence for an association between abnormal glucose metabolism and cancer.
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Affiliation(s)
- Pär Stattin
- Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University Hospital, 901 85 Umeå, Sweden.
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Suzuki R, Kohno H, Yasui Y, Hata K, Sugie S, Miyamoto S, Sugawara K, Sumida T, Hirose Y, Tanaka T. Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice. Int J Cancer 2007; 120:252-8. [PMID: 17066427 DOI: 10.1002/ijc.22240] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The modulatory effects of dietary citrus unshiu segment membrane (CUSM) on the occurrence of aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCACs) were determined in male C57BL/KsJ-db/db (db/db) mice initiated with azoxymethane (AOM). Male db/db, db/+ and +/+ mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they were fed the diet containing 0.02%, 0.1% or 0.5% CUSM for 7 weeks. At Week 12, a significant increase in the numbers of ACF and BCAC was noted in the db/db mice in comparison with the db/+ and +/+ mice. Feeding with CUSM caused reduction in the frequency of ACF in all genotypes of mice and the potency was high in order of the db/db mice, db/+ mice and +/+ mice. The number of BCACs was also reduced by feeding with CUSM, thus resulting in a 28-61% reduction in the db/db mice, possibly due to suppression of cell proliferation activity in the lesions by feeding with CUSM-containing diet. Clinical chemistry revealed a low serum level of triglyceride in mice fed CUSM. In addition, CUSM feeding inhibited fatty metamorphosis and fibrosis in the liver of db/db mice. Our findings show that CUSM in the diet has a chemopreventive ability against the early phase of AOM-induced colon carcinogenesis in the db/db as well as db/+ and +/+ mice, indicating potential use of CUSM in cancer chemoprevention in obese people.
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Affiliation(s)
- Rikako Suzuki
- Department of Oncologic Pathology, Kanazawa Medical University, Ishikawa, Japan
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Limburg PJ, Vierkant RA, Fredericksen ZS, Leibson CL, Rizza RA, Gupta AK, Ahlquist DA, Melton LJ, Sellers TA, Cerhan JR. Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Am J Gastroenterol 2006; 101:1872-9. [PMID: 16790032 DOI: 10.1111/j.1572-0241.2006.00725.x] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Patients with type 2 diabetes mellitus (DM) may be at increased colorectal cancer (CRC) risk. However, existing data are inconsistent. We investigated CRC risks, overall and by anatomic subsite, within a population-based inception cohort of clinically confirmed type 2 DM subjects. METHODS All residents of Rochester, Minnesota who first met standardized criteria for type 2 DM from 1970 to 1994 (997 men and 978 women) were identified and followed forward in time until emigration, death, or December 31, 1999. Incident CRC cases were identified by review of inpatient and outpatient medical records. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were estimated to compare CRC incidence within the type 2 DM inception cohort with previously published rates for the Rochester general population. RESULTS Over 19,158 person-years of follow-up, 51 incident CRC cases were identified within the type 2 DM cohort, while only 36.8 cases were expected (SIR = 1.39, 95% CI 1.03-1.82). Among men, type 2 DM was associated with increased overall (SIR = 1.67, 95% CI 1.16-2.33) and proximal (SIR = 1.96, 95% CI 1.16-3.10) CRC risks; distal CRC risk was also increased, but the point estimate was not statistically significant (SIR = 1.43, 95% CI 0.82-2.32). Among women, type 2 DM was not a risk factor for overall, proximal, or distal CRC (SIR = 1.03, 95% CI 0.60-1.66; SIR = 1.17, 95% CI 0.58-2.09; and SIR = 0.74, 95% CI 0.24-1.72, respectively). Within the type 2 DM cohort, current and former cigarette smokers were at higher CRC risk (SIR = 1.77, 95% CI 1.24-2.47) than never smokers (SIR = 0.99, 95% CI 0.57-1.61) and the interaction between type 2 DM and cigarette smoking status was statistically significant (p= 0.05). CONCLUSIONS In this population-based, retrospective cohort study, clinically confirmed type 2 DM was associated with increased CRC risk, predominantly among men. Cigarette smoking appeared to positively modify DM-associated CRC risk, which to our knowledge has not been previously reported. These data suggest that further investigation of potential interactions between endogenous and exogenous factors involved in colorectal carcinogenesis may help to clarify the magnitude and extent of CRC risk experienced by persons with type 2 DM.
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Affiliation(s)
- Paul J Limburg
- Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
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Batty GD, Shipley MJ, Marmot M, Smith GD. Diabetes status and post-load plasma glucose concentration in relation to site-specific cancer mortality: findings from the original Whitehall study. Cancer Causes Control 2005; 15:873-81. [PMID: 15577289 DOI: 10.1007/s10552-004-1050-z] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE While several studies have reported on the relation of diabetes status with pancreatic cancer risk, the predictive value of this disorder for other malignancies is unclear. METHODS The Whitehall study, a 25 year follow-up for mortality experience of 18,006 men with data on post-challenge blood glucose and self-reported diabetes, allowed us to address these issues. RESULTS There were 2158 cancer deaths at follow-up. Of the 15 cancer outcomes, diabetes status was positively associated with mortality from carcinoma of the pancreas and liver, while the relationship with lung cancer was inverse, after controlling for a range of potential covariates and mediators which included obesity and socioeconomic position. After excluding deaths occurring in the first 10 years of follow-up to examine the effect of reverse causality, the magnitude of the relationships for carcinoma of the pancreas and lung was little altered, while for liver cancer it was markedly attenuated. CONCLUSIONS In the present study, diabetes status was related to pancreatic, liver, and lung cancer risk. Cohorts with serially collected data on blood glucose and covariates are required to further examine this area.
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Affiliation(s)
- G David Batty
- MRC Social & Public Health Sciences Unit, University of Glasgow, 4 Lilybank Gardens, GLASGOW, G12 8RZ, UK.
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Abstract
Type 2 diabetes is a serious health problem that affects more than 7% of adults in developed countries. Up to 16% of patients with breast cancer have diabetes, and two major risk factors for type 2 diabetes-old age and obesity-are also associated with breast cancer. Three mechanisms have been postulated to associate diabetes with breast cancer: activation of the insulin pathway, activation of the insulin-like-growth-factor pathway, and regulation of endogenous sex hormones. Comparative cohort studies and case-control studies suggest that type 2 diabetes may be associated with 10-20% excess relative risk of breast cancer. Gestational diabetes mellitus, but not type 1 diabetes, might also be associated with excess risk of breast cancer. Moreover, diabetes and its complications can adversely affect cancer therapy and the use of screening, which will thus affect the outcome of patients with breast cancer.
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Affiliation(s)
- Ido Wolf
- Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
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Li XP, Chen Z, Meng ZQ, Huang WX, Liu LM. Concurrent hyperglycemia does not influence the long-term prognosis of unresectable hepatocellular carcinomas. World J Gastroenterol 2003; 9:1848-52. [PMID: 12918136 PMCID: PMC4611559 DOI: 10.3748/wjg.v9.i8.1848] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: The association has been established between the disorder of carbohydrate metabolism and liver cancer. However, little is known regarding the impact of concurrent hyperglycemia on prognosis of hepatocellular carcinoma (HCC). The present study aimed at solving this problem.
METHODS: A total of 225 patients included in this study, were admitted from January 1998 to December 2001 for an unresectable HCC proven by histological and imaging examinations. Most of the patients received interventional treatment, radiation and biotherapy. Response was evaluated by computerized tomography (CT) scan conducted 4-6 weeks following completion of the treatment, and then every 3 months. Survival was calculated from the beginning of treatment using the Kaplan-Meier method. Pretreatment, treatment and follow-up variables with possible prognostic significance were analyzed. A stepwise multivariate analysis was performed using the Cox regression model, and a prognostic index was obtained.
RESULTS: No differences were observed in survival parameters between the patients with and without hyperglycemia, median survival times of the patients were being 26 ± 3.46 months and 29.5 ± 2.04 months, respectively, and the 3-year survival rate was 8.36% and 9.62%, respectively. The univariate analysis indicated that there were several survival-associated variables including serum AFP level, clinical stage, Child-Pugh grade, method of treatment, size and number of tumor nodule (s). However, only the clinical stage, Child-Pugh grade and the treatment procedure were proved to be independent prognostic factors in the multivariate analysis.
CONCLUSION: This study indicates that hyperglycemia does not influence the long-term prognosis of HCC, and concurrent hyperglycemia should not be considered as an unfavorable prognostic factor during the treatment of patients with HCC.
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Affiliation(s)
- Xiao-Ping Li
- Department of Liver Neoplasms, Cancer Hospital, Fudan University, Shanghai 200032, China.
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