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Nguyen HP, An K, Ito Y, Kharbikar BN, Sheng R, Paredes B, Murray E, Pham K, Bruck M, Zhou X, Biellak C, Ushiki A, Nobuhara M, Fong SL, Bernards DA, Lynce F, Dillon DA, Magbanua MJM, Huppert LA, Hammerlindl H, Klein JA, Valdiviez L, Fiehn O, Esserman L, Desai TA, Yee SW, Rosenbluth JM, Ahituv N. Implantation of engineered adipocytes suppresses tumor progression in cancer models. Nat Biotechnol 2025:10.1038/s41587-024-02551-2. [PMID: 39905264 DOI: 10.1038/s41587-024-02551-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 12/19/2024] [Indexed: 02/06/2025]
Abstract
Tumors exhibit an increased ability to obtain and metabolize nutrients. Here, we implant engineered adipocytes that outcompete tumors for nutrients and show that they can substantially reduce cancer progression, a technology termed adipose manipulation transplantation (AMT). Adipocytes engineered to use increased amounts of glucose and fatty acids by upregulating UCP1 were placed alongside cancer cells or xenografts, leading to significant cancer suppression. Transplanting modulated adipose organoids in pancreatic or breast cancer genetic mouse models suppressed their growth and decreased angiogenesis and hypoxia. Co-culturing patient-derived engineered adipocytes with tumor organoids from dissected human breast cancers significantly suppressed cancer progression and proliferation. In addition, cancer growth was impaired by inducing engineered adipose organoids to outcompete tumors using tetracycline or placing them in an integrated cell-scaffold delivery platform and implanting them next to the tumor. Finally, we show that upregulating UPP1 in adipose organoids can outcompete a uridine-dependent pancreatic ductal adenocarcinoma for uridine and suppress its growth, demonstrating the potential customization of AMT.
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Affiliation(s)
- Hai P Nguyen
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
- Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA
| | - Kelly An
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Yusuke Ito
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Bhushan N Kharbikar
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
| | - Rory Sheng
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Breanna Paredes
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Elizabeth Murray
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Kimberly Pham
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Michael Bruck
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Xujia Zhou
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Cassandra Biellak
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Aki Ushiki
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Mai Nobuhara
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Sarah L Fong
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Daniel A Bernards
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
| | - Filipa Lynce
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Deborah A Dillon
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Mark Jesus M Magbanua
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Laura A Huppert
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Heinz Hammerlindl
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA
| | - Jace Anton Klein
- Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA
| | - Luis Valdiviez
- University of California Davis West Coast Metabolomics Center, Davis, CA, USA
| | - Oliver Fiehn
- University of California Davis West Coast Metabolomics Center, Davis, CA, USA
| | - Laura Esserman
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Tejal A Desai
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- School of Engineering, Brown University, Providence, RI, USA
| | - Sook Wah Yee
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
| | - Jennifer M Rosenbluth
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Nadav Ahituv
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
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Natalicchio A, Marrano N, Montagnani M, Gallo M, Faggiano A, Zatelli MC, Argentiero A, Del Re M, D'Oronzo S, Fogli S, Franchina T, Giuffrida D, Gori S, Ragni A, Marino G, Mazzilli R, Monami M, Morviducci L, Renzelli V, Russo A, Sciacca L, Tuveri E, Cortellini A, Di Maio M, Candido R, Perrone F, Aimaretti G, Avogaro A, Silvestris N, Giorgino F. Glycemic control and cancer outcomes in oncologic patients with diabetes: an Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), Italian Society of Pharmacology (SIF) multidisciplinary critical view. J Endocrinol Invest 2024; 47:2915-2928. [PMID: 38935200 PMCID: PMC11549129 DOI: 10.1007/s40618-024-02417-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 06/16/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a ∼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. PURPOSE The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.
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Affiliation(s)
- A Natalicchio
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, I-70124, Bari, Italy
| | - N Marrano
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, I-70124, Bari, Italy
| | - M Montagnani
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, University of Bari Aldo Moro, Bari, Italy
| | - M Gallo
- Endocrinology and Metabolic Diseases Unit, Azienda Ospedaliero-Universitaria SS Antonio e Biagio e Cesare Arrigo of Alessandria, Alessandria, Italy
| | - A Faggiano
- Endocrinology Unit, Department of Clinical & Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - M C Zatelli
- Section of Endocrinology, Geriatrics and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - A Argentiero
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - M Del Re
- Department of Clinical and Experimental Medicine, University of Pisa, 55, Via Roma, 56126, Pisa, Italy
| | - S D'Oronzo
- Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Bari, Italy
| | - S Fogli
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - T Franchina
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy
| | - D Giuffrida
- Department of Oncology, Istituto Oncologico del Mediterraneo, Viagrande, Catania, Italy
| | - S Gori
- Oncologia Medica, IRCCS Don Calabria-Sacro Cuore Hospital, Negrar, Verona, Italy
| | - A Ragni
- Endocrinology and Metabolic Diseases Unit, Azienda Ospedaliero-Universitaria SS Antonio e Biagio e Cesare Arrigo of Alessandria, Alessandria, Italy
| | - G Marino
- Internal Medicine Department, Ospedale dei Castelli, Asl Roma 6, Ariccia, Rome, Italy
| | - R Mazzilli
- Endocrinology Unit, Department of Clinical & Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - M Monami
- Diabetology, Careggi Hospital and University of Florence, Florence, Italy
| | - L Morviducci
- Diabetology and Nutrition Unit, Department of Medical Specialties, ASL Roma 1 - S. Spirito Hospital, Rome, Italy
| | - V Renzelli
- Diabetologist and Endocrinologist, Italian Association of Clinical Diabetologists, Rome, Italy
| | - A Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - L Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania, Catania, Italy
| | - E Tuveri
- Diabetology, Endocrinology and Metabolic Diseases Service, ASL-Sulcis, Carbonia, Italy
| | - A Cortellini
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128, Rome, Italy
- Department of Medicine and Surgery, Universitá Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
- Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, London, UK
| | - M Di Maio
- Department of Oncology, University of Turin, AOU Città Della Salute e della Scienza di Torino, Turin, Italy
| | - R Candido
- Department of Medical Surgical and Health Sciences, University of Trieste, 34149, Trieste, Italy
| | - F Perrone
- Clinical Trials Unit, National Cancer Institute, Naples, Italy
| | - G Aimaretti
- Endocrinology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - A Avogaro
- Department of Medicine, Section of Diabetes and Metabolic Diseases, University of Padova, Padua, Italy
| | - N Silvestris
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy
| | - F Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, I-70124, Bari, Italy.
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Grandhi N, Liu L, Wang M, Thomas T, Schoen M, Sanfilippo K, Gao F, Colditz GA, Carson KR, Janakiram M, Chang SH. Association between glucagon-like peptide-1 receptor agonist use and progression of monoclonal gammopathy of uncertain significance to multiple myeloma among patients with diabetes. JNCI Cancer Spectr 2024; 8:pkae095. [PMID: 39514091 PMCID: PMC11643351 DOI: 10.1093/jncics/pkae095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 08/26/2024] [Accepted: 09/22/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND In patients with diabetes and monoclonal gammopathy of uncertain significance (MGUS), the impact of glucagon-like peptide-1 (GLP-1) receptor agonists on the natural history of MGUS is unknown. We aimed to assess the association of GLP-1 receptor agonist use in the progression of MGUS to multiple myeloma in patients with diabetes. METHODS This is a population-based cohort study of veterans diagnosed with MGUS from 2006 to 2021 with a prior diagnosis of diabetes. A validated natural language processing algorithm was used to confirm MGUS and progression to multiple myeloma. We performed 1:2 matching for individuals with and without GLP-1 receptor agonist exposure. The Gray test was performed to detect the difference in cumulative incidence functions for progression by GLP-1 receptor agonist use status. The association between time-varying GLP-1 receptor agonist use and progression was estimated through multivariable-adjusted hazard ratio using a stratified Fine-Gray distribution hazard model, with death as a competing event and stratum for the matched patient triad. RESULTS Our matched cohort included 1097 individuals with MGUS who had ever used GLP-1 receptor agonists and the matched 2194 patients who had never used GLP-1 receptor agonists. Overall, 2.6% of individuals progressed in the GLP-1 receptor agonist ever use group compared with 5.0% in the GLP-1 receptor agonist never use group. Cumulative incidence functions were statistically significantly different between the exposed and unexposed groups (P = .02). GLP-1 receptor agonist use vs no use was associated with decreased progression to multiple myeloma (hazard ratio = 0.45, 95% confidence interval = 0.22 to 0.93, P = .03). CONCLUSIONS For patients with diabetes and MGUS, GLP-1 receptor agonist use is associated with a 55% reduction in risk of progression from MGUS to multiple myeloma compared with no use.
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Affiliation(s)
- Nikhil Grandhi
- Research Service, St Louis VA Medical Center, St Louis, MO, USA
- Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | - Lawrence Liu
- Research Service, St Louis VA Medical Center, St Louis, MO, USA
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Mei Wang
- Research Service, St Louis VA Medical Center, St Louis, MO, USA
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
| | - Theodore Thomas
- Research Service, St Louis VA Medical Center, St Louis, MO, USA
- Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | - Martin Schoen
- Research Service, St Louis VA Medical Center, St Louis, MO, USA
- Department of Medicine, Saint Louis University School of Medicine, St Louis, MO, USA
| | - Kristen Sanfilippo
- Research Service, St Louis VA Medical Center, St Louis, MO, USA
- Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | - Feng Gao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
| | - Graham A Colditz
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
| | - Kenneth R Carson
- Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | - Su-Hsin Chang
- Research Service, St Louis VA Medical Center, St Louis, MO, USA
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
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Jonusas J, Drevinskaitė M, Linkeviciute-Ulinskiene D, Ladukas A, Patašius A, Zabulienė L, Smailytė G. The risk of cancer among insulin glargine users in Lithuania: A retrospective population-based study. Open Med (Wars) 2024; 19:20241017. [PMID: 39434861 PMCID: PMC11491771 DOI: 10.1515/med-2024-1017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/25/2024] [Accepted: 07/18/2024] [Indexed: 10/23/2024] Open
Abstract
Objectives The aim of this study was to determine the association between insulin glargine usage and the potential increase in cancer risk among the Lithuanian population diagnosed with type 2 diabetes mellitus (T2DM). Methods A retrospective cohort study was conducted. The cohort of insulin users was established by identifying all male and female patients diagnosed with T2DM, as recorded in the National Health Insurance Fund database between 1 January 2000 and 31 December 2012. The risk of cancer among insulin glargine users was compared with the risk in non-glargine insulin users. Cox proportional hazard models were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI). Results The overall cancer risk for all sites combined showed no significant difference (HR 0.84, 95% CI 0.67-1.05). Although a general decrease in the risk of cancers was observed at most sites for glargine users, the use of insulin glargine was associated with a non-significant increase in the risk of mouth and pharynx, stomach, non-melanoma skin, breast, cervical, ovarian, and central nervous system cancers. There was a tendency for a lower risk of colon, rectum, rectosigmoid, and anus cancer among glargine users (HR 0.45, 95% CI 0.18-1.12, p = 0.09). Conclusions Our research contributes to the growing body of evidence showing that insulin glargine is not associated with an increased risk of all cancers or specific types of cancer.
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Affiliation(s)
- Justinas Jonusas
- Laboratory of Cancer Epidemiology, National Cancer Institute, LT-08406, Vilnius, Lithuania
- Brachytherapy Department, National Cancer Institute, LT-08406, Vilnius, Lithuania
| | - Mingailė Drevinskaitė
- Laboratory of Cancer Epidemiology, National Cancer Institute, LT-08406, Vilnius, Lithuania
| | | | - Adomas Ladukas
- Laboratory of Cancer Epidemiology, National Cancer Institute, LT-08406, Vilnius, Lithuania
| | - Aušvydas Patašius
- Laboratory of Cancer Epidemiology, National Cancer Institute, LT-08406, Vilnius, Lithuania
- Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, LT-03101Vilnius, Lithuania
| | - Lina Zabulienė
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 03101, Vilnius, Lithuania
| | - Giedrė Smailytė
- Laboratory of Cancer Epidemiology, National Cancer Institute, LT-08406, Vilnius, Lithuania
- Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, LT-03101Vilnius, Lithuania
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Popa Ilie IR, Vonica-Tincu AL, Dobrea CM, Butuca A, Frum A, Morgovan C, Gligor FG, Ghibu S. Safety Profiles Related to Dosing Errors of Rapid-Acting Insulin Analogs: A Comparative Analysis Using the EudraVigilance Database. Biomedicines 2024; 12:2273. [PMID: 39457586 PMCID: PMC11504911 DOI: 10.3390/biomedicines12102273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 09/18/2024] [Accepted: 10/05/2024] [Indexed: 10/28/2024] Open
Abstract
Insulin is essential for treating type 1 diabetes and insulin-requiring type 2 diabetes. BACKGROUND/OBJECTIVES Diabetes is a widespread condition that can lead to multiple and severe complications. Rapid-acting insulin analogs (RAIAs) and long-acting insulin analogs are prescribed for the effective management of diabetes. RAIAs are expected to be associated with a higher number of dosing errors because of their rapid onset, short duration of action, and the need for frequent dosing, compared to other insulin analogs. There are three approved RAIAs on the market: insulin lispro (LIS), insulin aspart (ASP), and insulin glulisine (GLU). The aim of this study is to evaluate the real-world evidence on dosing errors reported for RAIAs in EudraVigilance (EV), an established pharmacovigilance database, in comparison to other insulin analogs and human insulins. METHODS A descriptive analysis and a disproportionality analysis were conducted. RESULTS ASP and LIS were associated with high percentages of adverse drug reactions (ADRs) (22% and 17%, respectively), with over 70% of the reports involving serious ADRs. A higher frequency of cardiac and eye disorder ADRs was observed for LIS compared with ASP and GLU. GLU showed a higher frequency of ADRs in the skin and subcutaneous tissue disorders category. LIS dosing errors accounted for 5% of the total number of cases, while dosing errors for ASP and GLU were less than 3%. The most frequently reported dosing errors involved improper dosing (49%). CONCLUSIONS Although there were fewer dosing errors of RAIAs in comparison to other insulins, the severity of the potential outcome highlights the importance of precise dosing and timing. Improved the monitoring and reporting of these dosing errors could enhance diabetes patient care. Additionally, smart medical devices could improve therapeutic outcomes.
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Affiliation(s)
- Ioana Rada Popa Ilie
- Department of Endocrinology, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, 3-5 Louis Pasteur Street, 400349 Cluj-Napoca, Romania;
| | - Andreea Loredana Vonica-Tincu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (C.M.D.); (A.B.); (A.F.); (C.M.); (F.G.G.)
| | - Carmen Maximiliana Dobrea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (C.M.D.); (A.B.); (A.F.); (C.M.); (F.G.G.)
| | - Anca Butuca
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (C.M.D.); (A.B.); (A.F.); (C.M.); (F.G.G.)
| | - Adina Frum
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (C.M.D.); (A.B.); (A.F.); (C.M.); (F.G.G.)
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (C.M.D.); (A.B.); (A.F.); (C.M.); (F.G.G.)
| | - Felicia Gabriela Gligor
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (C.M.D.); (A.B.); (A.F.); (C.M.); (F.G.G.)
| | - Steliana Ghibu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 6A Louis Pasteur Street, 400349 Cluj-Napoca, Romania;
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Sirtori CR, Castiglione S, Pavanello C. METFORMIN: FROM DIABETES TO CANCER TO PROLONGATION OF LIFE. Pharmacol Res 2024; 208:107367. [PMID: 39191336 DOI: 10.1016/j.phrs.2024.107367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/12/2024] [Accepted: 08/21/2024] [Indexed: 08/29/2024]
Abstract
The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.
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Affiliation(s)
- Cesare R Sirtori
- Center of Dyslipidemias, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Centro E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
| | - Sofia Castiglione
- Center of Dyslipidemias, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Centro E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Chiara Pavanello
- Center of Dyslipidemias, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Centro E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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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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Tabernacki T, Wang L, Kaelber DC, Xu R, Berger NA. Non-Insulin Antidiabetic Agents and Lung Cancer Risk in Drug-Naive Patients with Type 2 Diabetes Mellitus: A Nationwide Retrospective Cohort Study. Cancers (Basel) 2024; 16:2377. [PMID: 39001440 PMCID: PMC11240387 DOI: 10.3390/cancers16132377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/21/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Lung cancer (LC) is the second most common cancer and the leading cause of cancer deaths in the U.S. Insulin therapy, a key treatment for managing Type 2 Diabetes Mellitus (T2DM), is associated with increased LC risk. The impact of non-insulin antidiabetic drugs, particularly GLP-1 receptor agonists (GLP-1RAs), on LC risk is not well understood. This study evaluated LC risk in T2DM patients, comparing seven non-insulin antidiabetic agents to insulin. Using the TriNetX Analytics platform, we analyzed the de-identified electronic health records of 1,040,341 T2DM patients treated between 2005 and 2019, excluding those with prior antidiabetic use or LC diagnoses. We calculated hazard ratios and confidence intervals for LC risk and used propensity score matching to control for confounding factors. All non-insulin antidiabetic drugs, except alpha-glucosidase inhibitors, were associated with significantly reduced LC risk compared to insulin, with GLP-1RAs showing the greatest reduction (HR: 0.49, 95% CI: 0.41, 0.59). GLP-1RAs were consistently associated with lowered LC risk across all histological types, races, genders, and smoking statuses. These findings suggest that non-insulin antidiabetic drugs, particularly GLP-1RAs, may be preferable for managing T2DM while reducing LC risk.
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Affiliation(s)
- Tomasz Tabernacki
- Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Lindsey Wang
- Center for Science, Health, and Society, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - David C. Kaelber
- Center for Clinical Informatics Research and Education, The MetroHealth System, Cleveland, OH 44109, USA
| | - Rong Xu
- Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Nathan A. Berger
- Center for Science, Health, and Society, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
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9
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Ayat P, Sawass Najjar D, Alkaissi H, Gill H, Otey J, AlFaraj M, McFarlane SI. Differential Effect of Hyperglycemia on the Odds of Cancer Among the Adult Population of the United States. Cureus 2024; 16:e63061. [PMID: 39050345 PMCID: PMC11268948 DOI: 10.7759/cureus.63061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2024] [Indexed: 07/27/2024] Open
Abstract
Objective Accumulating evidence indicates a relationship between diabetes and cancer risk, with obesity, insulin resistance, and hyperglycemia being implicated as the major underlying pathogenetic mechanisms of increased cancer risk among people with diabetes. We aim to assess the differential effect of dysglycemia (prediabetes and diabetes) on the strength of association (odds) of cancer amongst the adult US diabetic population. Material and methods We analyzed data from the 1997-2013 National Health Interview Survey (NHIS) dataset, which applies a multistage area probability sampling design. We used descriptive statistics and logistic regression analyses to test the strengths of the association between diabetes, prediabetes, and cancer before and after adjusting for major risk factors for cancer, including age and body mass index (BMI). Results A total of 722,532 individuals were surveyed, with a mean age of 47.18 ±0.3 years (±SEM) and a BMI of 26.9 ±0.01 kg/m2. Between 1997 and 2013, BMI increased from 26.0 to 27.4 kg/m2, the diabetes rate increased from 4.1% to 7.6%, and associated cancer rates increased from 6.6% to 9.0%. Body mass index was 27.1 vs. 26.8 kg/m2, P < 0.01, for those with and without cancer, respectively. The unadjusted odds ratio for cancer was 1.92 (1.78-2.08) (95% CI) and 2.20 (2.13-2.27) for prediabetes and diabetes, respectively. After adjusting for age, BMI, race, and cigarette smoking, the odds ratio for cancer was 1.12 (1.03-1.22), P < 0.01, and 1.15 (1.11-1.18), P <0.01, for prediabetes and diabetes, respectively. Conclusion Among US adults, the increasing rate of diabetes over the years was associated with an increased rate of cancer. Diabetes and prediabetes have a graduated effect on cancer risk. While obesity is generally implicated as an underlying pathophysiologic link between diabetes and cancer, our study showed a modest difference in BMI between those with and without cancer. In addition, the effect of diabetes and prediabetes on the odds of cancer persisted after adjusting for BMI. These data collectively suggest that hyperglycemia is an attractive pathophysiologic mechanism that may play a role in increasing the odds of cancer among diabetic and prediabetic populations. Our study is consistent with the accumulating evidence implicating hyperglycemia in the pathogenesis of cancer, where glucose is used in PET scanning to detect cancer (the Warburg effect), and the ketogenic diet appears to be useful in cancer management, enhancing the effect of chemotherapeutic agents.
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Affiliation(s)
- Parinaz Ayat
- Internal Medicine, State University of New York (SUNY) Downstate Health Science University, New York City, USA
| | - Diana Sawass Najjar
- Internal Medicine, State University of New York (SUNY) Downstate Health Science University, New York City, USA
| | - Hussam Alkaissi
- Internal Medicine, National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, USA
| | - Harjinder Gill
- Internal Medicine, State University of New York (SUNY) Downstate Health Science University, New York City, USA
| | - Jennifer Otey
- Medicine, State University of New York (SUNY) Downstate Health Science University, New York City, USA
| | - Marwa AlFaraj
- Integrative Medicine, State University of New York (SUNY) Downstate Health Science University, New York City, USA
| | - Samy I McFarlane
- Internal Medicine, Endocrine Division, State University of New York (SUNY) Downstate Health Science University, New York City, USA
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10
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Kawakita E, Kanasaki K. Cancer biology in diabetes update: Focusing on antidiabetic drugs. J Diabetes Investig 2024; 15:525-540. [PMID: 38456597 PMCID: PMC11060166 DOI: 10.1111/jdi.14152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/25/2023] [Accepted: 01/08/2024] [Indexed: 03/09/2024] Open
Abstract
The association of type 2 diabetes with certain cancer risk has been of great interest for years. However, the effect of diabetic medications on cancer development is not fully understood. Prospective clinical trials have not elucidated the long-term influence of hypoglycemic drugs on cancer incidence and the safety for cancer-bearing patients with diabetes, whereas numerous preclinical studies have shown that antidiabetic drugs could have an impact on carcinogenesis processes beyond the glycemic control effect. Because there is no evidence of the safety profile of antidiabetic agents on cancer biology, careful consideration would be required when prescribing any medicines to patients with diabetes and existing tumor. In this review, we discuss the potential influence of each diabetes therapy in cancer 'initiation', 'promotion' and 'progression'.
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Affiliation(s)
- Emi Kawakita
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
| | - Keizo Kanasaki
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
- The Center for Integrated Kidney Research and Advance, Faculty of MedicineShimane UniversityIzumoJapan
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11
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Sonoda A, Shimada T, Saito K, Kosugi R, Taguchi Y, Inoue T. Light and Shadow of Na-Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Points for Improvement Based on Our Clinical Experience. Int J Endocrinol 2024; 2024:3937927. [PMID: 38304078 PMCID: PMC10834091 DOI: 10.1155/2024/3937927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 12/04/2023] [Accepted: 01/04/2024] [Indexed: 02/03/2024] Open
Abstract
We analyzed the effect of Na-glucose cotransporter 2 inhibitors (SGLT2-I) in diabetic patients visiting our hospital. The study included 236 patients treated with SGLT2-I alone or with codiabetic drugs for at least two years. We analyzed overtime changes in glycosylated hemoglobin A1c (HbA1c) in the patients by repeated analyses of variance (ANOVA) and evaluated the therapeutic effect. HbA1c levels decreased significantly in the first six months after treatment. Afterward, they leveled off and increased slightly over the next two years. Six months after treatment, the mean (SD) of HbA1c was 8.19 (1.46) %; the mean difference dropped by 0.91%, and HbA1c in mild DM2 did not drop by below 8.0%. Overall, there was only a slight improvement. We performed multivariate logistic regression analysis using a model with or without improvement as the objective variable and several explanatory variables. Na and Hct were significant factors. They increased considerably over six months and then leveled off. eGFR significantly reduced in the hyperfiltration group six months after treatment. The annual decline rate in eGFR was also faster, even in the nonhyperfiltration group than in the healthy subjects, which may be a characteristic of renal clearance in SGLT2-I treatment. In conclusion, SGLT2-I is an excellent antidiabetic, nephroprotective agent to eliminate hyperfiltration, but unfortunately, SGLT2-I alone does not have enough power to reduce blood glucose levels. SGLT2-I, with insulin or insulin secretagogues, enhances insulin resistance, induces hyperinsulinemia, and exacerbates type 2 DM. In contrast, SGLT2-I, with noninsulin antidiabetic agents and a low-carbohydrate diet, may bring better results.
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Affiliation(s)
- Akihiro Sonoda
- Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
| | - Toshio Shimada
- Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
- Department of Clinical Laboratory, Shizuoka General Hospital, Shizuoka, Japan
| | - Kohei Saito
- Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
- Division of Diabetes, Endocrinology, and Metabolism, Shizuoka General Hospital, Shizuoka, Japan
| | - Rieko Kosugi
- Division of Diabetes, Endocrinology, and Metabolism, Shizuoka General Hospital, Shizuoka, Japan
| | - Yoshitaka Taguchi
- Division of Diabetes, Endocrinology, and Metabolism, Shizuoka General Hospital, Shizuoka, Japan
| | - Tatsuhide Inoue
- Division of Diabetes, Endocrinology, and Metabolism, Shizuoka General Hospital, Shizuoka, Japan
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12
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Podmore L, Poloz Y, Iorio C, Mouaaz S, Nixon K, Smirnov P, McDonnell B, Lam S, Zhang B, Tharmapalan P, Sarkar S, Vyas F, Ennis M, Dowling R, Stambolic V. Insulin receptor loss impairs mammary tumorigenesis in mice. Cell Rep 2023; 42:113251. [PMID: 37913774 DOI: 10.1016/j.celrep.2023.113251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 09/05/2023] [Accepted: 09/27/2023] [Indexed: 11/03/2023] Open
Abstract
Breast cancer (BC) prognosis and outcome are adversely affected by obesity. Hyperinsulinemia, common in the obese state, is associated with higher risk of death and recurrence in BC. Up to 80% of BCs overexpress the insulin receptor (INSR), which correlates with worse prognosis. INSR's role in mammary tumorigenesis was tested by generating MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC mouse models, respectively, with coordinate mammary epithelium-restricted deletion of INSR. In both models, deletion of either one or both copies of INSR leads to a marked delay in tumor onset and burden. Longitudinal phenotypic characterization of mouse tumors and cells reveals that INSR deletion affects tumor initiation, not progression and metastasis. INSR upholds a bioenergetic phenotype in non-transformed mammary epithelial cells, independent of its kinase activity. Similarity of phenotypes elicited by deletion of one or both copies of INSR suggest a dose-dependent threshold for INSR impact on mammary tumorigenesis.
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Affiliation(s)
- Lauren Podmore
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Yekaterina Poloz
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Catherine Iorio
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Samar Mouaaz
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Kevin Nixon
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Petr Smirnov
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Brianna McDonnell
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Sonya Lam
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Bowen Zhang
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Pirashaanthy Tharmapalan
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Soumili Sarkar
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Foram Vyas
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | | | - Ryan Dowling
- Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
| | - Vuk Stambolic
- Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada.
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13
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de Andrade Mesquita L, Wayerbacher LF, Schwartsmann G, Gerchman F. Obesity, diabetes, and cancer: epidemiology, pathophysiology, and potential interventions. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2023; 67:e000647. [PMID: 37364149 PMCID: PMC10660996 DOI: 10.20945/2359-3997000000647] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/22/2023] [Indexed: 06/28/2023]
Abstract
The proportion of deaths attributable to cancer is rising, and malignant neoplasms have become the leading cause of death in high-income countries. Obesity and diabetes are now recognized as risk factors for several types of malignancies, especially endometrial, colorectal, and postmenopausal breast cancers. Mechanisms implicated include disturbances in lipid-derived hormone secretion, sex steroids biosynthesis, hyperinsulinemia, and chronic inflammation. Intentional weight loss is associated with a mitigation of risk for obesity-related cancers, a phenomenon observed specially with bariatric surgery. The impact of pharmacological interventions for obesity and diabetes is not uniform: while metformin seems to protect against cancer, other agents such as lorcaserin may increase the risk of malignancies. However, these interpretations must be carefully considered, since most data stem from bias-prone observational studies, and high-quality randomized controlled trials with appropriate sample size and duration are needed to achieve definite conclusions. In this review, we outline epidemiological and pathophysiological aspects of the relationship between obesity, diabetes, and malignancies. We also highlight pieces of evidence regarding treatment effects on cancer incidence in these populations.
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Affiliation(s)
- Leonardo de Andrade Mesquita
- Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil
| | - Laura Fink Wayerbacher
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Gilberto Schwartsmann
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Fernando Gerchman
- Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil,
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14
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Nguyen HP, Sheng R, Murray E, Ito Y, Bruck M, Biellak C, An K, Lynce F, Dillon DA, Magbanua MJM, Huppert LA, Hammerlindl H, Esserman L, Rosenbluth JM, Ahituv N. Implantation of engineered adipocytes that outcompete tumors for resources suppresses cancer progression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.28.534564. [PMID: 37034710 PMCID: PMC10081280 DOI: 10.1101/2023.03.28.534564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/20/2023]
Abstract
Tumors acquire an increased ability to obtain and metabolize nutrients. Here, we engineered and implanted adipocytes to outcompete tumors for nutrients and show that they can substantially reduce cancer progression. Growing cells or xenografts from several cancers (breast, colon, pancreas, prostate) alongside engineered human adipocytes or adipose organoids significantly suppresses cancer progression and reduces hypoxia and angiogenesis. Transplanting modulated adipocyte organoids in pancreatic or breast cancer mouse models nearby or distal from the tumor significantly suppresses its growth. To further showcase therapeutic potential, we demonstrate that co-culturing tumor organoids derived from human breast cancers with engineered patient-derived adipocytes significantly reduces cancer growth. Combined, our results introduce a novel cancer therapeutic approach, termed adipose modulation transplantation (AMT), that can be utilized for a broad range of cancers.
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Affiliation(s)
- Hai P. Nguyen
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Rory Sheng
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Elizabeth Murray
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Yusuke Ito
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Michael Bruck
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Cassidy Biellak
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Kelly An
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Filipa Lynce
- Dana-Farber Cancer Institute, Harvard University, Boston, MA 02215, USA
| | - Deborah A. Dillon
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Mark Jesus M. Magbanua
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 04158, USA
| | - Laura A. Huppert
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Heinz Hammerlindl
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Laura Esserman
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Jennifer M. Rosenbluth
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Chan Zuckerberg Biohub – San Francisco, San Francisco, CA 94158, USA
| | - Nadav Ahituv
- Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
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15
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Oura K, Morishita A, Tani J, Masaki T. Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1279-1298. [PMID: 36545268 PMCID: PMC9760577 DOI: 10.2147/jhc.s392051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022] Open
Abstract
Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan,Correspondence: Kyoko Oura, Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki, Kida, Kagawa, Japan, Tel +81-87-891-2156, Fax +81-87-891-2158, Email
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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16
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Dobrică EC, Banciu ML, Kipkorir V, Khazeei Tabari MA, Cox MJ, Simhachalam Kutikuppala LV, Găman MA. Diabetes and skin cancers: Risk factors, molecular mechanisms and impact on prognosis. World J Clin Cases 2022; 10:11214-11225. [PMID: 36387789 PMCID: PMC9649529 DOI: 10.12998/wjcc.v10.i31.11214] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/20/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Diabetes and skin cancers have emerged as threats to public health worldwide. However, their association has been less intensively studied. In this narrative review, we explore the common risk factors, molecular mechanisms, and prognosis of the association between cutaneous malignancies and diabetes. Hyperglycemia, oxidative stress, low-grade chronic inflammation, genetic, lifestyle, and environmental factors partially explain the crosstalk between skin cancers and this metabolic disorder. In addition, diabetes and its related complications may interfere with the appropriate management of cutaneous malignancies. Antidiabetic medication seems to exert an antineoplastic effect, however, future large, observation studies with a prospective design are needed to clarify its impact on the risk of malignancy in diabetes. Screening for diabetes in skin cancers, as well as close follow-up for the development of cutaneous malignancies in subjects suffering from diabetes, is warranted.
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Affiliation(s)
- Elena-Codruta Dobrică
- Doctoral School, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
| | - Madalina Laura Banciu
- Department of Dermatology, "Elias" University Emergency Hospital, Bucharest 011461, Romania
| | - Vincent Kipkorir
- Department of Human Anatomy, University of Nairobi, College of Health Sciences, Nairobi 00100, Kenya
| | | | - Madeleine Jemima Cox
- University of New South Wales, University of New South Wales, Sydney 2052, Australia
| | | | - Mihnea-Alexandru Găman
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
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17
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Elkin PL, Mullin S, Tetewsky S, Resendez SD, McCray W, Barbi J, Yendamuri S. Identification of patient characteristics associated with survival benefit from metformin treatment in patients with stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2022; 164:1318-1326.e3. [PMID: 35469597 PMCID: PMC9463413 DOI: 10.1016/j.jtcvs.2022.02.046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 12/31/2021] [Accepted: 02/14/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) continues to be a major cause of cancer deaths. Previous investigation has suggested that metformin use can contribute to improved outcomes in NSCLC patients. However, this association is not uniform in all analyzed cohorts, implying that patient characteristics might lead to disparate results. Identification of patient characteristics that affect the association of metformin use with clinical benefit might clarify the drug's effect on lung cancer outcomes and lead to more rational design of clinical trials of metformin's utility as an intervention. In this study, we examined the association of metformin use with long-term mortality benefit in patients with NSCLC and the possible modulation of this benefit by body mass index (BMI) and smoking status, controlling for other clinical covariates. METHODS This was a retrospective cohort study in which we analyzed data from the Veterans Affairs (VA) Tumor Registry in the United States. Data from all patients with stage I NSCLC from 2000 to 2016 were extracted from a national database, the Corporate Data Warehouse that captures data from all patients, primarily male, who underwent treatment through the VA health system in the United States. Metformin use was measured according to metformin prescriptions dispensed to patients in the VA health system. The association of metformin use with overall survival (OS) after diagnosis of stage I NSCLC was examined. Patients were further stratified according to BMI and smoking status (previous vs current) to examine the association of metformin use with OS across these strata. RESULTS Metformin use was associated with improved survival in patients with stage I NSCLC (average hazard ratio, 0.82; P < .001). An interaction between the effect of metformin use and BMI on OS was observed (χ2 = 3268.42; P < .001) with a greater benefit of metformin use observed in patients as BMI increased. Similarly, an interaction between smoking status and metformin use on OS was also observed (χ2 = 2997.05; P < .001) with a greater benefit of metformin use observed in previous smokers compared with current smokers. CONCLUSIONS In this large retrospective study, we showed that a survival benefit is enjoyed by users of metformin in a robust stage I NSCLC patient population treated in the VA health system. Metformin use was associated with an 18% improved OS. This association was stronger in patients with a higher BMI and in previous smokers. These observations deserve further mechanistic study and can help rational design of clinical trials with metformin in patients with lung cancer.
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Affiliation(s)
- Peter L Elkin
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY; Department of Veterans Affairs, Buffalo, NY; Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY; Faculty of Engineering, University of Southern Denmark, Odense, Denmark.
| | - Sarah Mullin
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY
| | - Sheldon Tetewsky
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY; Department of Veterans Affairs, Buffalo, NY
| | - Skyler D Resendez
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY
| | - Wilmon McCray
- Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY; Department of Veterans Affairs, Buffalo, NY
| | - Joseph Barbi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Sai Yendamuri
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY; Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
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18
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Blonde L, Umpierrez GE, Reddy SS, McGill JB, Berga SL, Bush M, Chandrasekaran S, DeFronzo RA, Einhorn D, Galindo RJ, Gardner TW, Garg R, Garvey WT, Hirsch IB, Hurley DL, Izuora K, Kosiborod M, Olson D, Patel SB, Pop-Busui R, Sadhu AR, Samson SL, Stec C, Tamborlane WV, Tuttle KR, Twining C, Vella A, Vellanki P, Weber SL. American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract 2022; 28:923-1049. [PMID: 35963508 PMCID: PMC10200071 DOI: 10.1016/j.eprac.2022.08.002] [Citation(s) in RCA: 221] [Impact Index Per Article: 73.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.
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Affiliation(s)
| | | | - S Sethu Reddy
- Central Michigan University, Mount Pleasant, Michigan
| | | | | | | | | | | | - Daniel Einhorn
- Scripps Whittier Diabetes Institute, La Jolla, California
| | | | | | - Rajesh Garg
- Lundquist Institute/Harbor-UCLA Medical Center, Torrance, California
| | | | | | | | | | | | - Darin Olson
- Colorado Mountain Medical, LLC, Avon, Colorado
| | | | | | - Archana R Sadhu
- Houston Methodist; Weill Cornell Medicine; Texas A&M College of Medicine; Houston, Texas
| | | | - Carla Stec
- American Association of Clinical Endocrinology, Jacksonville, Florida
| | | | - Katherine R Tuttle
- University of Washington and Providence Health Care, Seattle and Spokane, Washington
| | | | | | | | - Sandra L Weber
- University of South Carolina School of Medicine-Greenville, Prisma Health System, Greenville, South Carolina
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19
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Zhong W, Mao Y. Daily Insulin Dose and Cancer Risk Among Patients With Type 1 Diabetes. JAMA Oncol 2022; 8:1356-1358. [PMID: 35900757 PMCID: PMC9335241 DOI: 10.1001/jamaoncol.2022.2960] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Wenjun Zhong
- Merck Research Labs, Merck & Co Inc, West Point, Pennsylvania
| | - Yuanjie Mao
- Diabetes Institute, Ohio University, Athens.,Diabetes and Endocrinology Clinic, OhioHealth Castrop Center, Athens
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20
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Guo J, Liu C, Pan J, Yang J. Relationship between diabetes and risk of gastric cancer: A systematic review and meta-analysis of cohort studies. Diabetes Res Clin Pract 2022; 187:109866. [PMID: 35398143 DOI: 10.1016/j.diabres.2022.109866] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/16/2022] [Accepted: 04/04/2022] [Indexed: 12/29/2022]
Abstract
Patients with diabetes mellitus (DM) are at increased risk of developing several cancers; however, there is a lack of consensus on the relationship between gastric cancer (GC) and DM. This study aimed to explore the association between GC and DM based on the type and duration of DM. We searched nine databases from inception to December 1, 2021, and 40 cohort studies that evaluated the relationship between DM and the incidence of GC were included in this review. The summary relative ratios for the relationship of GC incidence with type 1 DM (T1DM) and type 2 DM (T2DM) were estimated using the fixed-effect and random-effect models, respectively. The risk of GC was 46% and 14% higher in individuals with T1DM and T2DM, respectively, than in those without diabetes. The risk of GC development in patients with diabetes showed a U-shape curve of change with DM duration. Our meta-analysis suggested that both T1DM and T2DM present a higher risk of GC development. The risk of GC may be influenced by the different time windows following the onset of diabetes. Future studies are required to explore the mechanism by which the duration of DM, antidiabetic medication use, and sex affect this association.
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Affiliation(s)
- Jinru Guo
- School of Medicine, Xiamen University, Xiamen, Fujian, PR China
| | - Changqin Liu
- Department of Endocrinology and Diabetes, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, PR China
| | - Jinshui Pan
- Department of Hepatology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, PR China
| | - Jinqiu Yang
- School of Medicine, Xiamen University, Xiamen, Fujian, PR China.
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21
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Zhu B, Qu S. The Relationship Between Diabetes Mellitus and Cancers and Its Underlying Mechanisms. Front Endocrinol (Lausanne) 2022; 13:800995. [PMID: 35222270 PMCID: PMC8873103 DOI: 10.3389/fendo.2022.800995] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/12/2022] [Indexed: 12/27/2022] Open
Abstract
Epidemiological studies suggest associations between diabetes mellitus and some cancers. The risk of a number of cancers appears to be increased in diabetes mellitus. On the other hand, some cancer and cancer therapies could lead to diabetes mellitus. Genetic factors, obesity, inflammation, oxidative stress, hyperglycemia, hyperinsulinemia, cancer therapies, insulin and some oral hypoglycemic drugs appear to play a role in the crosstalk between diabetes mellitus and cancers. This review summarized the associations between various types of diabetes and cancers and updated available evidence of underlying mechanisms between diabetes and cancers.
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Affiliation(s)
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
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22
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Pretta A, Ziranu P, Puzzoni M, Lai E, Orsi G, Liscia N, Molinaro E, Mariani S, Riggi L, Rovesti G, Dubois M, Migliari M, Persano M, Saba G, Impera V, Musio F, Batzella E, Demurtas L, Pusceddu V, Astara G, Faloppi L, Casadei Gardini A, Andrikou K, Cascinu S, Scartozzi M. Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus. TUMORI JOURNAL 2021; 107:550-555. [PMID: 33243068 DOI: 10.1177/0300891620976945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. METHODS We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. RESULTS In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months (p = 0.03). CONCLUSIONS Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.
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Affiliation(s)
- Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giulia Orsi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Molinaro
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Laura Riggi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Rovesti
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Erich Batzella
- Department of Statistical Science, University of Padova, Padova, Veneto, Italy
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Luca Faloppi
- Department of Medical Oncology, Macerata General Hospital, Macerata, Italy
| | - Andrea Casadei Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Kalliopi Andrikou
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Cascinu
- IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
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Durrani IA, Bhatti A, John P. The prognostic outcome of 'type 2 diabetes mellitus and breast cancer' association pivots on hypoxia-hyperglycemia axis. Cancer Cell Int 2021; 21:351. [PMID: 34225729 PMCID: PMC8259382 DOI: 10.1186/s12935-021-02040-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 06/24/2021] [Indexed: 12/24/2022] Open
Abstract
Type 2 diabetes mellitus and breast cancer are complex, chronic, heterogeneous, and multi-factorial diseases; with common risk factors including but not limited to diet, obesity, and age. They also share mutually inclusive phenotypic features such as the metabolic deregulations resulting from hyperglycemia, hypoxic conditions and hormonal imbalances. Although, the association between diabetes and cancer has long been speculated; however, the exact molecular nature of this link remains to be fully elucidated. Both the diseases are leading causes of death worldwide and a causal relationship between the two if not addressed, may translate into a major global health concern. Previous studies have hypothesized hyperglycemia, hyperinsulinemia, hormonal imbalances and chronic inflammation, as some of the possible grounds for explaining how diabetes may lead to cancer initiation, yet further research still needs to be done to validate these proposed mechanisms. At the crux of this dilemma, hyperglycemia and hypoxia are two intimately related states involving an intricate level of crosstalk and hypoxia inducible factor 1, at the center of this, plays a key role in mediating an aggressive disease state, particularly in solid tumors such as breast cancer. Subsequently, elucidating the role of HIF1 in establishing the diabetes-breast cancer link on hypoxia-hyperglycemia axis may not only provide an insight into the molecular mechanisms underlying the association but also, illuminate on the prognostic outcome of the therapeutic targeting of HIF1 signaling in diabetic patients with breast cancer or vice versa. Hence, this review highlights the critical role of HIF1 signaling in patients with both T2DM and breast cancer, potentiates its significance as a prognostic marker in comorbid patients, and further discusses the potential prognostic outcome of targeting HIF1, subsequently establishing the pressing need for HIF1 molecular profiling-based patient selection leading to more effective therapeutic strategies emerging from personalized medicine.
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Affiliation(s)
- Ilhaam Ayaz Durrani
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan
| | - Attya Bhatti
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan.
| | - Peter John
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan
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24
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Zhang AM, Wellberg EA, Kopp JL, Johnson JD. Hyperinsulinemia in Obesity, Inflammation, and Cancer. Diabetes Metab J 2021; 45:285-311. [PMID: 33775061 PMCID: PMC8164941 DOI: 10.4093/dmj.2020.0250] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.
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Affiliation(s)
- Anni M.Y. Zhang
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Elizabeth A. Wellberg
- Department of Pathology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Harold Hamm Diabetes Center, Oklahoma City, OK, USA
| | - Janel L. Kopp
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - James D. Johnson
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
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25
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Bustamante-Marin XM, Merlino JL, Devericks E, Carson MS, Hursting SD, Stewart DA. Mechanistic Targets and Nutritionally Relevant Intervention Strategies to Break Obesity-Breast Cancer Links. Front Endocrinol (Lausanne) 2021; 12:632284. [PMID: 33815289 PMCID: PMC8011316 DOI: 10.3389/fendo.2021.632284] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 02/17/2021] [Indexed: 12/29/2022] Open
Abstract
The worldwide prevalence of overweight and obesity has tripled since 1975. In the United States, the percentage of adults who are obese exceeds 42.5%. Individuals with obesity often display multiple metabolic perturbations, such as insulin resistance and persistent inflammation, which can suppress the immune system. These alterations in homeostatic mechanisms underlie the clinical parameters of metabolic syndrome, an established risk factor for many cancers, including breast cancer. Within the growth-promoting, proinflammatory milieu of the obese state, crosstalk between adipocytes, immune cells and breast epithelial cells occurs via obesity-associated hormones, angiogenic factors, cytokines, and other mediators that can enhance breast cancer risk and/or progression. This review synthesizes evidence on the biological mechanisms underlying obesity-breast cancer links, with emphasis on emerging mechanism-based interventions in the context of nutrition, using modifiable elements of diet alone or paired with physical activity, to reduce the burden of obesity on breast cancer.
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Affiliation(s)
| | - Jenna L. Merlino
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, United States
| | - Emily Devericks
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, United States
| | - Meredith S. Carson
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, United States
| | - Stephen D. Hursting
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, United States
- Nutrition Research Institute, University of North Carolina, Kannapolis, NC, United States
| | - Delisha A. Stewart
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, United States
- Nutrition Research Institute, University of North Carolina, Kannapolis, NC, United States
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26
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Dąbrowski M. Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors. Int J Mol Sci 2021; 22:1680. [PMID: 33562380 PMCID: PMC7915237 DOI: 10.3390/ijms22041680] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/14/2022] Open
Abstract
In the last decade, cancer became the leading cause of death in the population under 65 in the European Union. Diabetes is also considered as a factor increasing risk of cancer incidence and mortality. Type 2 diabetes is frequently associated with being overweight and obese, which also plays a role in malignancy. Among biological mechanisms linking diabetes and obesity with cancer hyperglycemia, hyperinsulinemia, insulin resistance, increased levels of growth factors, steroid and peptide hormones, oxidative stress and increased activity of pro-inflammatory cytokines are listed. Antidiabetic medications can modulate cancer risk through directly impacting metabolism of cancer cells as well as indirectly through impact on risk factors of malignancy. Some of them are considered beneficial (metformin and thiazolidinedions-with the exception of bladder cancer); on the other hand, excess of exogenous insulin may be potentially harmful, while other medications seem to have neutral impact on cancer risk. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) are increasingly used in the treatment of type 2 diabetes. However, their association with cancer risk is unclear. The aim of this review was to analyze the anticancer potential of this class of drugs, as well as risks of site-specific malignancies associated with their use.
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Affiliation(s)
- Mariusz Dąbrowski
- College of Medical Sciences, University of Rzeszów, Al. Rejtana 16C, 35-959 Rzeszów, Poland
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27
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Affiliation(s)
- Anne Kilvert
- Consultant Physician, Northampton Community Diabetes Team UK
| | - Charles Fox
- Honorary Lecturer, Leicester Diabetes Centre Leicester UK
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28
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Semlitsch T, Engler J, Siebenhofer A, Jeitler K, Berghold A, Horvath K. (Ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev 2020; 11:CD005613. [PMID: 33166419 PMCID: PMC8095010 DOI: 10.1002/14651858.cd005613.pub4] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer insulin analogues may result in fewer macrovascular and microvascular events. OBJECTIVES To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues (insulin glargine U100 and U300, insulin detemir and insulin degludec) with NPH (neutral protamine Hagedorn) insulin (human isophane insulin) in adults with type 2 diabetes mellitus. SEARCH METHODS For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting insulin analogues to NPH in adults with type 2 diabetes mellitus. DATA COLLECTION AND ANALYSIS Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses. MAIN RESULTS We identified 24 RCTs. Of these, 16 trials compared insulin glargine to NPH insulin and eight trials compared insulin detemir to NPH insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to insulin glargine and 1321 people to insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing insulin glargine to NPH insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing insulin detemir to NPH insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, insulin glargine and insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH insulin. Changes in HbA1c were comparable for long-acting insulin analogues and NPH insulin. Insulin glargine compared to NPH insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with insulin detemir compared to NPH insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between insulin-analogues and NPH insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting insulin glargine U300 or insulin degludec with NPH insulin. AUTHORS' CONCLUSIONS While the effects on HbA1c were comparable, treatment with insulin glargine and insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH insulin. Treatment with insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with insulin detemir instead of NPH insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes.
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Affiliation(s)
- Thomas Semlitsch
- Institute of General Practice and Evidence-Based Health Services Research, Medical University of Graz, Graz, Austria
| | - Jennifer Engler
- Institute for General Practice, Goethe University, Frankfurt am Main, Germany
| | - Andrea Siebenhofer
- Institute of General Practice and Evidence-Based Health Services Research, Medical University of Graz, Graz, Austria / Institute of General Practice, Goethe University, Frankfurt am Main, Austria
| | - Klaus Jeitler
- Institute of General Practice and Evidence-Based Health Services Research / Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Andrea Berghold
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Karl Horvath
- Institute of General Practice and Evidence-Based Health Services Research / Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria
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Deshpande RP, Sharma S, Watabe K. The Confounders of Cancer Immunotherapy: Roles of Lifestyle, Metabolic Disorders and Sociological Factors. Cancers (Basel) 2020; 12:E2983. [PMID: 33076303 PMCID: PMC7602474 DOI: 10.3390/cancers12102983] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/06/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
Checkpoint blockade immunotherapy (CPI) is an effective treatment option for many types of cancers. Irrespective of its wide clinical implications, the overall efficacy remains unpredictable and even poor in certain pathologies such as breast cancer. Thus, it is imperative to understand the role of factors affecting its responsiveness. In this review, we provide an overview on the involvement of sociological factors, lifestyles and metabolic disorders in modulating the CPI response in patients from multiple malignancies. Lifestyle habits including exercise, and diet promoted therapeutic responsiveness while alcohol consumption mitigated the CPI effect by decreasing mutational burden and hampering antigen presentation by dendritic cells. Metabolic disorder such as obesity was recognized to enhance the PD-1 expression while diabetes and hypertension were consequences of CPI therapy rather than causes. Among the sociologic factors, sex and race positively influenced the CPI effectiveness on account of increased effector T cell activity and increased PD-1 expression while ageing impaired CPI responsiveness by decreasing functional T cell and increased toxicity. The combined effect of these factors was observed for obesity and gender, in which obese males had the most significant effect of CPI. Therefore these variables should be carefully considered before treating patients with CPI for optimal treatment outcome.
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Affiliation(s)
| | | | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA; (R.P.D.); (S.S.)
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30
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Chiu HY, Chiang CM, Yeh SP, Jong DS, Wu LS, Liu HC, Chiu CH. Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor via the PI3K/AKT pathway in non-small cell lung cancer cells in vitro. Oncol Lett 2020; 20:206. [PMID: 32963612 PMCID: PMC7491043 DOI: 10.3892/ol.2020.12069] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 08/03/2020] [Indexed: 12/29/2022] Open
Abstract
Patients with lung cancer harboring activating epidermal growth factor (EGFR) mutations and pre-existing diabetes have been demonstrated to exhibit poor responses to first-line EGFR-tyrosine kinase inhibitor (TKI) therapy. Strategies for the management of acquired resistance to EGFR-TKIs in patients with advanced non-small cell lung cancer (NSCLC) are urgently required. Only a limited number of studies have been published to date on the effects of insulin on EGFR-TKI resistance in NSCLC. Hence, the aim of the present study was to investigate the roles of hyperinsulinemia and hyperglycemia in mediating gefitinib resistance in NSCLC cells with activating EGFR mutations. In the present study, the HCC4006 cell line, which harbors EGFR mutations, was co-treated with gefitinib and long-acting insulin glargine. Whether hyperinsulinemia is able to mediate EGFR-TKI resistance in the NSCLC cell line harboring activating EGFR mutations was also investigated, and the possible underlying mechanisms responsible for these actions were explored. The inhibition of cell proliferation, and the potential mechanism of gefitinib resistance, were examined using an MTS proliferation assay and western blot analysis, and through the transfection of siRNAs. Whether the inhibition of AKT is able to overcome EGFR-TKI resistance induced by long-acting insulin was also investigated. The results obtained suggested that hyperinsulinemia induced by glargine upregulated NSCLC cell proliferation and survival, and induced gefitinib resistance. By contrast, the morphology and proliferation of the cells in a medium containing a 2-fold concentration of glucose were not significantly affected. Gefitinib resistance induced by hyperinsulinemia may have been mediated via the phosphoinositide 3-kinase (PI3K)/AKT pathway rather than the mitogen-activated protein kinase extracellular signal regulated kinase (MAPK/ERK) pathway. AKT serine/threonine kinase 1 knockdown by siRNA rescued the gefitinib resistance that was induced by hyperinsulinemia. In conclusion, hyperinsulinemia, but not hyperglycemia, was identified to cause the development of gefitinib resistance in NSCLC cells with activating EGFR mutations. However, additional studies are required to investigate strategies, such as co targeting hyperinsulinemia and the PI3K/AKT pathway, for overcoming EGFR-TKI resistance in patients with NSCLC.
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Affiliation(s)
- Hsin-Yi Chiu
- Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan, R.O.C.,Division of Thoracic Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan, R.O.C.,Department of Medical Education, Taipei Medical University Hospital, Taipei 110, Taiwan, R.O.C.,Department of Education and Humanities in Medicine, School of Medicine, Taipei Medical University, Taipei 110, Taiwan, R.O.C.,Department of Surgery, School of Medicine, Taipei Medical University, Taipei 110, Taiwan, R.O.C
| | - Chi-Ming Chiang
- Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan, R.O.C.,Department of Orthopedics Surgery, Cardinal Tien Hospital, New Taipei City 231, Taiwan, R.O.C
| | - Szu-Peng Yeh
- Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan, R.O.C
| | - De-Shien Jong
- Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan, R.O.C
| | - Leang-Shin Wu
- Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan, R.O.C
| | - Hung-Chang Liu
- Division of Thoracic Surgery, Department of Surgery, MacKay Memorial Hospital (Tamsui Branch), New Taipei City 251, Taiwan, R.O.C
| | - Chih-Hsien Chiu
- Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan, R.O.C
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31
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Vigneri R, Sciacca L, Vigneri P. Rethinking the Relationship between Insulin and Cancer. Trends Endocrinol Metab 2020; 31:551-560. [PMID: 32600959 DOI: 10.1016/j.tem.2020.05.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 03/20/2020] [Accepted: 05/13/2020] [Indexed: 12/14/2022]
Abstract
In addition to being a major metabolic hormone, insulin is also a growth factor with a mitogenic effect on all cells, more marked in malignant cells that often overexpress the insulin receptor. In patients with metabolic diseases characterized by hyperinsulinemia (obesity, type 2 diabetes, and metabolic syndrome), the incidence of several types of cancer is increased, as is cancer-related mortality. Because of the worldwide growing prevalence of metabolic diseases and the diffuse use of insulin and its analogs for treating diabetes, the relationship between insulin and cancer has become a clinically relevant issue. Clinical studies have not clarified the degree to which hyperinsulinemia can influence cancer occurrence and prognosis. To better understand this issue, an improved scientific approach is required, with more careful consideration of the mechanisms related to hyperinsulinemia and carcinogenesis.
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Affiliation(s)
- R Vigneri
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.
| | - L Sciacca
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy
| | - P Vigneri
- Center of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, University of Catania, A.O.U. Policlinico Vittorio-Emanuele, Catania, Italy
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Manipulation of Metabolic Pathways and Its Consequences for Anti-Tumor Immunity: A Clinical Perspective. Int J Mol Sci 2020; 21:ijms21114030. [PMID: 32512898 PMCID: PMC7312891 DOI: 10.3390/ijms21114030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 05/28/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023] Open
Abstract
In the relatively short history of anti-tumor treatment, numerous medications have been developed against a variety of targets. Intriguingly, although many anti-tumor strategies have failed in their clinical trials, metformin, an anti-diabetic medication, demonstrated anti-tumor effects in observational studies and even showed its synergistic potential with immune checkpoint inhibitors (ICIs) in subsequent clinical studies. Looking back from bedside-to-bench, it may not be surprising that the anti-tumor effect of metformin derives largely from its ability to rewire aberrant metabolic pathways within the tumor microenvironment. As one of the most promising breakthroughs in oncology, ICIs were also found to exert their immune-stimulatory effects at least partly via rewiring metabolic pathways. These findings underscore the importance of correcting metabolic pathways to achieve sufficient anti-tumor immunity. Herein, we start by introducing the tumor microenvironment, and then we review the implications of metabolic syndrome and treatments for targeting metabolic pathways in anti-tumor therapies. We further summarize the close associations of certain aberrant metabolic pathways with impaired anti-tumor immunity and introduce the therapeutic effects of targeting these routes. Lastly, we go through the metabolic effects of ICIs and conclude an overall direction to manipulate metabolic pathways in favor of anti-tumor responses.
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33
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Srivastava SP, Goodwin JE. Cancer Biology and Prevention in Diabetes. Cells 2020; 9:cells9061380. [PMID: 32498358 PMCID: PMC7349292 DOI: 10.3390/cells9061380] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.
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Affiliation(s)
- Swayam Prakash Srivastava
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
| | - Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
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34
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Lee YN, Chowdhury TA. Diabetes: an Overview for Clinical Oncologists. Clin Oncol (R Coll Radiol) 2020; 32:579-590. [PMID: 32299722 DOI: 10.1016/j.clon.2020.03.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 02/12/2020] [Accepted: 03/20/2020] [Indexed: 12/29/2022]
Abstract
Diabetes and cancer are common conditions highly prevalent in the general population. The co-existence of diabetes and cancer in a patient is therefore not unexpected. Diabetes increases the risk of mortality from cancer and morbidity from the treatment of cancer. Furthermore, many cancer chemotherapeutic regimens increase glucose levels, especially those involving glucocorticoids. Many clinical oncologists will deal with patients with diabetes in their clinical work, and some working knowledge of diabetes diagnosis and management is helpful when managing such patients. This overview aims to summarise the clinical diagnosis and management of diabetes, review the potential links between diabetes and cancer, and provide some practical guidance on the management of hyperglycaemia in patients undergoing cancer therapy.
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Affiliation(s)
- Y-N Lee
- Department of Diabetes and Metabolism, The Royal London Hospital, London, UK
| | - T A Chowdhury
- Department of Diabetes and Metabolism, The Royal London Hospital, London, UK.
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35
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Liu C, Liu Q, Yan A, Chang H, Ding Y, Tao J, Qiao C. Metformin revert insulin-induced oxaliplatin resistance by activating mitochondrial apoptosis pathway in human colon cancer HCT116 cells. Cancer Med 2020; 9:3875-3884. [PMID: 32248666 PMCID: PMC7286444 DOI: 10.1002/cam4.3029] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 03/05/2020] [Accepted: 03/14/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Several studies have suggested that drug resistance in colon cancer patients with diabetes may be associated with long-term insulin administration, which in turn decreases the survival rate. Metformin is a commonly used drug to treat diabetes but has been recently demonstrated to have a potential therapeutic effect on colon cancer. This study aimed to elucidate the underlying mechanism by which metformin reverts insulin-induced oxaliplatin resistance in human colon cancer HCT116 cells. METHODS Two colon cancer cell lines (HCT116 and LoVo) were used to verify whether the expression of insulin receptor substrate 1 (IRS-1) could impact the half maximal inhibitory concentration (IC50) of oxaliplatin after chronic insulin treatment. The IC50 of oxaliplatin in both cell lines was measured to identify metformin sensitization to oxaliplatin. The adenosine monophosphate-activated protein kinase (AMPK) inhibitor, namely AMPK small interfering RNA, was used to block AMPK activation to identify critical proteins in the AMPK/Erk signaling pathway. Bcl-2 is a vital antiapoptotic protein involved in the mitochondrial apoptosis pathway. Finally, immunofluorescence and electron microscopy were performed to investigate how metformin affects the ultrastructural integrity of mitochondria. RESULTS The IC50 of oxaliplatin in HCT116 cells was noticeably increased. After the cells were treated with metformin, oxaliplatin resistance was reversed. According to the results of the western blotting assay of vital proteins involved in the classical apoptosis pathway, cleaved caspase-9 was noticeably upregulated, suggesting that the mitochondrial apoptosis pathway was activated. These results were verified by imaging of mitochondria using electron microscopy. The AMPK/Erk signaling pathway experiments revealed that the upregulation of Bcl-2 induced by insulin through Erk phosphorylation was inhibited by metformin and that such inhibition could be mitigated by the inhibition of AMPK. CONCLUSIONS Insulin-induced oxaliplatin resistance was reversed by metformin-mediated AMPK activation. Accordingly, metformin is likely to sensitize patients with diabetes to chemotherapeutic drugs used to treat colon cancer.
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Affiliation(s)
- Chao Liu
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qianqian Liu
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Aiwen Yan
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hui Chang
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuyin Ding
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Junye Tao
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chen Qiao
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
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36
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Lan ZJ, Lei Z, Yiannikouris A, Yerramreddy TR, Li X, Kincaid H, Eastridge K, Gadberry H, Power C, Xiao R, Lei L, Seale O, Dawson K, Power R. Non-peptidyl small molecule, adenosine, 5'-Se-methyl-5'-seleno-, 2',3'-diacetate, activates insulin receptor and attenuates hyperglycemia in type 2 diabetic Lepr db/db mice. Cell Mol Life Sci 2020; 77:1623-1643. [PMID: 31378829 PMCID: PMC7162833 DOI: 10.1007/s00018-019-03249-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 07/05/2019] [Accepted: 07/23/2019] [Indexed: 12/29/2022]
Abstract
The pathophysiology of type 2 diabetes mellitus (T2D) is characterized by reduced or absent insulin receptor (INSR) responsiveness to its ligand, elevated hepatic glucose output and impaired glucose uptake in peripheral tissues, particularly skeletal muscle. Treatments to reduce hyperglycemia and reestablish normal insulin signaling are much sought after. Any agent which could be orally administered to restore INSR function, in an insulin-independent manner, would have major implications for the management of this global disease. We have discovered a non-peptidyl small molecule, adenosine, 5'-Se-methyl-5'-seleno-, 2',3'-diacetate [referred to as non-peptidyl compound #43 (NPC43)], which restores INSR signaling in the complete absence of insulin. Initial screening of numerous compounds in human HepG2 liver cells revealed that NPC43 significantly inhibited glucose production. The compound was potently anti-hyperglycemic and anti-hyperinsulinemic in vivo, in insulin-resistant T2D Leprdb/db mice, following either acute or chronic treatment by oral gavage and intraperitoneal injection, respectively. The compound acted at the level of INSR and activated it in both liver and skeletal muscle of Leprdb/db mice. In cell culture, the compound activated INSR in both liver and skeletal muscle cells; furthermore, it cooperated with insulin to depress glucose-6-phosphatase catalytic subunit (G6pc) expression and stimulate glucose uptake, respectively. Our results indicated that the compound directly interacted with INSRα, triggering appropriate phosphorylation and activation of the receptor and its downstream targets. Unlike insulin, NPC43 did not activate insulin-like growth factor 1 receptor in either liver or skeletal muscle. We believe this compound represents a potential oral and/or injectable insulin replacement therapy for diabetes and diseases associated with insulin resistance.
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Affiliation(s)
- Zi-Jian Lan
- Division of Life Sciences, Alltech, Inc, 3031 Catnip Hill Road, Nicholasville, KY, 40356, USA.
| | - Zhenmin Lei
- Department of OB/GYN, University of Louisville School of Medicine, MDR Building/Room 121, 511 South Floyd St., Louisville, KY, 40202, USA
| | | | | | - Xian Li
- Department of OB/GYN, University of Louisville School of Medicine, MDR Building/Room 121, 511 South Floyd St., Louisville, KY, 40202, USA
| | - Hayley Kincaid
- Division of Life Sciences, Alltech, Inc, 3031 Catnip Hill Road, Nicholasville, KY, 40356, USA
| | - Katie Eastridge
- Division of Life Sciences, Alltech, Inc, 3031 Catnip Hill Road, Nicholasville, KY, 40356, USA
| | - Hannah Gadberry
- Division of Life Sciences, Alltech, Inc, 3031 Catnip Hill Road, Nicholasville, KY, 40356, USA
| | - Chloe Power
- Division of Life Sciences, Alltech, Inc, 3031 Catnip Hill Road, Nicholasville, KY, 40356, USA
| | - Rijin Xiao
- Division of Life Sciences, Alltech, Inc, 3031 Catnip Hill Road, Nicholasville, KY, 40356, USA
| | - Lei Lei
- Department of OB/GYN, University of Louisville School of Medicine, MDR Building/Room 121, 511 South Floyd St., Louisville, KY, 40202, USA
| | - Olivia Seale
- Division of Life Sciences, Alltech, Inc, 3031 Catnip Hill Road, Nicholasville, KY, 40356, USA
| | - Karl Dawson
- Division of Life Sciences, Alltech, Inc, 3031 Catnip Hill Road, Nicholasville, KY, 40356, USA
- Chemistry Department, Alltech, Inc, Nicholasville, KY, 40356, USA
| | - Ronan Power
- Division of Life Sciences, Alltech, Inc, 3031 Catnip Hill Road, Nicholasville, KY, 40356, USA.
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Bradley MC, Chillarige Y, Lee H, Wu X, Parulekar S, Wernecke M, Bright P, Soukup M, MaCurdy TE, Kelman JA, Graham DJ. Similar Breast Cancer Risk in Women Older Than 65 Years Initiating Glargine, Detemir, and NPH Insulins. Diabetes Care 2020; 43:785-792. [PMID: 32075848 DOI: 10.2337/dc19-0614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 01/26/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To assess whether initiation of insulin glargine (glargine), compared with initiation of NPH or insulin detemir (detemir), was associated with an increased risk of breast cancer in women with diabetes. RESEARCH DESIGN AND METHODS This was a retrospective new-user cohort study of female Medicare beneficiaries aged ≥65 years initiating glargine (203,159), detemir (67,012), or NPH (47,388) from September 2006 to September 2015, with follow-up through May 2017. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for incidence of breast cancer according to ever use, cumulative duration of use, cumulative dose of insulin, length of follow-up time, and a combination of dose and length of follow-up time. RESULTS Ever use of glargine was not associated with an increased risk of breast cancer compared with NPH (HR 0.97; 95% CI 0.88-1.06) or detemir (HR 0.98; 95% CI 0.92-1.05). No increased risk was seen with glargine use compared with either NPH or detemir by duration of insulin use, length of follow-up, or cumulative dose of insulin. No increased risk of breast cancer was observed in medium- or high-dose glargine users compared with low-dose users. CONCLUSIONS Overall, glargine use was not associated with an increased risk of breast cancer compared with NPH or detemir in female Medicare beneficiaries.
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Affiliation(s)
- Marie C Bradley
- Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD
| | | | - Hana Lee
- Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD
| | | | | | | | - Patricia Bright
- Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD
| | - Mat Soukup
- Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD
| | | | | | - David J Graham
- Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD
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Lindauer K, Bartels T, Scherer P, Kabiri M. Development and Validation of an Image Analysis System for the Measurement of Cell Proliferation in Mammary Glands of Rats. Toxicol Pathol 2020; 47:634-644. [PMID: 31409263 DOI: 10.1177/0192623319863129] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Reliable detection and measurement of cell proliferation are essential in the preclinical assessment of carcinogenic risk of therapeutics. In this context, the assessment of mitogenic potential on mammary glands is crucial in the preclinical safety evaluation of novel insulins. The existing manual counting is time-consuming and subject to operator bias. To standardize the processes, make it faster, and resistant to errors, we developed a semiautomated image analysis system (CEPA software, which is open-source) for counting of proliferating cells in photomicrographs of mammary gland sections of rats labeled with Ki-67. We validated the software and met the predefined targets for specificity, accuracy, and reproducibility. In comparison to manual counting, the respective mean differences in absolute labeling indices (LIs) for CEPA software were 3.12% for user 1 and 3.05% for user 2. The respective regression analysis revealed a good correlation between the CEPA software user and manual counting. Moreover, the CEPA software showed enhanced reproducibility between independent users. The interuser variability is centered around 0 and the absolute difference was about 0.53% LI. Based on validation data, our software has superiority to the manual counting and is a valid and reliable tool for the routine analysis of cell proliferation in mammary glands from rats exposed to insulin analogs.
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Affiliation(s)
- Klaus Lindauer
- 1 Sanofi-Aventis Deutschland GmbH, R&D TMED PKDM, Frankfurt, Germany.,The first two authors contributed equally to this work
| | - Thomas Bartels
- 2 Sanofi France, R&D Preclinical Safety, Pathology, Paris, France.,The first two authors contributed equally to this work
| | - Petra Scherer
- 3 Sanofi-Aventis Deutschland GmbH, R&D TIM Global Discovery Pathology, Frankfurt, Germany
| | - Mostafa Kabiri
- 4 Sanofi-Aventis Deutschland GmbH, R&D TIM Transgenic Models and Technology, Frankfurt, Germany
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39
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Lega IC, Lipscombe LL. Review: Diabetes, Obesity, and Cancer-Pathophysiology and Clinical Implications. Endocr Rev 2020; 41:5625127. [PMID: 31722374 DOI: 10.1210/endrev/bnz014] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023]
Abstract
Obesity and diabetes have both been associated with an increased risk of cancer. In the face of increasing obesity and diabetes rates worldwide, this is a worrying trend for cancer rates. Factors such as hyperinsulinemia, chronic inflammation, antihyperglycemic medications, and shared risk factors have all been identified as potential mechanisms underlying the relationship. The most common obesity- and diabetes-related cancers are endometrial, colorectal, and postmenopausal breast cancers. In this review, we summarize the existing evidence that describes the complex relationship between obesity, diabetes, and cancer, focusing on epidemiological and pathophysiological evidence, and also reviewing the role of antihyperglycemic agents, novel research approaches such as Mendelian Randomization, and the methodological limitations of existing research. In addition, we also describe the bidirectional relationship between diabetes and cancer with a review of the evidence summarizing the risk of diabetes following cancer treatment. We conclude this review by providing clinical implications that are relevant for caring for patients with obesity, diabetes, and cancer and provide recommendations for improving both clinical care and research for patients with these conditions.
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Affiliation(s)
- Iliana C Lega
- Department of Medicine, Women's College Hospital, Toronto, ON, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada.,IC/ES, Toronto, ON, Canada
| | - Lorraine L Lipscombe
- Department of Medicine, Women's College Hospital, Toronto, ON, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada.,IC/ES, Toronto, ON, Canada.,Institute for Health Policy, Management and Evaluation, University of Toronto; Toronto, ON, Canada
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40
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Cheng Y, Chen Y, Zhou C, Shen L, Tu F, Xu J, Liu C. For colorectal cancer patients with type II diabetes, could metformin improve the survival rate? A meta-analysis. Clin Res Hepatol Gastroenterol 2020; 44:73-81. [PMID: 31300371 DOI: 10.1016/j.clinre.2019.06.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/04/2019] [Accepted: 06/13/2019] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Current research is controversial about whether metformin can improve the survival rate of patients with colon cancer. Therefore, we conducted a meta-analysis to identify the association between metformin and the survival rate of colorectal cancer (CRC) patients with type II diabetes. METHODS We conducted a search in databases including Pubmed, EMBASE and Cochrane Library. All articles were published in the last decade, and the quality of each study was evaluated by the Newcastle-Ottawa Scale. Odds ratios (ORs) and its corresponding 95% confidence intervals (CIs) for each study were calculated and summary relative risk estimates with corresponding 95% CIs were generated using the random-effects model. Heterogeneity and publication bias were assessed. RESULTS Ten articles were included in this meta-analysis. The included articles were all cohort studies. In a pooled analysis of all studies, metformin using was associated with increased overall survival (OS) rate (OR, 0.54; 95% CI, 0.47 to 0.63) and cancer-specific survival (CS) rate (OR 0.59; 95% CI 0.43 to 0.82) of CRC patients with diabetes. We found that the effect of metformin is associated with geographical region through subgroup meta-analysis. CONCLUSIONS Metformin using was associated with an increased OS rate and CS rate of colorectal cancer.
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Affiliation(s)
- Yifan Cheng
- Department of Coloproctology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yanyu Chen
- Department of Coloproctology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chongjun Zhou
- Department of Coloproctology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Leibin Shen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Fuyang Tu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jingxuan Xu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Changbao Liu
- Department of Coloproctology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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41
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Al-Qadsy I, Saeed WS, Al-Odayni AB, Ahmed Saleh Al-Faqeeh L, Alghamdi AA, Farooqui M. Novel Metformin-Based Schiff Bases: Synthesis, Characterization, and Antibacterial Evaluation. MATERIALS 2020; 13:ma13030514. [PMID: 31978979 PMCID: PMC7040619 DOI: 10.3390/ma13030514] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 01/15/2020] [Accepted: 01/17/2020] [Indexed: 12/13/2022]
Abstract
Novel Schiff bases of metformin hydrochloride and (ortho)para-nitrobenzaldehyde were synthesized by employing two efficient environmentally friendly methods, namely, stirring and microwave-assisted methods using water as the solvent. The advantage of microwave irradiation over the other methods was represented in the reduction of reaction time and wastes, and good yields; however, water in both methods plays the role of eco-friendly solvent. The structural properties of the (ortho)para-isomer products were analyzed by elemental analysis, Fourier transform infrared (FTIR) spectroscopy, UV-Visible (UV-Vis) spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, 13C NMR spectroscopy, mass spectroscopy, and differential scanning calorimetry (DSC). The newly synthesized compounds were screened for their antibacterial activity against selected Gram-positive (ATCC 25923, ATCC 43300, and ATCC 29212) and Gram-negative (ATCC 25922, ATCC 27853, and ATCC 700603) bacteria using the agar well diffusion method. Compared with the standard drug streptomycin, both Schiff bases exhibited moderate bactericidal activity against the tested bacteria with higher values of ortho-nitro compared with the para-nitro isomer; however, no effect on ATCC 43300 and ATCC 27853 was observed under the experimental conditions employed.
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Affiliation(s)
- Inas Al-Qadsy
- Maulana Azad of Arts, Science and Commerce, P.O. Box 27, Aurangabad 431001, India;
| | - Waseem Sharaf Saeed
- Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (W.S.S.); (A.A.A.)
| | - Abdel-Basit Al-Odayni
- Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (W.S.S.); (A.A.A.)
- Correspondence: (A.-B.A.-O.); (M.F.)
| | - Lena Ahmed Saleh Al-Faqeeh
- Microbiology Department, Dr. Babasaheb Ambedkar Marathwada University, P.O. Box 27, Aurangabad 431004, India;
| | - Abdulaziz Ali Alghamdi
- Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; (W.S.S.); (A.A.A.)
| | - Mazahar Farooqui
- Maulana Azad of Arts, Science and Commerce, P.O. Box 27, Aurangabad 431001, India;
- Correspondence: (A.-B.A.-O.); (M.F.)
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Zerem E. Dilemmas about instructions for administering drugs and indications for their use: is there negative effect of pharmaceutical industry? Clin Transl Med 2020; 9:11. [PMID: 32002701 PMCID: PMC6992826 DOI: 10.1186/s40169-020-0267-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/24/2020] [Indexed: 11/30/2022] Open
Abstract
Instructions for administering some drugs and indications for their use raise certain dilemmas and controversies questioning the appropriateness of the treatment in this way. In this article, some controversies regarding the prescribing of statins in patients whose blood cholesterol level is normal and the use of anticoagulants in the elderly patients without blood clots prior to the treatment are described. Also, it is discussed about some controversies regarding the use of the insulin analogues in the treatment of patients with diabetes mellitus.
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Affiliation(s)
- Enver Zerem
- Department of Medical SciencesThe Academy of Sciences and Arts of Bosnia and HerzegovinaBistrik 771000SarajevoBosnia and Herzegovina
- Department of Internal MedicineCantonal Hospital Safet Mujić88000MostarBosnia and Herzegovina
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43
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Yee LD, Mortimer JE, Natarajan R, Dietze EC, Seewaldt VL. Metabolic Health, Insulin, and Breast Cancer: Why Oncologists Should Care About Insulin. Front Endocrinol (Lausanne) 2020; 11:58. [PMID: 32153503 PMCID: PMC7045050 DOI: 10.3389/fendo.2020.00058] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 01/29/2020] [Indexed: 12/13/2022] Open
Abstract
Studies investigating the potential link between adult pre-menopausal obesity [as measured by body mass index (BMI)] and triple-negative breast cancer have been inconsistent. Recent studies show that BMI is not an exact measure of metabolic health; individuals can be obese (BMI > 30 kg/m2) and metabolically healthy or lean (BMI < 25 kg/m2) and metabolically unhealthy. Consequently, there is a need to better understand the molecular signaling pathways that might be activated in individuals that are metabolically unhealthy and how these signaling pathways may drive biologically aggressive breast cancer. One key driver of both type-2 diabetes and cancer is insulin. Insulin is a potent hormone that activates many pathways that drive aggressive breast cancer biology. Here, we review (1) the controversial relationship between obesity and breast cancer, (2) the impact of insulin on organs, subcellular components, and cancer processes, (3) the potential link between insulin-signaling and cancer, and (4) consider time points during breast cancer prevention and treatment where insulin-signaling could be better controlled, with the ultimate goal of improving overall health, optimizing breast cancer prevention, and improving breast cancer survival.
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Jensen MH, Hejlesen O, Vestergaard P. Risk of major cardiovascular events, severe hypoglycaemia, and all-cause mortality for users of insulin degludec versus insulin glargine U100-A Danish cohort study. Diabetes Metab Res Rev 2020; 36:e3225. [PMID: 31647163 DOI: 10.1002/dmrr.3225] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/06/2019] [Accepted: 09/14/2019] [Indexed: 12/29/2022]
Abstract
AIMS Real-world evidence of the safety of insulin degludec compared with insulin glargine U100 is sparse. This study sought to investigate the risk of major cardiovascular events, severe hypoglycaemia, and all-cause mortality after initiation of degludec or glargine U100 in the population of Denmark. MATERIALS AND METHODS All Danish people with diabetes initiating treatment on degludec (n=5159) or glargine (n=4041) in 2016 to 2017 were included in the study. The effect of insulin treatment on the endpoints of major cardiovascular events, severe hypoglycaemia, and all-cause mortality was analysed with Cox proportional hazard models. The models were adjusted for age, sex, diabetes duration, diabetes type, highest completed education, and annual income. The model of severe hypoglycaemia was also adjusted for severe hypoglycaemia prior to baseline. The model of mortality was also adjusted for history of alcohol abuse, use of antidepressants, use of opioids, and use of anxiolytics. Lastly, the models of major cardiovascular events and mortality were also adjusted for Charlson comorbidity index. RESULTS Use of degludec resulted in an almost twofold decrease in risk of death (hazard rate [HR]: 0.54, 95% CI: 0.44-0.65) compared with use of glargine. No statistically significant risk changes were found for major cardiovascular events (HR: 0.86, 95% CI: 0.62-1.19) and severe hypoglycaemia (HR: 1.13, 95% CI: 0.66-1.93). The proportion of cause of death due to malignant neoplasm of pancreas was almost doubled for glargine compared with degludec. CONCLUSIONS These results indicate that insulin degludec has a safer profile with respect to all-cause mortality as compared with insulin glargine U100.
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Affiliation(s)
- Morten Hasselstrøm Jensen
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Ole Hejlesen
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Peter Vestergaard
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
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Pradhan R, Yin H, Yu OHY, Azoulay L. The Use of Long-Acting Insulin Analogs and the Risk of Colorectal Cancer Among Patients with Type 2 Diabetes: A Population-Based Cohort Study. Drug Saf 2019; 43:103-110. [DOI: 10.1007/s40264-019-00892-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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47
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Liu YC, Nguyen PA, Humayun A, Chien SC, Yang HC, Asdary RN, Syed-Abdul S, Hsu MH, Moldovan M, Yen Y, Li YC(J, Jian WS, Iqbal U. Does long-term use of antidiabetic drugs changes cancer risk? Medicine (Baltimore) 2019; 98:e17461. [PMID: 31577776 PMCID: PMC6783244 DOI: 10.1097/md.0000000000017461] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Antidiabetic medications are commonly used around the world, but their safety is still unclear. The aim of this study was to investigate whether long-term use of insulin and oral antidiabetic medications is associated with cancer risk.We conducted a well-designed case-control study using 12 years of data from Taiwan's National Health Insurance Research Database and investigated the association between antidiabetic medication use and cancer risk over 20 years. We identified 42,500 patients diagnosed with cancer and calculated each patient's exposure to antidiabetic drugs during the study period. We matched cancer and noncancer subjects matched 1:6 by age, gender, and index date, and used Cox proportional hazard regression and conditional logistic regression, adjusted for potential confounding factors, that is, medications and comorbid diseases that could influence cancer risk during study period.Pioglitazone (adjusted odds ratio [AOR], 1.20; 95% confidence interval [CI], 1.05-1.38); and insulin and its analogs for injection, intermediate or long acting combined with fast acting (AOR, 1.22; 95% CI, 1.05-1.43) were significantly associated with a higher cancer risk. However, metformin (AOR, 1.00; 95% CI, 0.93-1.07), glibenclamide (AOR, 0.98; 95% CI, 0.92-1.05), acarbose (AOR, 1.06; 95% CI, 0.96-1.16), and others do not show evidence of association with cancer risk. Moreover, the risk for specific cancers among antidiabetic users as compared with nonantidiabetic medication users was significantly increased for pancreas cancer (by 45%), liver cancer (by 32%), and lung cancer (by 18%).Antidiabetic drugs do not seem to be associated with an increased cancer risk incidence except for pioglitazone, insulin and its analogs for injection, intermediate or long acting combined with fast acting.
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Affiliation(s)
- Yi-Chun Liu
- Division of Nephrology, Department of Internal Medicine, Yuan's General Hospital, Kaohsiung City
| | - Phung-Anh Nguyen
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Ayesha Humayun
- Department of Public Health and Community Medicine, Shaikh Khalifa Bin Zayed Al-Nahyan Medical College, Shaikh Zayed Medical Complex, Lahore, Pakistan
| | - Shuo-Chen Chien
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- International Center for Health Information Technology (ICHIT)
| | - Hsuan-Chia Yang
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- International Center for Health Information Technology (ICHIT)
| | - Rahma Novita Asdary
- Masters Program in Global Health & Department, College of Public Health, Taipei Medical University, Taipei
| | - Shabbir Syed-Abdul
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- International Center for Health Information Technology (ICHIT)
| | - Min-Huei Hsu
- Graduate Institute of Data Science
- Research Center of Artificial Intelligence in Medicine and Health (TAIMH), Taipei Medical University, Taipei, Taiwan
| | - Max Moldovan
- South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Yun Yen
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University
- Taipei Medical University Research Center of Cancer Translational Medicine
| | - Yu-Chuan (Jack) Li
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- International Center for Health Information Technology (ICHIT)
- Research Center of Artificial Intelligence in Medicine and Health (TAIMH), Taipei Medical University, Taipei, Taiwan
- Department of Dermatology, Wan Fang Hospital
| | - Wen-Shan Jian
- School of Health Care Administration, Taipei Medical University, Taipei, Taiwan
- Faculty of Health Sciences, Macau University of Science and Technology, Macau
| | - Usman Iqbal
- Department of Public Health and Community Medicine, Shaikh Khalifa Bin Zayed Al-Nahyan Medical College, Shaikh Zayed Medical Complex, Lahore, Pakistan
- International Center for Health Information Technology (ICHIT)
- Masters Program in Global Health & Development Department, PhD Program in Global Health and Health Security, College of Public Health, Taipei Medical University, Taipei, Taiwan
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Bykov K, He M, Franklin JM, Garry EM, Seeger JD, Patorno E. Glucose-lowering medications and the risk of cancer: A methodological review of studies based on real-world data. Diabetes Obes Metab 2019; 21:2029-2038. [PMID: 31062453 PMCID: PMC6684441 DOI: 10.1111/dom.13766] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/23/2019] [Accepted: 05/02/2019] [Indexed: 12/13/2022]
Abstract
AIM To review the methodology of observational studies examining the association between glucose-lowering medications and cancer to identify the most common methodological challenges and sources of bias. METHODS We searched PubMed systematically to identify observational studies on glucose-lowering medications and cancer published between January 2000 and January 2016. We assessed the design and analytical methods used in each study, with a focus on their ability to achieve study validity, and further evaluated the prevalence of major methodological choices over time. RESULTS Of 155 studies evaluated, only 26% implemented a new-user design, 41% used an active comparator, 33% implemented a lag or latency period, and 51% adjusted for diabetes duration. Potential for immortal person-time bias was identified in 63% of the studies; 55% of the studies adjusted for variables measured during the follow-up without appropriate statistical methods. Aside from a decreasing trend in adjusting for variables measured during the follow-up, we observed no trends in methodological choices over time. CONCLUSIONS The prevalence of well-known design and analysis flaws that may lead to biased results remains high among observational studies on glucose-lowering medications and cancer, limiting the conclusions that can be drawn from these studies. Avoiding known pitfalls could substantially improve the quality and validity of real-world evidence in this field.
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Affiliation(s)
- Katsiaryna Bykov
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mengdong He
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jessica M Franklin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | | | | | - Elisabetta Patorno
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Sheng X, Yao K, Shao A, Tu S, Zhang X, Chen T, Yao D. The Role of Insulin Glargine and Human Insulin in the Regulation of Thyroid Proliferation Through Mitogenic Signaling. Front Endocrinol (Lausanne) 2019; 10:594. [PMID: 31555212 PMCID: PMC6723759 DOI: 10.3389/fendo.2019.00594] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 08/13/2019] [Indexed: 12/29/2022] Open
Abstract
Our aim was to investigate whether human insulin (HI) or insulin glargine treatment could promote the proliferation of thyroid cells and determine the association between type 2 diabetes and thyroid disease. Rats were treated with different doses of HI and insulin glargine. Plasma glucose and the phosphorylation levels of the insulin receptor (IR), insulin-like growth factor 1 receptor (IGF-1R), protein kinase B (Akt), and extracellular signal-regulated kinase 1/2 (ERK1/2) were measured. A total of 105 rats were randomly assigned to three groups as follows: control group, HI group, and glargine group. Both drugs promoted the phosphorylation of IR, Akt, and ERK1/2 in a dose-dependent manner (p < 0.05), and the effect of glargine persisted for longer period. Treatment with ultra-therapeutic doses of HI or glargine (p < 0.05) increased the expression of Ki-67 in thyroid cells. The results demonstrated that therapeutic doses of glargine have a longer-lasting hypoglycemic control than HI. Based on the results, HI or glargine did not stimulate thyroid cell proliferation at therapeutic doses, but high doses did.
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Affiliation(s)
- Xiaoli Sheng
- Department of Obstetrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Kannan Yao
- The Second Central Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Anwen Shao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Tu
- Department of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xinxia Zhang
- Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ting Chen
- Department of Ultrasonography, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Dingguo Yao
- Department of Endocrinology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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Chowdhury TA, Jacob P. Challenges in the management of people with diabetes and cancer. Diabet Med 2019; 36:795-802. [PMID: 30706527 DOI: 10.1111/dme.13919] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2019] [Indexed: 12/17/2022]
Abstract
Although micro- and macrovascular complications of diabetes are the most important cause of mortality and morbidity in people with diabetes, it is increasingly recognized that diabetes increases the risk of developing cancer. Diabetes and cancer commonly co-exist, and outcomes in people with both conditions are poorer than in those who have cancer but no diabetes. There is no randomized trial evidence that treating hyperglycaemia in people with cancer improves outcomes, but therapeutic nihilism should be avoided, and a personalized approach to managing hyperglycaemia in people with cancer is needed. This review aims to outline the link between diabetes therapies and cancer, and discuss the reasons why glucose should be actively managed people with both. In addition, we discuss clinical challenges in the management of hyperglycaemia in cancer, specifically in relation to glucocorticoids, enteral feeding and end-of-life care.
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Affiliation(s)
- T A Chowdhury
- Department of Diabetes and Metabolism, Barts and the London School of Medicine and Dentistry, London, UK
| | - P Jacob
- Department of Diabetes and Metabolism, Barts and the London School of Medicine and Dentistry, London, UK
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