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Mostafaei Z, Paknahad Z, Majdizadeh G, Djazayery A, Movahedi A. Dietary Antioxidant Minerals (Cr, Mg, Cu, Se, Zn) in Diabetic Children and their Relationship with Fasting and Postprandial Blood Glucose. Int J Prev Med 2025; 16:24. [PMID: 40376080 PMCID: PMC12080940 DOI: 10.4103/ijpvm.ijpvm_119_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 12/18/2024] [Indexed: 05/18/2025] Open
Abstract
Background Dietary micronutrient levels can influence glucose and insulin regulation. Studies show micronutrients can have a positive effect on blood sugar control. This study aimed to investigate the relationship between blood sugar levels and dietary antioxidant minerals (Cr, Mg, Cu, Se, Zn) in children with type 1 diabetes. Methods This cross-sectional study was conducted on 82 children aged 3-18 with type 1 diabetes. A three-day food record was used to collect dietary information. Fasting blood sugar and 2-hour postprandial glucose were recorded by parents. Dietary data were extracted by N4. SPSS Version 27 was used for all statistical analyses. Results The average age of subjects was 10/3 ± 3/3 years. According to the comparison of intake amounts of antioxidant minerals based on age and sex with Recommended Dietary Allowance (RDA), most children reported enough intake. A significant positive relationship was observed between the intake of copper and 2 hours of blood sugar after breakfast (P values < 0.05). We found a significant relationship between intake of chromium, magnesium, selenium, and zinc with blood sugar levels, after adjusting for confounding variables (P values < 0.05). Conclusions The amount of dietary antioxidant minerals in most children was within the appropriate range compared with the RDA. There is a significant relationship between dietary antioxidant minerals (chromium, magnesium, selenium, and zinc) and fasting and postprandial blood glucose after adjusting for confounding variables.
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Affiliation(s)
- Zahra Mostafaei
- Department of Nutrition, Science and Research Branch Islamic Azad University, Tehran, Iran
| | - Zamzam Paknahad
- Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Golnaz Majdizadeh
- Department of Nutrition, Science and Research Branch Islamic Azad University, Tehran, Iran
| | - Abolghasem Djazayery
- Department of Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ariyo Movahedi
- Department of Nutrition, Science and Research Branch Islamic Azad University, Tehran, Iran
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Wang X, Zeng Z, Li D, Wang K, Zhang W, Yu Y, Wang X. Advancements and Challenges in Immune Protection Strategies for Islet Transplantation. J Diabetes 2025; 17:e70048. [PMID: 39829227 PMCID: PMC11744047 DOI: 10.1111/1753-0407.70048] [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: 09/23/2024] [Revised: 12/16/2024] [Accepted: 12/31/2024] [Indexed: 01/22/2025] Open
Abstract
Pancreatic islet transplantation is a crucial treatment for managing type 1 diabetes (T1D) in clinical settings. However, the limited availability of human cadaveric islet donors and the need for ongoing administration of immunosuppressive agents post-transplantation hinder the widespread use of this treatment. Stem cell-derived islet organoids have emerged as an effective alternative to primary human islets. Nevertheless, implementing this cell replacement therapy still requires chronic immune suppression, which may result in life-long side effects. To address these challenges, innovations such as encapsulation devices, universal stem cells, and immunomodulatory strategies are being developed to mitigate immune rejection and prolong the function of the transplant. This review outlines the contemporary challenges in pancreatic β cell therapy, particularly immune rejection, and recent progress in immune-isolation devices, hypoimmunogenic stem cells, and immune regulation of transplants. A comprehensive evaluation of the advantages and limitations of these approaches will contribute to improved future clinical investigations. With these promising advancements, the application of pancreatic β cell therapy holds the potential to effectively treat T1D and benefit a larger population of T1D patients.
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Affiliation(s)
- Xue Wang
- State Key Laboratory of Female Fertility Promotion, Department of Obstetrics and Gynecology, Clinical Stem Cell Research CenterPeking University Third HospitalBeijingChina
| | - Ziyuan Zeng
- State Key Laboratory of Female Fertility Promotion, Department of Obstetrics and Gynecology, Clinical Stem Cell Research CenterPeking University Third HospitalBeijingChina
| | - Dayan Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and RemodelingClinical Stem Cell Research Center, Peking University Third Hospital, Peking UniversityBeijingChina
| | - Kai Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and RemodelingClinical Stem Cell Research Center, Peking University Third Hospital, Peking UniversityBeijingChina
- Beijing Advanced Center of Cellular Homeostasis and Aging‐Related DiseasesPeking UniversityBeijingChina
| | - Wei Zhang
- TianXinFu (Beijing) Medical Appliance co. Ltd.BeijingChina
| | - Yang Yu
- State Key Laboratory of Female Fertility Promotion, Department of Obstetrics and Gynecology, Clinical Stem Cell Research CenterPeking University Third HospitalBeijingChina
- Beijing Advanced Center of Cellular Homeostasis and Aging‐Related DiseasesPeking UniversityBeijingChina
| | - Xi Wang
- State Key Laboratory of Female Fertility Promotion, Department of Obstetrics and Gynecology, Clinical Stem Cell Research CenterPeking University Third HospitalBeijingChina
- Beijing Advanced Center of Cellular Homeostasis and Aging‐Related DiseasesPeking UniversityBeijingChina
- Institute of Advanced Clinical Medicine, Peking UniversityBeijingChina
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Pathak P, Thampy R, Schat R, Bellin M, Beilman G, Hosseini N, Spilseth B. Transplantation for type 1 diabetes: radiologist's primer on islet, pancreas and pancreas-kidney transplantation imaging. Abdom Radiol (NY) 2024; 49:3637-3665. [PMID: 38806704 DOI: 10.1007/s00261-024-04368-8] [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: 03/30/2024] [Revised: 04/29/2024] [Accepted: 05/03/2024] [Indexed: 05/30/2024]
Abstract
Whole-organ pancreas, pancreatic-kidney and islet transplantation are surgical therapeutic options for the treatment of type 1 diabetes. They can enable effective glycemic control, improve quality of life and delay/reduce the secondary complications of type 1 diabetes mellitus. Radiologists are integral members of the multidisciplinary transplantation team involved in these procedures, with multimodality imaging serving as the mainstay for early recognition and management of transplant related complications. This review highlights the transplantation procedures available for patients with type 1 Diabetes Mellitus with a focus on the imaging appearance of transplantation-related complications.
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Affiliation(s)
- Priya Pathak
- Department of Radiology, Body Imaging Division, University of Minnesota Medical School, 420 Delaware St SE, Minneapolis, MN, 55455, USA.
| | - Rajesh Thampy
- Department of Radiology, Body Imaging Division, University of Minnesota Medical School, 420 Delaware St SE, Minneapolis, MN, 55455, USA
| | - Robben Schat
- Department of Radiology, Body Imaging Division, University of Minnesota Medical School, 420 Delaware St SE, Minneapolis, MN, 55455, USA
| | - Melena Bellin
- Department of Pediatric Endocrinology, and Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Greg Beilman
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | | | - Benjamin Spilseth
- Department of Radiology, Body Imaging Division, University of Minnesota Medical School, 420 Delaware St SE, Minneapolis, MN, 55455, USA
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Gu L, Du Y, Liang F. Meta-Analysis and Network Analysis Differentially Detect Various Pro-Inflammatory Mediators and Risk Factors for Type 2 Diabetes in the Elderly. Horm Metab Res 2024; 56:727-736. [PMID: 38195796 DOI: 10.1055/a-2241-5281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
Type 2 diabetes (T2D) has a pathophysiological component that includes inflammation. Inflammation-sensitive marker measurement may be helpful in determining the risk of complications for both older T2D patients and the public. This study aimed to investigate the association between blood pro-inflammatory mediators and the characteristics of elderly patients with T2D using meta and network analyses. The Web of Science, Scopus, PubMed, and Cochrane Library databases were selected as study methodology. The Quality in Prognosis Studies (QUIPS) tool in the meta-analysis assessed the studies' methodological quality. The selected studies were statistically analyzed using the META-MAR tool based on the standardized mean difference (SMD). The selected studies included nine examinations involving 6399 old people [+>+55 years old, 65.9+±+4.09 (mean+±+SD)]. The meta-analysis showed that pro-inflammatory mediators (SMD 0.82) and patient-related variables [risk factors (SMD 0.71)] were significantly associated with T2D (p+<+0.05). Subgroup analysis revealed that tumor necrosis factor alpha (TNF-α; SMD 1.08), body mass index (SMD 0.64), high-density lipoprotein (HDL; SMD -0.61), body weight (SMD 0.50), and blood pressure (SMD 1.11) were factors significantly associated with T2D (p+<+0.05). Network analysis revealed that among patient characteristics, diastolic blood pressure and, among inflammatory mediators, leptin were the most closely associated factors with T2D in older adults. Moreover, network analysis showed that TNF-α and systolic blood pressure were most closely associated with leptin. Overall, alternate techniques, such as meta-analysis and network analysis, might identify different markers for T2D in older people. A therapeutic decision-making process needs to consider these differences in advance.
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Affiliation(s)
- Linlin Gu
- Endocrine Metabolism Department and Geriatric Department, 7th People's Hospital of Chengdu, Chengdu, China
| | - Yue Du
- Endocrine Metabolism Department and Geriatric Department, 7th People's Hospital of Chengdu, Chengdu, China
| | - Fang Liang
- General Medicine Department, 7th People's Hospital of Chengdu, Chengdu, China
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Ho BX, Teo AKK, Ng NHJ. Innovations in bio-engineering and cell-based approaches to address immunological challenges in islet transplantation. Front Immunol 2024; 15:1375177. [PMID: 38650946 PMCID: PMC11033429 DOI: 10.3389/fimmu.2024.1375177] [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: 01/23/2024] [Accepted: 03/11/2024] [Indexed: 04/25/2024] Open
Abstract
Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness and high risk of severe hypoglycemia. However, intensive immunosuppression is required to prevent immune rejection of the graft, that may in turn lead to undesirable side effects such as toxicity to the islet cells, kidney toxicity, occurrence of opportunistic infections, and malignancies. The shortage of cadaveric human islet donors further limits islet transplantation as a treatment option for widespread adoption. Alternatively, porcine islets have been considered as another source of insulin-secreting cells for transplantation in T1D patients, though xeno-transplants raise concerns over the risk of endogenous retrovirus transmission and immunological incompatibility. As a result, technological advancements have been made to protect transplanted islets from immune rejection and inflammation, ideally in the absence of chronic immunosuppression, to improve the outcomes and accessibility of allogeneic islet cell replacement therapies. These include the use of microencapsulation or macroencapsulation devices designed to provide an immunoprotective environment using a cell-impermeable layer, preventing immune cell attack of the transplanted cells. Other up and coming advancements are based on the use of stem cells as the starting source material for generating islet cells 'on-demand'. These starting stem cell sources include human induced pluripotent stem cells (hiPSCs) that have been genetically engineered to avoid the host immune response, curated HLA-selected donor hiPSCs that can be matched with recipients within a given population, and multipotent stem cells with natural immune privilege properties. These strategies are developed to provide an immune-evasive cell resource for allogeneic cell therapy. This review will summarize the immunological challenges facing islet transplantation and highlight recent bio-engineering and cell-based approaches aimed at avoiding immune rejection, to improve the accessibility of islet cell therapy and enhance treatment outcomes. Better understanding of the different approaches and their limitations can guide future research endeavors towards developing more comprehensive and targeted strategies for creating a more tolerogenic microenvironment, and improve the effectiveness and sustainability of islet transplantation to benefit more patients.
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Affiliation(s)
- Beatrice Xuan Ho
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- BetaLife Pte Ltd, Singapore, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Natasha Hui Jin Ng
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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Luiro K, Auvinen AM, Auvinen J, Jokelainen J, Järvelä I, Knip M, Tapanainen JS. Autoantibodies predict type 1 diabetes after gestational diabetes - a 23-year cohort study. Front Endocrinol (Lausanne) 2023; 14:1286375. [PMID: 38192417 PMCID: PMC10773701 DOI: 10.3389/fendo.2023.1286375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 12/04/2023] [Indexed: 01/10/2024] Open
Abstract
Objective To study the predictive value of autoantibodies for type 1 (T1DM) and type 2 (T2DM) diabetes morbidity after gestational diabetes (GDM) in a 23-year follow-up study. Design Prospective population-based cohort study. Methods We studied 391 women with GDM, and 391 age- and parity-matched controls, who delivered in 1984-1994. Four autoantibodies were analysed in first-trimester blood samples: islet cell autoantibodies (ICAs), glutamic acid decarboxylase autoantibodies (GADAs), insulin autoantibodies (IAAs) and insulinoma-associated antigen-2 autoantibodies (IA-2As). Two follow-up questionnaires (1995-1996, 2012-2013) were sent to assess development of T1DM and T2DM. Predictive value of autoantibodies and clinical factors were analysed by conditional linear regression and ROC analyses. Results Single autoantibody positivity was detected in 12% (41/342) of the GDM cohort and in 2.3% (8/353) of the control cohort. In the GDM cohort, 2.6% (9/342) tested positive for two autoantibodies and 2.3% (8/342) for three autoantibodies, whereas only one subject in the control cohort had two autoantibodies. ICA positivity was found in 12.5% of the cases, followed by GADA (6.0%), IA-2A (4.9%) and IAA (1.2%). In the control cohort, GADA positivity was found in 1.4%, IA-2A in 0.8%, IAA in 0.6%, and ICA in 0.3% of the subjects. Detection of ICA, GADA and/or IA-2A autoantibodies decreased T1DM-free survival time and time to diagnosis. All subjects with three positive autoantibodies developed T1DM within seven years from the GDM pregnancy. Development of T2DM after GDM occurred independent of autoantibody positivity. Conclusion Development of T1DM can be reliably predicted with GADA and ICA autoantibodies during early pregnancy.
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Affiliation(s)
- Kaisu Luiro
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Anna-Maaria Auvinen
- Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Juha Auvinen
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
- Research Unit of Population Health, University of Oulu, Oulu, Finland
| | - Jari Jokelainen
- Northern Finland Birth Cohorts, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland
| | - Ilkka Järvelä
- Department of Obstetrics and Gynecology, Kuopio University Hospital, Kuopio, Finland
| | - Mikael Knip
- Pediatric Research Center, New Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
| | - Juha S. Tapanainen
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
- Department of Obstetrics and Gynecology, HFR – Cantonal Hospital of Fribourg and University of Fribourg, Fribourg, Switzerland
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Park JY, Choe YJ, Lim Y, Kim H, Kim J. Association between the incidence of type 1 diabetes mellitus and tuberculosis or bacillus Calmette-Guérin immunization in children and adolescents. Ann Pediatr Endocrinol Metab 2023; 28:251-257. [PMID: 38173381 PMCID: PMC10765028 DOI: 10.6065/apem.2244254.127] [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: 11/11/2022] [Revised: 03/20/2023] [Accepted: 07/07/2023] [Indexed: 01/05/2024] Open
Abstract
PURPOSE The correlation between the incidence of type 1 diabetes mellitus (T1DM) and tuberculosis or bacillus Calmette-Guérin (BCG) vaccination rate in individuals aged <15 years was investigated using worldwide data. METHODS The incidence of T1DM, rate of BCG vaccination, and incidence of tuberculosis were obtained from the Diabetes Atlas 9th edition of the International Diabetes Federation and the Global Health Observatory data repository of the World Health Organization. Gross domestic product (GDP) per capita and population data by country were obtained from the World Bank and United Nations, respectively. RESULTS GDP per capita negatively correlated with the incidence of tuberculosis and positively correlated with the incidence of T1DM (coefficient=-0.630 and 0.596, respectively; all P<0.001). The incidence of T1DM and tuberculosis was significantly associated with the Organisation for Economic Cooperation and Development (OECD) status (P<0.001). After adjusting for GDP per capita, regional grouping, and OECD status, the incidence of T1DM negatively correlated with that of tuberculosis (R2 =0.729, P=0.009). However, there was no association between the BCG vaccination rate and incidence of T1DM (P=0.890). CONCLUSION There was a negative correlation between the incidence of tuberculosis and T1DM in children and adolescents aged <15 years at the country level.
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Affiliation(s)
- Ji Young Park
- Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea
| | - Young June Choe
- Department of Pediatrics, Korea University Anam Hospital, Seoul, Korea
| | - Yaeji Lim
- Department of Applied Statistics, Chung-Ang University, Seoul, Korea
| | - Hyunsung Kim
- Department of Applied Statistics, Chung-Ang University, Seoul, Korea
| | - Jaehyun Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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Huang SM, Lin CH, Chang WF, Shih CC. Antidiabetic and antihyperlipidemic activities of Phyllanthus emblica L. extract in vitro and the regulation of Akt phosphorylation, gluconeogenesis, and peroxisome proliferator-activated receptor α in streptozotocin-induced diabetic mice. Food Nutr Res 2023; 67:9854. [PMID: 37850072 PMCID: PMC10578056 DOI: 10.29219/fnr.v67.9854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/05/2023] [Accepted: 09/15/2023] [Indexed: 10/19/2023] Open
Abstract
Background The fruits of Phyllanthus emblica L. are high in nutrients and have excellent health care function and developmental value. There are many management strategies available for diabetes and hyperlipidemia. Nevertheless, there is a lack of an effective and nontoxic drug. Objective The present study was designed to first screen four extracts of P. emblica L. on insulin signaling target gene expression levels, including glucose transporter 4 (GLUT4) and p-Akt/t-Akt. The ethyl acetate extract of P. emblica L. (EPE) exhibited the most efficient activity among the four extracts and was thus chosen to explore the antidiabetic and antihyperlipidemic activities in streptozotocin (STZ)-induced type 1 diabetic mice. Design All mice (in addition to one control (CON) group) were administered STZ injections (intraperitoneal) for 5 consecutive days, and then STZ-induced mice were administered EPE (at 100, 200, or 400 mg/kg body weight), fenofibrate (Feno) (at 250 mg/kg body weight), glibenclamide (Glib) (at 10 mg/kg body weight), or vehicle by oral gavage once daily for 4 weeks. Finally, histological examination, blood biochemical parameters, and target gene mRNA expression levels were measured, and liver tissue was analyzed for the levels of malondialdehyde (MDA), a maker of lipid peroxidation. Results EPE treatment resulted in decreased levels of blood glucose, HbA1C, triglycerides (TGs), and total cholesterol and increased levels of insulin compared with the vehicle-treated STZ group. EPE treatment decreased blood levels of HbA1C and MDA but increased glutathione levels in liver tissue, implying that EPE exerts antioxidant activity and could prevent oxidative stress and diabetes. The EPE-treated STZ mice displayed an improvement in the sizes and numbers of insulin-expressing β cells. EPE treatment increased the membrane expression levels of skeletal muscular GLUT4, and also reduced hepatic mRNA levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase thereby inhibiting hepatic gluconeogenesis. This resulted in a net glucose lowering effect in EPE-treated STZ mice. Furthermore, EPE increased the expression levels of p-AMPK/t-AMPK in both the skeletal muscle and liver tissue compared with vehicle-treated STZ mice. EPE-treated STZ mice showed enhanced expression levels of fatty acid oxidation enzymes, including peroxisome proliferator-activated receptor α (PPARα), but reduced expression levels of lipogenic genes including fatty acid synthase, as well as decreased mRNA levels of sterol regulatory element binding protein 1c (SREBP1c), apolipoprotein-CIII (apo-CIII), and diacylglycerol acyltransferase-2 (DGAT2). This resulted in a reduction in plasma TG levels. EPE-treated STZ mice also showed reduced expression levels of PPAR γ. This resulted in decreased adipogenesis, fatty acid synthesis, and lipid accumulation within liver tissue, and consequently, lower TG levels in liver tissue and blood. Furthermore, EPE treatment not only displayed an increase in the Akt activation in liver tissue, but also in C2C12 myotube in the absence of insulin. These results implied that EPE acts as an activator of AMPK and /or as a regulator of the insulin (Akt) pathway. Conclusions Taken together, EPE treatment exhibited amelioration of the diabetic and hyperlipidemic state in STZ-induced diabetic mice.
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Affiliation(s)
- Shin-Ming Huang
- Department of Gastroenterology, Jen-Ai Hospital, Dali Branch, Taichung City, Taiwan
| | - Cheng-Hsiu Lin
- Department of Internal Medicine, Fengyuan Hospital, Ministry of Health and Welfare, Taichung City, Taiwan
| | - Wen-Fang Chang
- Department of Cardiology, Jen-Ai Hospital, Taichung City, Taiwan
| | - Chun-Ching Shih
- Department of Nursing, College of Nursing, Central Taiwan University of Science and Technology, Taichung City, Taiwan
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Shen L, Wang X, Zhai C, Chen Y. Ferroptosis: A potential therapeutic target in autoimmune disease (Review). Exp Ther Med 2023; 26:368. [PMID: 37408857 PMCID: PMC10318600 DOI: 10.3892/etm.2023.12067] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 05/26/2023] [Indexed: 07/07/2023] Open
Abstract
Ferroptosis is a distinct type of regulated cell death characterized by iron overload and lipid peroxidation. Ferroptosis is regulated by numerous factors and controlled by several mechanisms. This cell death type has a relationship with the immune system, which may be regulated by damage-associated molecular patterns. Ferroptosis participates in the progression of autoimmune diseases, including autoimmune hepatitis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, Parkinson's Disease, psoriasis and insulin-dependent diabetes mellitus. The present review summarizes the role of ferroptosis in autoimmune disorders and discusses ferroptosis as a potential therapeutic target for autoimmune disease.
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Affiliation(s)
- Liang Shen
- Department of Cardiology, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Xiaohan Wang
- Department of Gastroenterology, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Changlin Zhai
- Department of Cardiology, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Yunqing Chen
- Department of Infectious Diseases, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
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Lin CH, Kuo YH, Shih CC. Antidiabetic and Immunoregulatory Activities of Extract of Phyllanthus emblica L. in NOD with Spontaneous and Cyclophosphamide-Accelerated Diabetic Mice. Int J Mol Sci 2023; 24:9922. [PMID: 37373070 DOI: 10.3390/ijms24129922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/25/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Oil-Gan, also known as emblica, is the fruit of the genus Phyllanthus emblica L. The fruits are high in nutrients and display excellent health care functions and development values. The primary aim of this study was to investigate the activities of ethyl acetate extract from Phyllanthus emblica L. (EPE) on type 1 diabetes mellitus (T1D) and immunoregulatory activities in non-obese diabetes (NOD) mice with spontaneous and cyclophosphamide (Cyp)-accelerated diabetes. EPE was vehicle-administered to spontaneous NOD (S-NOD) mice or Cyp-accelerated NOD (Cyp-NOD) mice once daily at a dose of 400 mg/kg body weight for 15 or 4 weeks, respectively. At the end, blood samples were collected for biological analyses, organ tissues were dissected for analyses of histology and immunofluorescence (IF) staining (including expressions of Bcl and Bax), the expression levels of targeted genes by Western blotting and forkhead box P3 (Foxp3), and helper T lymphocyte 1 (Th1)/Th2/Th17/Treg regulatory T cell (Treg) cell distribution by flow cytometry. Our results showed that EPE-treated NOD mice or Cyp-accelerated NOD mice display a decrease in levels of blood glucose and HbA1c, but an increase in blood insulin levels. EPE treatment decreased blood levels of IFN-γ and tumor necrosis α (TNF-α) by Th1 cells, and reduced interleukin (IL)-1β and IL-6 by Th17 cells, but increased IL-4, IL-10, and transforming growth factor-β1 (TGF-β1) by Th2 cells in both of the two mice models by enzyme-linked immunosorbent assay (ELISA) analysis. Flow cytometric data showed that EPE-treated Cyp-NOD mice had decreased the CD4+ subsets T cell distribution of CD4+IL-17 and CD4+ interferon gamma (IFN-γ), but increased the CD4+ subsets T cell distribution of CD4+IL-4 and CD4+Foxp3. Furthermore, EPE-treated Cyp-NOD mice had decreased the percentage per 10,000 cells of CD4+IL-17 and CD4+IFNγ, and increased CD4+IL-4 and CD4+Foxp3 compared with the Cyp-NOD Con group (p < 0.001, p < 0.05, p < 0.05, and p < 0.05, respectively). For target gene expression levels in the pancreas, EPE-treated mice had reduced expression levels of inflammatory cytokines, including IFN-γ and TNF-α by Th1 cells, but increased expression levels of IL-4, IL-10, and TGF-1β by Th2 cells in both two mice models. Histological examination of the pancreas revealed that EPE-treated mice had not only increased pancreatic insulin-expressing β cells (brown), and but also enhanced the percentage of Bcl-2 (green)/Bax (red) by IF staining analyses of islets compared with the S-NOD Con and the Cyp-NOD Con mice, implying that EPE displayed the protective effects of pancreas β cells. EPE-treated mice showed an increase in the average immunoreactive system (IRS) score on insulin within the pancreas, and an enhancement in the numbers of the pancreatic islets. EPE displayed an improvement in the pancreas IRS scores and a decrease in proinflammatory cytokines. Moreover, EPE exerted blood-glucose-lowering effects by regulating IL-17 expressions. Collectively, these results implied that EPE inhibits the development of autoimmune diabetes by regulating cytokine expression. Our results demonstrated that EPE has a therapeutic potential in the preventive effects of T1D and immunoregulation as a supplementary.
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Affiliation(s)
- Cheng-Hsiu Lin
- Department of Internal Medicine, Fengyuan Hospital, Ministry of Health and Welfare, Taichung City 42055, Taiwan
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung City 40402, Taiwan
| | - Chun-Ching Shih
- Department of Nursing, College of Nursing, Central Taiwan University of Science and Technology, Taichung City 40601, Taiwan
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11
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Rasouli-Saravani A, Jahankhani K, Moradi S, Gorgani M, Shafaghat Z, Mirsanei Z, Mehmandar A, Mirzaei R. Role of microbiota short-chain fatty acids in the pathogenesis of autoimmune diseases. Biomed Pharmacother 2023; 162:114620. [PMID: 37004324 DOI: 10.1016/j.biopha.2023.114620] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/27/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
There is emerging evidence that microbiota and its metabolites play an important role in helath and diseases. In this regard, gut microbiota has been found as a crucial component that influences immune responses as well as immune-related disorders such as autoimmune diseases. Gut bacterial dysbiosis has been shown to cause disease and altered microbiota metabolite synthesis, leading to immunological and metabolic dysregulation. Of note, microbiota in the gut produce short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, and remodeling in these microbiota metabolites has been linked to the pathophysiology of a number of autoimmune disorders such as type 1 diabetes, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, celiac disease, and systemic lupus erythematosus. In this review, we will address the most recent findings from the most noteworthy studies investigating the impact of microbiota SCFAs on various autoimmune diseases.
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Affiliation(s)
- Ashkan Rasouli-Saravani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kasra Jahankhani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shadi Moradi
- Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Melika Gorgani
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Shafaghat
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Mirsanei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirreza Mehmandar
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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12
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Li TT, Lin CL, Chiang M, He JT, Hung CH, Hsieh CC. Cytokine-Induced Myeloid-Derived Suppressor Cells Demonstrate Their Immunoregulatory Functions to Prolong the Survival of Diabetic Mice. Cells 2023; 12:1507. [PMID: 37296628 PMCID: PMC10253032 DOI: 10.3390/cells12111507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/21/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Type 1 diabetes is an inflammatory state. Myeloid-derived suppressive cells (MDSCs) originate from immature myeloid cells and quickly expand to control host immunity during infection, inflammation, trauma, and cancer. This study presents an ex vivo procedure to develop MDSCs from bone marrow cells propagated from granulocyte-macrophage-colony-stimulating factor (GM-CSF), interleukin (IL)-6, and IL-1β cytokines expressing immature morphology and high immunosuppression of T-cell proliferation. The adoptive transfer of cytokine-induced MDSCs (cMDSCs) improved the hyperglycemic state and prolonged the diabetes-free survival of nonobese diabetic (NOD) mice with severe combined immune deficiency (SCID) induced by reactive splenic T cells harvested from NOD mice. In addition, the application of cMDSCs reduced fibronectin production in the renal glomeruli and improved renal function and proteinuria in diabetic mice. Moreover, cMDSCs use mitigated pancreatic insulitis to restore insulin production and reduce the levels of HbA1c. In conclusion, administering cMDSCs propagated from GM-CSF, IL-6, and IL-1β cytokines provides an alternative immunotherapy protocol for treating diabetic pancreatic insulitis and renal nephropathy.
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Affiliation(s)
- Tung-Teng Li
- Division of General Surgery, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan; (T.-T.L.)
| | - Chun-Liang Lin
- Department of Nephrology, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan;
- Kidney and Diabetic Complications Research Team (KDCRT), Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan
- College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan
| | - Meihua Chiang
- Division of General Surgery, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan; (T.-T.L.)
| | - Jie-Teng He
- Division of General Surgery, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan; (T.-T.L.)
| | - Chien-Hui Hung
- College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan
- Division of Infectious Diseases, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan
| | - Ching-Chuan Hsieh
- Division of General Surgery, Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan; (T.-T.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang-Gung Memorial Hospital, Chiayi 61302, Taiwan
- College of Medicine, Chang-Gung University, Taoyuan 33302, Taiwan
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13
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Limanaqi F, Vicentini C, Saulle I, Clerici M, Biasin M. The role of endoplasmic reticulum aminopeptidases in type 1 diabetes mellitus. Life Sci 2023; 323:121701. [PMID: 37059356 DOI: 10.1016/j.lfs.2023.121701] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/05/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023]
Abstract
Type-I diabetes mellitus (T1DM) is generally considered as a chronic, T-cell mediated autoimmune disease. This notwithstanding, both the endogenous characteristics of β-cells, and their response to environmental factors and exogenous inflammatory stimuli are key events in disease progression and exacerbation. As such, T1DM is now recognized as a multifactorial condition, with its onset being influenced by both genetic predisposition and environmental factors, among which, viral infections represent major triggers. In this frame, endoplasmic reticulum aminopeptidase 1 (ERAP1) and 2 (ERAP2) hold center stage. ERAPs represent the main hydrolytic enzymes specialized in trimming of N-terminal antigen peptides to be bound by MHC class I molecules and presented to CD8+ T cells. Thus, abnormalities in ERAPs expression alter the peptide-MHC-I repertoire both quantitatively and qualitatively, fostering both autoimmune and infectious diseases. Although only a few studies succeeded in determining direct associations between ERAPs variants and T1DM susceptibility/outbreak, alterations of ERAPs do impinge on a plethora of biological events which might indeed contribute to the disease development/exacerbation. Beyond abnormal self-antigen peptide trimming, these include preproinsulin processing, nitric oxide (NO) production, ER stress, cytokine responsiveness, and immune cell recruitment/activity. The present review brings together direct and indirect evidence focused on the immunobiological role of ERAPs in T1DM onset and progression, covering both genetic and environmental aspects.
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Affiliation(s)
- Fiona Limanaqi
- Department of Biomedical and Clinical Sciences, University of Milan, Via G.B. Grassi, 20122 Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza, 20122 Milan, Italy
| | - Chiara Vicentini
- Department of Biomedical and Clinical Sciences, University of Milan, Via G.B. Grassi, 20122 Milan, Italy
| | - Irma Saulle
- Department of Biomedical and Clinical Sciences, University of Milan, Via G.B. Grassi, 20122 Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza, 20122 Milan, Italy
| | - Mario Clerici
- Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza, 20122 Milan, Italy; Don C. Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Via A. Capecelatro 66, 20148 Milan, Italy
| | - Mara Biasin
- Department of Biomedical and Clinical Sciences, University of Milan, Via G.B. Grassi, 20122 Milan, Italy.
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14
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Stadinski BD, Cleveland SB, Brehm MA, Greiner DL, Huseby PG, Huseby ES. I-A g7 β56/57 polymorphisms regulate non-cognate negative selection to CD4 + T cell orchestrators of type 1 diabetes. Nat Immunol 2023; 24:652-663. [PMID: 36807641 PMCID: PMC10623581 DOI: 10.1038/s41590-023-01441-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 01/20/2023] [Indexed: 02/22/2023]
Abstract
Genetic susceptibility to type 1 diabetes is associated with homozygous expression of major histocompatibility complex class II alleles that carry specific beta chain polymorphisms. Why heterozygous expression of these major histocompatibility complex class II alleles does not confer a similar predisposition is unresolved. Using a nonobese diabetic mouse model, here we show that heterozygous expression of the type 1 diabetes-protective allele I-Ag7 β56P/57D induces negative selection to the I-Ag7-restricted T cell repertoire, including beta-islet-specific CD4+ T cells. Surprisingly, negative selection occurs despite I-Ag7 β56P/57D having a reduced ability to present beta-islet antigens to CD4+ T cells. Peripheral manifestations of non-cognate negative selection include a near complete loss of beta-islet-specific CXCR6+ CD4+ T cells, an inability to cross-prime islet-specific glucose-6-phosphatase catalytic subunit-related protein and insulin-specific CD8+ T cells and disease arrest at the insulitis stage. These data reveal that negative selection on non-cognate self-antigens in the thymus can promote T cell tolerance and protection from autoimmunity.
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Affiliation(s)
- Brian D Stadinski
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Sarah B Cleveland
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Michael A Brehm
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
| | - Dale L Greiner
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
| | - Priya G Huseby
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Eric S Huseby
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
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15
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Mansueto G, Lanza G, Falleti J, Orabona P, Alaouieh D, Hong E, Girolami S, Montella M, Fisicaro F, Galdieri A, Singh P, Di Napoli M. Central and Peripheral Nervous System Complications of Vasculitis Syndromes from Pathology to Bedside: Part 2-Peripheral Nervous System. Curr Neurol Neurosci Rep 2023; 23:83-107. [PMID: 36820992 PMCID: PMC9947450 DOI: 10.1007/s11910-023-01249-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2023] [Indexed: 02/24/2023]
Abstract
PURPOSE OF REVIEW Peripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV. RECENT FINDINGS Progress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.
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Affiliation(s)
- Gelsomina Mansueto
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania “Luigi Vanvitelli”, Piazza L. Miraglia 2, 80138 Naples, Italy
- Clinical Department of Laboratory Services and Public Health—Legal Medicine Unit, University of Campania “Luigi Vanvitelli”, Via Luciano Armanni 5, 80138 Naples, Italy
- Pathology-Unit of Federico II University, Via S. Pansini 3, 80131 Naples, Italy
| | - Giuseppe Lanza
- Department of Surgery and Medical-Surgical Specialties, University of Catania, Via Santa Sofia 78, 95123 Catania, Italy
- Clinical Neurophysiology Research Unit, Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy
| | - Jessica Falleti
- Pathology Unit, Sant’Anna E San Sebastiano Hospital, 81100 Caserta, Italy
| | - Pasquale Orabona
- Pathology Unit, Sant’Anna E San Sebastiano Hospital, 81100 Caserta, Italy
| | | | - Emily Hong
- School of Medicine, University of New Mexico, Albuquerque, NM USA
| | - Sara Girolami
- Neurological Service, SS Annunziata Hospital, Viale Mazzini 100, 67039 Sulmona, L’Aquila Italy
| | - Marco Montella
- Mental and Physical Health and Preventive Medicine Department, University of Campania “Luigi Vanvitelli”, Via Luciano Armanni 5, 80138 Naples, Italy
| | - Francesco Fisicaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy
| | - Anna Galdieri
- AOU “Luigi Vanvitelli”, Via Santa Maria Di Costantinopoli 104, 80138 Naples, Italy
| | - Puneetpal Singh
- Department of Human Genetics, Punjabi University, Patiala, 147002 Punjab India
| | - Mario Di Napoli
- Neurological Service, SS Annunziata Hospital, Viale Mazzini 100, 67039 Sulmona, L’Aquila Italy
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16
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Harsunen M, Kettunen JLT, Härkönen T, Dwivedi O, Lehtovirta M, Vähäsalo P, Veijola R, Ilonen J, Miettinen PJ, Knip M, Tuomi T. Identification of monogenic variants in more than ten per cent of children without type 1 diabetes-related autoantibodies at diagnosis in the Finnish Pediatric Diabetes Register. Diabetologia 2023; 66:438-449. [PMID: 36418577 PMCID: PMC9892083 DOI: 10.1007/s00125-022-05834-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/05/2022] [Indexed: 11/25/2022]
Abstract
AIMS/HYPOTHESIS Monogenic forms of diabetes (MODY, neonatal diabetes mellitus and syndromic forms) are rare, and affected individuals may be misclassified and treated suboptimally. The prevalence of type 1 diabetes is high in Finnish children but systematic screening for monogenic diabetes has not been conducted. We assessed the prevalence and clinical manifestations of monogenic diabetes in children initially registered with type 1 diabetes in the Finnish Pediatric Diabetes Register (FPDR) but who had no type 1 diabetes-related autoantibodies (AABs) or had only low-titre islet cell autoantibodies (ICAs) at diagnosis. METHODS The FPDR, covering approximately 90% of newly diagnosed diabetic individuals aged ≤15 years in Finland starting from 2002, includes data on diabetes-associated HLA genotypes and AAB data (ICA, and autoantibodies against insulin, GAD, islet antigen 2 and zinc transporter 8) at diagnosis. A next generation sequencing gene panel including 42 genes was used to identify monogenic diabetes. We interpreted the variants in HNF1A by using the gene-specific standardised criteria and reported pathogenic and likely pathogenic findings only. For other genes, we also reported variants of unknown significance if an individual's phenotype suggested monogenic diabetes. RESULTS Out of 6482 participants, we sequenced DNA for 152 (2.3%) testing negative for all AABs and 49 (0.8%) positive only for low-titre ICAs (ICAlow). A monogenic form of diabetes was revealed in 19 (12.5%) of the AAB-negative patients (14 [9.2%] had pathogenic or likely pathogenic variants) and two (4.1%) of the ICAlow group. None had ketoacidosis at diagnosis or carried HLA genotypes conferring high risk for type 1 diabetes. The affected genes were GCK, HNF1A, HNF4A, HNF1B, INS, KCNJ11, RFX6, LMNA and WFS1. A switch from insulin to oral medication was successful in four of five patients with variants in HNF1A, HNF4A or KCNJ11. CONCLUSIONS/INTERPRETATION More than 10% of AAB-negative children with newly diagnosed diabetes had a genetic finding associated with monogenic diabetes. Because the genetic diagnosis can lead to major changes in treatment, we recommend referring all AAB-negative paediatric patients with diabetes for genetic testing. Low-titre ICAs in the absence of other AABs does not always indicate a diagnosis of type 1 diabetes.
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Affiliation(s)
- Minna Harsunen
- New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
| | - Jarno L T Kettunen
- Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
- Abdominal Centre, Endocrinology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
| | - Taina Härkönen
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
| | - Om Dwivedi
- Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
| | - Mikko Lehtovirta
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
| | - Paula Vähäsalo
- Department of Pediatrics, PEDEGO Research Unit, University of Oulu, Oulu, Finland
- Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Riitta Veijola
- Department of Pediatrics, PEDEGO Research Unit, University of Oulu, Oulu, Finland
- Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Päivi J Miettinen
- New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Translational Stem Cell Biology and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Mikael Knip
- New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
| | - Tiinamaija Tuomi
- Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Abdominal Centre, Endocrinology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Lund, Sweden
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17
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Pérez‐Fernández A, Fernández‐Berrocal P, Gutiérrez‐Cobo MJ. The relationship between well-being and HbA1c in adults with type 1 diabetes: A systematic review. J Diabetes 2023; 15:152-164. [PMID: 36796311 PMCID: PMC9934956 DOI: 10.1111/1753-0407.13357] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 12/20/2022] [Accepted: 12/26/2022] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND Diabetes has been associated with psychological problems, which in turn have been related to poorer glycemic control (glycosylated hemoglobin [HbA1c]). On the contrary, psychological well-being constructs have been associated with superior medical outcomes, including better HbA1c. AIM The main objective of this study was to systematically review the existing literature about the relationships between subjective well-being (SWB) and HbA1c in adults with type 1 diabetes (T1D). METHODS Comprehensive searches were conducted in PubMed, Scopus, and Medline, time restricted to 2021, for studies examining the link between HbA1c and the cognitive (CWB) and affective (AWB) components of SWB. A total of 16 eligible studies were selected according to the inclusion criteria, of which 15 measured CWB and 1 AWB. RESULTS Of the 15 studies included, 11 showed a relationship between CWB and HbA1c, with a higher level of HbA1c being related to poorer CWB. The other four studies did not find any significant association. Finally, the only study examining the relationship between AWB and HbA1c found a marginally association between these variables in the expected direction. CONCLUSION The overall data suggest that CWB is negatively related to HbA1c in this population, but these results are inconclusive. This systematic review offers clinical implications, such as the possible evaluation, prevention, and treatment of the problems associated with diabetes through the study and training of the psychosocial variables that may directly influence SWB. Limitations and future lines of investigation are discussed.
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Affiliation(s)
- Aida Pérez‐Fernández
- Department of Basic Psychology, Faculty of PsychologyUniversity of MálagaMálagaSpain
| | | | - María José Gutiérrez‐Cobo
- Department of Developmental and Educational Psychology, Faculty of PsychologyUniversity of MálagaMálagaSpain
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18
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Li Y, Peng Q, Shang J, Dong W, Wu S, Guo X, Xie Z, Chen C. The role of taurine in male reproduction: Physiology, pathology and toxicology. Front Endocrinol (Lausanne) 2023; 14:1017886. [PMID: 36742382 PMCID: PMC9889556 DOI: 10.3389/fendo.2023.1017886] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 01/04/2023] [Indexed: 01/20/2023] Open
Abstract
Taurine, a sulfur-containing amino acid, has a wide range of biological effects, such as bile salt formation, osmotic regulation, oxidative stress inhibition, immunomodulation and neuromodulation. Taurine has been proved to be synthesized and abundant in male reproductive organs. Recently, accumulating data showed that taurine has a potential protective effect on reproductive function of male animals. In physiology, taurine can promote the endocrine function of the hypothalamus-pituitary-testis (HPT) axis, testicular tissue development, spermatogenesis and maturation, delay the aging of testicular structure and function, maintain the homeostasis of the testicular environment, and enhance sexual ability. In pathology, taurine supplement may be beneficial to alleviate pathological damage of male reproductive system, including oxidative damage of sperm preservation in vitro, testicular reperfusion injury and diabetes -induced reproductive complications. In addition, taurine acts as a protective agent against toxic damage to the male reproductive system by exogenous substances (e.g., therapeutic drugs, environmental pollutants, radiation). Related mechanisms include reduced oxidative stress, increased antioxidant capacity, inhibited inflammation and apoptosis, restored the secretory activity of the HPT axis, reduced chromosomal variation, enhanced sperm mitochondrial energy metabolism, cell membrane stabilization effect, etc. Therefore, this article reviewed the protective effect of taurine on male reproductive function and its detailed mechanism, in order to provide reference for further research and clinical application.
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Affiliation(s)
- Yuanyuan Li
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Qianwen Peng
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Jia Shang
- Arts Department, School of Kaifeng Culture and Tourism, Henan, Kaifeng, China
| | - Wanglin Dong
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Sijia Wu
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Xiajun Guo
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Zhenxing Xie
- School of Basic Medical Science, Henan University, Henan, Kaifeng, China
| | - Chaoran Chen
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
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19
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Gerace D, Zhou Q, Kenty JHR, Veres A, Sintov E, Wang X, Boulanger KR, Li H, Melton DA. Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance. Cell Rep Med 2023; 4:100879. [PMID: 36599351 PMCID: PMC9873825 DOI: 10.1016/j.xcrm.2022.100879] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 09/02/2022] [Accepted: 12/08/2022] [Indexed: 01/06/2023]
Abstract
Immunological protection of transplanted stem cell-derived islet (SC-islet) cells is yet to be achieved without chronic immunosuppression or encapsulation. Existing genetic engineering approaches to produce immune-evasive SC-islet cells have so far shown variable results. Here, we show that targeting human leukocyte antigens (HLAs) and PD-L1 alone does not sufficiently protect SC-islet cells from xenograft (xeno)- or allograft (allo)-rejection. As an addition to these approaches, we genetically engineer SC-islet cells to secrete the cytokines interleukin-10 (IL-10), transforming growth factor β (TGF-β), and modified IL-2 such that they promote a tolerogenic local microenvironment by recruiting regulatory T cells (Tregs) to the islet grafts. Cytokine-secreting human SC-β cells resist xeno-rejection and correct diabetes for up to 8 weeks post-transplantation in non-obese diabetic (NOD) mice. Thus, genetically engineering human embryonic SCs (hESCs) to induce a tolerogenic local microenvironment represents a promising approach to provide SC-islet cells as a cell replacement therapy for diabetes without the requirement for encapsulation or immunosuppression.
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Affiliation(s)
- Dario Gerace
- Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA
| | - Quan Zhou
- Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA
| | - Jennifer Hyoje-Ryu Kenty
- Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA
| | - Adrian Veres
- Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA
| | - Elad Sintov
- Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA
| | - Xi Wang
- Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA
| | - Kyle R Boulanger
- Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA
| | - Hongfei Li
- Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA
| | - Douglas A Melton
- Department of Stem Cell and Regenerative Biology, Harvard University, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Boston, MA, USA.
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20
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Younger DS. Adult and childhood vasculitis. HANDBOOK OF CLINICAL NEUROLOGY 2023; 195:653-705. [PMID: 37562892 DOI: 10.1016/b978-0-323-98818-6.00008-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability, making this a disorder of paramount importance to all clinicians. There has been remarkable progress in the pathogenesis, diagnosis, and treatment of primary CNS and PNS vasculitides, predicated on achievement in primary systemic forms. Primary neurological vasculitides can be diagnosed with assurance after intensive evaluation that incudes tissue confirmation whenever possible. Clinicians must choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, unfortunately without the benefit of RCTs, and tempered by the recognition of anticipated medication side effects. It may be said that efforts to define a disease are attempts to understand the very concept of the disease. This has been especially evident in systemic and neurological disorders associated with vasculitis. For the past 100 years, since the first description of granulomatous angiitis of the brain, the CNS vasculitides have captured the attention of generations of clinical investigators around the globe to reach a better understanding of vasculitides involving the central and peripheral nervous system. Since that time it has become increasingly evident that this will necessitate an international collaborative effort.
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Affiliation(s)
- David S Younger
- Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States; Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States.
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21
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Abou Daher A, Alkhansa S, Azar WS, Rafeh R, Ghadieh HE, Eid AA. Translational Aspects of the Mammalian Target of Rapamycin Complexes in Diabetic Nephropathy. Antioxid Redox Signal 2022; 37:802-819. [PMID: 34544257 DOI: 10.1089/ars.2021.0217] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Despite the many efforts put into understanding diabetic nephropathy (DN), direct treatments for DN have yet to be discovered. Understanding the mechanisms behind DN is an essential step in the development of novel therapeutic regimens. The mammalian target of rapamycin (mTOR) pathway has emerged as an important candidate in the quest for drug discovery because of its role in regulating growth, proliferation, as well as protein and lipid metabolism. Recent Advances: Kidney cells have been found to rely on basal autophagy for survival and for conserving kidney integrity. Recent studies have shown that diabetes induces renal autophagy deregulation, leading to kidney injury. Hyper-activation of the mTOR pathway and oxidative stress have been suggested to play a role in diabetes-induced autophagy imbalance. Critical Issues: A detailed understanding of the role of mTOR signaling in diabetes-associated complications is of major importance in the search for a cure. In this review, we provide evidence that mTOR is heavily implicated in diabetes-induced kidney injury. We suggest possible mechanisms through which mTOR exerts its negative effects by increasing insulin resistance, upregulating oxidative stress, and inhibiting autophagy. Future Directions: Both increased oxidative stress and autophagy deregulation are deeply embedded in DN. However, the mechanisms controlling oxidative stress and autophagy are not well understood. Although Akt/mTOR signaling seems to play an important role in oxidative stress and autophagy, further investigation is required to uncover the details of this signaling pathway. Antioxid. Redox Signal. 37, 802-819.
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Affiliation(s)
- Alaa Abou Daher
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Sahar Alkhansa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - William S Azar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,Department of Physiology and Biophysics, Georgetown University Medical School, Washington, District of Columbia, USA
| | - Rim Rafeh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Hilda E Ghadieh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
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22
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Kleiner A, Cum B, Pisciotta L, Cincione IR, Cogorno L, Prigione A, Tramacere A, Vignati A, Carmisciano L, Sukkar SG. Safety and Efficacy of Eucaloric Very Low-Carb Diet (EVLCD) in Type 1 Diabetes: A One-Year Real-Life Retrospective Experience. Nutrients 2022; 14:nu14153208. [PMID: 35956384 PMCID: PMC9370810 DOI: 10.3390/nu14153208] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 11/26/2022] Open
Abstract
A eucaloric very low carbohydrate diet (EVLCD) is a diet with a daily caloric intake equal to the total daily energy expenditure (TDEE) with a carbohydrate content of <50 g/day. The literature on very low carbohydrate diets (VLCD) in type 1 diabetes (DM 1) is limited, although recently published scientific studies have highlighted their safety and efficacy in managing DM 1. In this retrospective analysis, we report the clinical data of 33 patients affected by DM 1 carrying out insulin therapy who switched voluntarily from their usual diet (high carb, low fat) to an EVLCD. Our aim is to evaluate the glycemic control, the amount of insulin needed in order to maintain glycemic control and safety of EVLCD. The switch improved glycemic control (mean glycated hemoglobin decreased from 8.3% to 6.8% (p < 0.01). The number of patients who reached a glycated hemoglobin value of <7% increased statistically from 12% to 57% (p < 0.01), and there was a statistically significant decrease (p < 0.01) in the units of daily insulin (from 36.7± 14.9 IU to 28.9 ±9.1 IU) A reduction from 54% to 24% in clinical level 2 hypoglycemia episodes was reported. No cases of severe hypoglycemia or ketoacidosis were observed. The results of the study support that EVLCD in DM 1 seems safe and effective when adopted under tight medical supervision.
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Affiliation(s)
| | - Barbara Cum
- Salus AlpeAdria Diabetes Center, 33100 Udine, Italy
| | - Livia Pisciotta
- Dietetics and Clinical Nutrition Unit, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
| | - Ivan Raffaele Cincione
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| | - Ludovica Cogorno
- Dietetics and Clinical Nutrition Unit, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
- Department of Experimental Medicine-Medical Pathophysiology, Food Science and Endocrinology Section, Sapienza University of Rome, 00185 Rome, Italy
| | - Amalia Prigione
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
| | - Antonio Tramacere
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
| | - Andrea Vignati
- Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy
| | - Luca Carmisciano
- Department of Health Sciences (DISSAL), Section of Biostatistics, University of Genoa, Via Pastore, 16132 Genoa, Italy
| | - Samir Giuseppe Sukkar
- Dietetics and Clinical Nutrition Unit, IRCCS Policlinic Hospital San Martino, 16132 Genoa, Italy
- Correspondence: or ; Tel.: +0039-3356098178
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23
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Danioth S, Wiesli P. [CME: Can Slim People Have Type-2 Diabetes?]. PRAXIS 2022; 111:598-602. [PMID: 35975416 DOI: 10.1024/1661-8157/a003915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
CME: Can Slim People Have Type-2 Diabetes? Abstract. Most patients with type-2 diabetes mellitus are obese or overweight. In slim patients with suspected type 2 diabetes mellitus the possibility of other types of diabetes must be considered. In addition to type-1 diabetes in adulthood and genetic forms of diabetes (MODY, mitochondrial diabetes), it could also be diabetes due to a disease of the exocrine pancreas, a condition which is generally underdiagnosed.
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Affiliation(s)
- Simona Danioth
- Medizinische Klinik, Endokrinologie und Diabetologie, Kantonsspital Frauenfeld, Schweiz
| | - Peter Wiesli
- Medizinische Klinik, Endokrinologie und Diabetologie, Kantonsspital Frauenfeld, Schweiz
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24
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Nemati M, Fathi-Azarbayjani A, Al-Salami H, Roshani Asl E, Rasmi Y. Bile acid-based advanced drug delivery systems, bilosomes and micelles as novel carriers for therapeutics. Cell Biochem Funct 2022; 40:623-635. [PMID: 35830577 DOI: 10.1002/cbf.3732] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 06/07/2022] [Accepted: 06/11/2022] [Indexed: 12/17/2022]
Abstract
Diabetes mellitus affects almost half a billion patients worldwide and results from either destruction of β-cells responsible for insulin secretion or increased tissue resistance to insulin stimulation and the reduction of glycemic control. Novel drug delivery systems can improve treatment efficacy in diabetic patients. The low aqueous solubility of most oral antidiabetic drugs decreases drug bioavailability; therefore, there is a demand for the use of novel methods to overcome this issue. The application of bile acids mixed micelles and bilosomes can provide an enhancement in drug efficacy. Bile acids are amphiphilic steroidal molecules that contain a saturated tetracyclic hydrocarbon cyclopentanoperhydrophenanthrene ring, and consist of three 6-membered rings and a 5-membered ring, a short aliphatic side chain, and a tough steroid nucleus. This review offers a comprehensive and informative data focusing on the great potential of bile acid, their salts, and their derivatives for the development of new antidiabetic drug delivery system.
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Affiliation(s)
- Mohadeseh Nemati
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Anahita Fathi-Azarbayjani
- Experimental and Applied Pharmaceutical Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Hani Al-Salami
- Biotechnology and Drug Development Research Laboratory, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Elmira Roshani Asl
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Rasmi
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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25
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Pancreatic Transdifferentiation Using β-Cell Transcription Factors for Type 1 Diabetes Treatment. Cells 2022; 11:cells11142145. [PMID: 35883588 PMCID: PMC9315695 DOI: 10.3390/cells11142145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/01/2022] [Accepted: 07/06/2022] [Indexed: 01/25/2023] Open
Abstract
Type 1 diabetes is a chronic illness in which the native beta (β)-cell population responsible for insulin release has been the subject of autoimmune destruction. This condition requires patients to frequently measure their blood glucose concentration and administer multiple daily exogenous insulin injections accordingly. Current treatments fail to effectively treat the disease without significant side effects, and this has led to the exploration of different approaches for its treatment. Gene therapy and the use of viral vectors has been explored extensively and has been successful in treating a range of diseases. The use of viral vectors to deliver β-cell transcription factors has been researched in the context of type 1 diabetes to induce the pancreatic transdifferentiation of cells to replace the β-cell population destroyed in patients. Studies have used various combinations of pancreatic and β-cell transcription factors in order to induce pancreatic transdifferentiation and have achieved varying levels of success. This review will outline why pancreatic transcription factors have been utilised and how their application can allow the development of insulin-producing cells from non β-cells and potentially act as a cure for type 1 diabetes.
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26
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Ujah G, Emmanuel IB, Ansa F, Ukoh A, Ani EJ, Osim EE. Insulin and Zinc Co-Administration Ameliorate Diabetes Mellitus-Induced Reproductive Dysfunction in Male Rats. Niger J Physiol Sci 2022; 37:49-58. [PMID: 35947835 DOI: 10.54548/njps.v37i1.7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 07/19/2022] [Indexed: 06/15/2023]
Abstract
Impaired male reproductive function is a major complication associated with diabetes mellitus (DM). Whether or not insulin, when co-administered with zinc will reverse or ameliorate reproductive dysfunction in male diabetics is not known. This study thus sought to establish if co-administration of insulin and zinc reverses or ameliorates male reproductive dysfunction in DM better than either insulin or zinc. Five (5) normal and twenty (20) diabetic sexually mature rats were assigned into five groups of five animals each. Group A consisted of normal rats and had access to only food and water. Group B consisted of diabetic animals with no treatment and served as DM control. Groups C and D consisted of diabetic animals and received insulin and zinc respectively. Group E consisted of diabetic animals and received both insulin and zinc. All diabetic animals had free access to food and water. Insulin in all cases was given subcutaneously twice daily in the morning and evening at 1 unit and 4 units respectively. Zinc (10mg/kg) was given orally once daily. Treatments in all cases commenced two weeks after DM was confirmed. The treatment lasted ten days. Samples were thereafter collected for analyses. DM decreased sperm count, sperm motility, sperm viability, normal sperm cells, semen pH, serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone, while increasing sperm cells with defective tails. DM also impaired testicular morphology. Insulin and zinc co-administration improved sperm viability, sertoli cell count, Johnsen's score, serum FSH, LH and testosterone. Co-administration also improved semen pH towards normal. Insulin or zinc ameliorated several aspects of DM-induced male sexual dysfunction. However, the co-administration of insulin and zinc provided better results.
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Affiliation(s)
- G Ujah
- University of Calabar, Calabar.
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27
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Wang SC, Liao JY. Epidemiologic Implication of the Association between Herpes Simplex Virus Infection and the Risk of Type 1 Diabetes Mellitus: A Nationwide Case-Control Study in Taiwan. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19137832. [PMID: 35805493 PMCID: PMC9265894 DOI: 10.3390/ijerph19137832] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 02/05/2023]
Abstract
Enterovirus infection is a known risk factor for type 1 diabetes (T1DM). Whether infection with other viruses induces T1DM remains undetermined. This study investigated the association between human herpesvirus (HHV) infection and the development of T1DM, using the data from Taiwan’s National Health Insurance Research Database. Patients with T1DM and age- and sex-matched controls were included. Subjects with HHV infection were subgrouped into those with histories of varicella-zoster virus, herpes simplex virus (HSV), Epstein-Barr virus, and human cytomegalovirus infections. The odds ratio of the risk of T1DM was calculated using a multivariable conditional logistic regression model. Atopic diseases, autoimmune thyroid diseases, and history of enterovirus infection served as adjusted comorbidities. Our findings suggested a significant association between HSV infection and the risk of T1DM (adjusted odds ratio: 1.21; 95% CI: 1.01–1.47, p = 0.048), while infection with other HHVs was not. The result of HSV infection remained significant when subjects were restricted to age ≤ 18 years (adjusted odds ratio: 1.35; 95% CI: 1.08–1.70, p = 0.010). We found a history of HSV infection might be an independent predictive risk factor for T1DM. This could be potentially helpful to the practice in public health.
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Affiliation(s)
- Shao-Chang Wang
- Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan;
| | - Jung-Yu Liao
- Department of Public Health, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: ; Tel.: +886-7-3121101 (ext. 2106)
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28
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Ashrafizadeh M, Kumar AP, Aref AR, Zarrabi A, Mostafavi E. Exosomes as Promising Nanostructures in Diabetes Mellitus: From Insulin Sensitivity to Ameliorating Diabetic Complications. Int J Nanomedicine 2022; 17:1229-1253. [PMID: 35340823 PMCID: PMC8943613 DOI: 10.2147/ijn.s350250] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 03/07/2022] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus (DM) is among the chronic metabolic disorders that its incidence rate has shown an increase in developed and wealthy countries due to lifestyle and obesity. The treatment of DM has always been of interest, and significant effort has been made in this field. Exosomes belong to extracellular vesicles with nanosized features (30-150 nm) that are involved in cell-to-cell communication and preserving homeostasis. The function of exosomes is different based on their cargo, and they may contain lipids, proteins, and nucleic acids. The present review focuses on the application of exosomes in the treatment of DM; both glucose and lipid levels are significantly affected by exosomes, and these nanostructures enhance lipid metabolism and decrease its deposition. Furthermore, exosomes promote glucose metabolism and affect the level of glycolytic enzymes and glucose transporters in DM. Type I DM results from the destruction of β cells in the pancreas, and exosomes can be employed to ameliorate apoptosis and endoplasmic reticulum (ER) stress in these cells. The exosomes have dual functions in mediating insulin resistance/sensitivity, and M1 macrophage-derived exosomes inhibit insulin secretion. The exosomes may contain miRNAs, and by transferring among cells, they can regulate various molecular pathways such as AMPK, PI3K/Akt, and β-catenin to affect DM progression. Noteworthy, exosomes are present in different body fluids such as blood circulation, and they can be employed as biomarkers for the diagnosis of diabetic patients. Future studies should focus on engineering exosomes derived from sources such as mesenchymal stem cells to treat DM as a novel strategy.
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Affiliation(s)
- Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, 34956, Istanbul, Turkey
| | - Alan Prem Kumar
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Translational Sciences, Xsphera Biosciences Inc., Boston, MA, 02210, USA
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
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29
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Leão IS, Araujo DB, Barone B, Dantas JR, de Souza Nolasco da Silva MV, Soares MO, Kendler DB, Kupfer R, Zajdenverg L, Rodacki M. Ten years follow up of first degree relatives of type 1 diabetes patients: presence of autoimmune biomarkers and the progression to diabetes in a retrospective cohort. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:436-442. [PMID: 34283897 PMCID: PMC10522178 DOI: 10.20945/2359-3997000000370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 02/15/2021] [Indexed: 06/13/2023]
Abstract
OBJECTIVE The aim of the study was to assess the autoimmunity in first degrees relatives (FDR) of patients with type 1 diabetes (T1DM) and the progression to T1DM after 10 years of follow up in the Brazilian population. METHODS Non-diabetic FDR of T1DM patients were interviewed and blood was drawn for autoantibodies measurement (GADA, IA-2A, IAA, ZnT8A). Serum samples were analyzed by standard radioligand binding assays performed at the Federal University of Rio de Janeiro (GADA, IAA and IA2A), and at the Skäne University Hospital, Sweden (ZnT8A). The FDR were interviewed by phone after 10 years to determine if they had developed T1DM. Descriptive statistical analysis was performed and results were described as means and standard deviation (SD). RESULTS 81 individuals were analyzed. Thirteen subjects had positive autoantibodies associated with T1DM.10 were positive for 1 autoantibody and 3 subjects were positive for multiple autoantibodies (1 of them showed positivity for 2 autoantibodies - GADA, ZnT8A - and the other two were positive for 3 autoantibodies - GADA, IA2A, ZnT8A). The 3 subjects with multiple positive autoantibodies developed T1DM within 10 years. CONCLUSION In Brazilian FDR of T1DM patients, the positivity for multiple autoantibodies indicate a greater chance of progression to T1DM, similar to observed in Caucasians. ZnT8A was helpful in the risk assessment for T1DM development.
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Affiliation(s)
- Isabella Sued Leão
- Departamento de Nutrologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brasil,
| | - Débora Batista Araujo
- Departamento de Nutrologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brasil
| | - Bianca Barone
- Departamento de Nutrologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brasil
| | - Joana Rodrigues Dantas
- Departamento de Nutrologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brasil
| | | | - Marina Oliveira Soares
- Faculdade de Medicina, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brasil
| | - Daniel Barretto Kendler
- Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione (Iede), Rio de Janeiro, RJ, Brasil
| | - Rosane Kupfer
- Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione (Iede), Rio de Janeiro, RJ, Brasil
| | - Lenita Zajdenverg
- Departamento de Nutrologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brasil
| | - Melanie Rodacki
- Departamento de Nutrologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brasil
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30
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Lampousi AM, Carlsson S, Löfvenborg JE. Dietary factors and risk of islet autoimmunity and type 1 diabetes: a systematic review and meta-analysis. EBioMedicine 2021; 72:103633. [PMID: 34656932 PMCID: PMC8523874 DOI: 10.1016/j.ebiom.2021.103633] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/21/2021] [Accepted: 10/05/2021] [Indexed: 12/13/2022] Open
Abstract
Background Numerous dietary components have been linked to the development of islet autoimmunity (IA) and type 1 diabetes (T1D); however, no associations are firmly established. This systematic review and meta-analysis aimed to synthesize current knowledge on diet and incidence of IA and T1D. Methods Literature search was performed in Medline, Embase, and Cochrane Library, from inception until October 2020. Eligible studies had IA or T1D as outcome; any dietary exposure; case-control, cohort, or randomized controlled trial design; and hazard, risk, or odds ratios as measures of association. Summary relative risks (RR) and 95% confidence intervals (CI) were estimated with random-effects models. Certainty of evidence was assessed with GRADE. PROSPERO registration number: CRD42020212505. Findings Among 5935 identified records, 96 were eligible, and pooled estimates could be produced for 26 dietary factors. Evidence with moderate/high certainty indicated lower risk of T1D in relation to longer (≥6-12 vs <6-12 months, RR: 0⋅39, CI: 0⋅26-0⋅58, I2=43%) and exclusive (≥2-3 vs <2-3 months, RR: 0⋅68, CI: 0⋅58-0⋅80, I2=0%) breastfeeding, later introduction to gluten (3-6 vs <3-5 months, RR: 0⋅36, CI: 0⋅17-0⋅75, I2=0%), cow's milk (≥2-3 vs <2-3 months, RR: 0⋅69, CI: 0⋅59-0⋅81, I2=0%), and fruit (4-6 vs <4-5 months, RR: 0⋅47, CI: 0⋅25-0⋅86, I2=0%). Higher childhood intake of cow's milk was associated with increased risk of both IA (per 2-3 portions/day, RR: 1⋅25, CI: 1⋅06-1⋅47, I2=0%) and T1D (≥2-3 vs <2-3 glasses/day, RR: 1⋅81, CI: 1⋅12-2⋅91, I2=31%). For the remaining dietary factors investigated, there was no association, or the evidence was of low certainty. Interpretation This study suggests that breastfeeding and late introduction of gluten, fruit, and cow's milk may reduce the risk of T1D, whereas high childhood cow's milk intake may increase it. Funding Swedish Research Council, Swedish Research Council for Health, Working Life and Welfare (FORTE), Novo Nordisk Foundation, and Swedish Diabetes Foundation.
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Affiliation(s)
- Anna-Maria Lampousi
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Sofia Carlsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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31
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Ooms M, Strom A, Strassburger K, Menart B, Leslie RD, Schloot NC. Increased spontaneous CCL2 (MCP-1) and CCL5 (RANTES) secretion in vitro in LADA compared to type 1 diabetes and type 2 diabetes: Action LADA 14. Diabetes Metab Res Rev 2021; 37:e3431. [PMID: 33369072 DOI: 10.1002/dmrr.3431] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/22/2020] [Accepted: 12/14/2020] [Indexed: 11/11/2022]
Abstract
AIMS Immune-mediated type 1 diabetes (T1D) in adulthood and latent autoimmune diabetes in adults (LADA) share similar pathological mechanisms but differ clinically in disease progression. The aim of this study was to acquire insights into spontaneous and stimulated chemokine secretion of immune cells in different diabetes types. MATERIALS AND METHODS We investigated in vitro spontaneous, mitogen (PI) and antigen (HSP60, p277, pGAD, pIA2) stimulated chemokine secretion of leucocytes from patients with T1D (n = 32), LADA (n = 22), type 2 diabetes (T2D; n = 49), and glucose-tolerant individuals (n = 13). Chemokine concentration in supernatants was measured for CCL2 (MCP-1), CXCL10 (IP10) and CCL5 (RANTES) using a multiplex bead array assay. RESULTS Spontaneous secretion of CCL2 and CCL5 were higher in LADA compared to T1D and T2D (all p < 0.05) while CXCL10 was similar in the groups. Mitogen-stimulated secretion of CCL2 in LADA was lower compared to T1D and T2D (all p < 0.05) while CXCL10 and CCL5 were similar in all groups. Upon stimulation with pIA2 the secretion of CCL2 in LADA was lower compared to T2D (p < 0.05). Spontaneous CXCL10 secretion in LADA was positively associated with body mass index (r2 = 0.35; p = 0.0035) and C-peptide (r2 = 0.30; p = 0.009). CONCLUSIONS Chemokine secretion is altered between different diabetes types. Increased spontaneous secretion of CCL2 and CCL5 and decreased secretion of CCL2, upon stimulation with PI and pIA2, in LADA compared to T1D and T2D could reflect altered immune responsiveness in LADA patients in association with their slower clinical progression compared to insulin dependence.
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Affiliation(s)
- Mark Ooms
- Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich-Heine-University, Duesseldorf, Germany
- Clinic and Policlinic for Oral and Maxillofacial Surgery, University Hospital Aachen, Aachen, Germany
| | - Alexander Strom
- Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich-Heine-University, Duesseldorf, Germany
| | - Klaus Strassburger
- Institute for Biometrics and Epidemiology, Leibniz Center for Diabetes Research at Heinrich-Heine-University, Duesseldorf, Germany
| | - Barbara Menart
- Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich-Heine-University, Duesseldorf, Germany
| | - Richard D Leslie
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Nanette C Schloot
- Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich-Heine-University, Duesseldorf, Germany
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Pepe M, Napoli G, Carulli E, Moscarelli M, Forleo C, Nestola PL, Biondi-Zoccai G, Giordano A, Favale S. Autoimmune diseases in patients undergoing percutaneous coronary intervention: A risk factor for in-stent restenosis? Atherosclerosis 2021; 333:24-31. [PMID: 34418682 DOI: 10.1016/j.atherosclerosis.2021.08.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 06/25/2021] [Accepted: 08/04/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Despite the relation between autoimmune diseases and increased atherosclerotic risk is established, the influence of autoimmune disorders on in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is only partly known. ISR is an aberrant reparative process mainly characterized by an increased number of vascular smooth muscle cells and excessive deposition of extracellular proteoglycans and type III collagen. Chronic inflammation, always present in autoimmune diseases, modulates the endothelial response to PCI. Aim of this review is to resume the current evidence on the association between ISR and autoimmune diseases, focusing on pathogenic mechanisms and therapeutic targets. METHODS We conducted a comprehensive review of the literature on the relationship between ISR and insulin-dependent diabetes mellitus (IDDM), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid-antibodies syndrome (APS), inflammatory bowel diseases (IBD), and Hashimoto's thyroiditis (HT). RESULTS Patients affected with IDDM, RA, SLE, APS, IBD and HT proved to face higher rates of ISR compared to the general population. The endothelial dysfunction seems the principal common pathogenic pathway for ISR and is attributed to both the immune system disorder and the systemic inflammation. Some evidence suggested that methotrexate and anti-tumor necrosis factor treatments can be effective in reducing ISR, while antibodies against vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 showed to reduce neointimal hyperplasia in animal models. CONCLUSIONS Autoimmune diseases are a risk factor for ISR. The study of the potential cardiovascular benefits of the current therapies, mainly anti-inflammatory drugs, and the pursuit of innovative treatments appear of paramount interest.
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Affiliation(s)
- Martino Pepe
- Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Piazza G. Cesare 11, Bari (BA), 70120, Italy.
| | - Gianluigi Napoli
- Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Piazza G. Cesare 11, Bari (BA), 70120, Italy
| | - Eugenio Carulli
- Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Piazza G. Cesare 11, Bari (BA), 70120, Italy
| | - Marco Moscarelli
- Cardiothoracic and Vascular Department, Maria Cecilia Hospital GVM Care & Research, Via Via Corriera 1,Cotignola, 48033, Ravenna, Italy
| | - Cinzia Forleo
- Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Piazza G. Cesare 11, Bari (BA), 70120, Italy
| | - Palma Luisa Nestola
- Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Piazza G. Cesare 11, Bari (BA), 70120, Italy
| | - Giuseppe Biondi-Zoccai
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Republica 79, Latina, 04100,Latina, Italy; Mediterranea Cardiocentro, Via Orazio 2, Napoli, 80122, Napoli, Italy
| | - Arturo Giordano
- Invasive Cardiology Unit, "Pineta Grande" Hospital, Via Domitiana km 30, Castel Volturno, 81030, Caserta, Italy
| | - Stefano Favale
- Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University of Bari, Piazza G. Cesare 11, Bari (BA), 70120, Italy
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Chou WC, Chou YY, Pan YW, Tsai MC. Is Non-Stimulated C-Peptide at Diagnosis a Good Predictive Value for Insulin Use at Two Years after Diagnosis in Pediatric Diabetic Patients? MEDICINA-LITHUANIA 2021; 57:medicina57090902. [PMID: 34577825 PMCID: PMC8465312 DOI: 10.3390/medicina57090902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 11/21/2022]
Abstract
Background and Objectives: Insulin treatment may be initially required to stabilize patients presenting with metabolic crisis at type 1 and 2 diabetes mellitus (DM) onset. Some patients with type 2 DM may need persistent insulin treatment. This study aimed to examine the predictive performance of non-stimulated C-peptide level at the time of diagnosis for future insulin use in pediatric diabetic patients. Materials and Methods: We reviewed the medical charts of diabetic patients aged 18 years or younger in a medical center in southern Taiwan from January 2000 to December 2019. Clinical and individual data were collected at the time of DM diagnosis. Outcomes were persistent insulin use at the time of diagnosis, as well as at one and two years after diagnosis. Results: The final analysis included a total of 250 patients. The best cut-off point of non-stimulated C-peptide was 0.95 ng/mL, and the predictive indices for the insulin use were 0.84 for sensitivity and 0.94 for specificity at two years after DM diagnosis. Incorporating age at onset and presence of GAD antibodies can further increase the predictive power of non-stimulated C-peptide. Conclusions: The value of non-stimulated C-peptide at diabetic onset was feasible and effective for predicting future insulin treatment up to the time point of two years after diagnosis.
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Affiliation(s)
- Wei-Chih Chou
- Division of Genetics, Endocrinology, and Metabolism, Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; (W.-C.C.); (Y.-Y.C.); (Y.-W.P.)
- Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
| | - Yen-Yin Chou
- Division of Genetics, Endocrinology, and Metabolism, Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; (W.-C.C.); (Y.-Y.C.); (Y.-W.P.)
| | - Yu-Wen Pan
- Division of Genetics, Endocrinology, and Metabolism, Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; (W.-C.C.); (Y.-Y.C.); (Y.-W.P.)
| | - Meng-Che Tsai
- Division of Genetics, Endocrinology, and Metabolism, Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; (W.-C.C.); (Y.-Y.C.); (Y.-W.P.)
- Correspondence: ; Tel.: +886-6-235-3535 (ext. 4190)
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Komiyama S, Numata K, Ogushi K, Chuma M, Tanaka R, Chiba S, Otani M, Inayama Y, Nakano M, Maeda S. Liver Injury and Use of Contrast-Enhanced Ultrasound for Evaluating Intrahepatic Recurrence in a Case of TACE-Refractory Hepatocellular Carcinoma Receiving Atezolizumab-Bevacizumab Combination Therapy: A Case Report. Diagnostics (Basel) 2021; 11:diagnostics11081394. [PMID: 34441328 PMCID: PMC8392634 DOI: 10.3390/diagnostics11081394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/26/2021] [Accepted: 07/29/2021] [Indexed: 12/29/2022] Open
Abstract
A 67-year-old male with type 2 diabetes (T2DM) was diagnosed with postoperative intrahepatic recurrence for hepatocellular carcinoma (HCC). Nine sessions of transarterial chemoembolization (TACE) proved ineffective, and the patient was diagnosed as having TACE-refractory disease and received seven cycles of atezolizumab-bevacizumab combination therapy. After that, the patient developed hyperglycemia with the HbA1c elevation and the marked fasting serum C-peptide reduction and was diagnosed with developed immune-mediated diabetes (IMD) (T2DM exacerbation with insulin-dependent diabetes development). Subsequently, the hepatobiliary enzyme levels, which were high before the systemic therapy, worsened. Thus, we clinically diagnosed an exacerbation of liver injury due to TACE-induced liver injury complicated by drug-induced liver injury such as immune-mediated hepatotoxicity (IMH). Meanwhile, after contrast-enhanced computed tomography revealed complete response, contrast-enhanced ultrasound was performed to assess intrahepatic recurrence. We found that the latter modality allowed earlier and more definitive diagnosis of intrahepatic recurrence of HCC. Subsequently, despite systemic therapy discontinuation and steroids administration, the liver injury worsened, and the patient died. The autopsy revealed intrahepatic recurrence of HCC and extensive arterial obstruction by the beads used for TACE within the liver, which indicated that disturbed circulation was the primary cause of the liver injury and histopathologically confirmed IMD, but not IMH.
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Affiliation(s)
- Satoshi Komiyama
- Chemotherapy Department, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Kanagawa, Japan;
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Kanagawa, Japan; (K.O.); (M.C.)
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Kanagawa, Japan; (K.O.); (M.C.)
- Correspondence: ; Tel.: +81-45-261-5656
| | - Katsuaki Ogushi
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Kanagawa, Japan; (K.O.); (M.C.)
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Kanagawa, Japan; (K.O.); (M.C.)
| | - Reiko Tanaka
- Division of Diagnostic Pathology, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Kanagawa, Japan; (R.T.); (M.O.); (Y.I.)
| | - Sawako Chiba
- Department of Clinical Laboratory, Yokohama Medical Center, National Hospital Organization, 3-60-2 Harajuku, Totsuka-ku, Yokohama 245-8575, Kanagawa, Japan;
| | - Masako Otani
- Division of Diagnostic Pathology, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Kanagawa, Japan; (R.T.); (M.O.); (Y.I.)
| | - Yoshiaki Inayama
- Division of Diagnostic Pathology, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Kanagawa, Japan; (R.T.); (M.O.); (Y.I.)
| | - Masayuki Nakano
- Tokyo Central Pathology Laboratory, 838-1, Utsukimachi, Hachioji-shi, Tokyo 192-0024, Japan;
| | - Shin Maeda
- Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Kanagawa, Japan;
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Dowey R, Iqbal A, Heller SR, Sabroe I, Prince LR. A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity. Front Immunol 2021; 12:678771. [PMID: 34149714 PMCID: PMC8209466 DOI: 10.3389/fimmu.2021.678771] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/10/2021] [Indexed: 12/16/2022] Open
Abstract
Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality.
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Affiliation(s)
- Rebecca Dowey
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Ahmed Iqbal
- Sheffield Teaching Hospitals National Health Service (NHS) Foundation Trust, Sheffield, United Kingdom
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Simon R. Heller
- Sheffield Teaching Hospitals National Health Service (NHS) Foundation Trust, Sheffield, United Kingdom
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Ian Sabroe
- Sheffield Teaching Hospitals National Health Service (NHS) Foundation Trust, Sheffield, United Kingdom
| | - Lynne R. Prince
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
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Lagarde WH, Courtney KL, Reiner B, Steinmann K, Tsalikian E, Willi SM. Human plasma-derived alpha 1 -proteinase inhibitor in patients with new-onset type 1 diabetes mellitus: A randomized, placebo-controlled proof-of-concept study. Pediatr Diabetes 2021; 22:192-201. [PMID: 33244872 PMCID: PMC7984376 DOI: 10.1111/pedi.13162] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 09/11/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND While circulating levels of alpha1 -proteinase inhibitor (alpha1 -PI) are typically normal, antiprotease activity appears to be compromised in patients with Type 1 diabetes mellitus (T1DM). Because alpha1 -PI [human] (alpha1 -PI[h]) therapy can inhibit pro-inflammatory mediators associated with β-cell destruction and reduced insulin production, it has been proposed for T1DM disease prevention. The aim of this study was to evaluate safety, tolerability, and efficacy of intravenous (IV) alpha1 -PI[h] in preserving C-peptide production in newly diagnosed T1DM patients. PARTICIPANTS Seventy-six participants (aged 6-35 years) were randomized at 25 centers within 3 months of T1DM diagnosis. METHODS A Phase II, multicenter, partially blinded, placebo-controlled, proof-of-concept study evaluating four dosing regimens of alpha1 -PI[h] (NCT02093221, GTI1302): weekly IV infusions of either 90 or 180 mg/kg, each for either 13 or 26 weeks. Safety and efficacy were monitored over 52 weeks with an efficacy evaluation planned at 104 weeks. The primary efficacy endpoint was change from baseline in the 2-h area-under-the-curve C-peptide level from a mixed-meal tolerance test at 52 weeks. A battery of laboratory tests, including inflammatory biomarkers, constituted exploratory efficacy variables. RESULTS Infusions were well tolerated with no new safety signals. All groups exhibited highly variable declines in the primary outcome measure at 52 weeks with no statistically significant difference from placebo. Interleukin-6 (IL-6) was reduced from baseline in all alpha1 -PI treatment groups but not the placebo group. CONCLUSION Pharmacologic therapy with alpha1 -PI[h] is safe, well tolerated, and able to reduce IL-6 levels; however, due to variability in the efficacy endpoint, its effects on preservation of C-peptide production were inconclusive.
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Affiliation(s)
- William H. Lagarde
- Division of Pediatric Endocrinology, Department of PediatricsWakeMed Children's HospitalRaleighNorth CarolinaUSA
| | - Kecia L. Courtney
- Clinical DevelopmentGrifols Therapeutics Inc. Research Triangle ParkNorth CarolinaUSA,Present address:
BiogenResearch Triangle ParkNorth CarolinaUSA
| | | | - Kimberly Steinmann
- Clinical DevelopmentGrifols Therapeutics Inc. Research Triangle ParkNorth CarolinaUSA
| | - Eva Tsalikian
- Pediatric Endocrinology and Diabetes, Stead Family Department of PediatricsUniversity of Iowa Carver College of MedicineIowa CityIowaUSA
| | - Steven M. Willi
- Department of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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Ninić A, Bojanin D, Sopić M, Mihajlović M, Munjas J, Milenković T, Stefanović A, Vekić J, Spasojević-Kalimanovska V. Transforming Growth Factor-β1 and Receptor for Advanced Glycation End Products Gene Expression and Protein Levels in Adolescents with Type 1 iabetes Mellitus. J Clin Res Pediatr Endocrinol 2021; 13:61-71. [PMID: 32936764 PMCID: PMC7947732 DOI: 10.4274/jcrpe.galenos.2020.2020.0155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVE Type 1 diabetes (T1D) mellitus is one of the most frequent autoimmune diseases in childhood. Chronic complications are the main causes of cardiovascular morbidity and mortality in T1D. Although interactions between advanced glycation end products (AGE) and their receptors (RAGE) and transforming growth factor-β1 (TGF-β1) are implicated in development and progression of diabetic microand macro-vascular complications, they also have important roles in immune system regulation. METHODS Blood samples were obtained from 156 adolescents with T1D and 80 apparently healthy controls. T1D patients diagnosed with any other autoimmune disease and receiving any kind of drugs except insulin therapy were excluded from this study. Exclusion criteria for controls were positive family history of T1D and drugs/supplements application. TGF-β1 and transmembrane full-length RAGE (flRAGE) messenger ribonucleic acid (mRNA) levels in peripheral blood mononuclear cells (PBMC) were obtained by quantitative polymerase chain reaction (qPCR) method. Circulating levels of biochemical markers, TGF-β1 and soluble RAGE (sRAGE) levels were also determined. RESULTS TGF-β1 and flRAGE mRNA levels were significantly higher in controls compared to patients (p<0.001, for both). However, TGF-β1 and sRAGE levels were higher in patients than controls (p<0.001, for both). There were significant independent associations of all mRNA and protein levels with T1D. TGF-β1 mRNA was the only marker independently negatively associated with urinary albumin excretion rate in T1D adolescents (p=0.005). CONCLUSION Our results indicated gene expression downregulation of TGF-β1 and flRAGE in PBMC of T1D adolescents. TGF-β1 mRNA downregulation may be useful for predicting early elevation of urinary albumin excretion rate.
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Affiliation(s)
- Ana Ninić
- University of Belgrade Faculty of Pharmacy, Department for Medical Biochemistry, Belgrade, Serbia,* Address for Correspondence: University of Belgrade Faculty of Pharmacy, Department for Medical Biochemistry, Belgrade, Serbia Phone: +381 11 3951 266 E-mail:
| | - Dragana Bojanin
- Mother and Child Health Care Institute of Serbia “Dr Vukan Čupić”, Biochemical Laboratory, Belgrade, Serbia
| | - Miron Sopić
- University of Belgrade Faculty of Pharmacy, Department for Medical Biochemistry, Belgrade, Serbia
| | - Marija Mihajlović
- University of Belgrade Faculty of Pharmacy, Department for Medical Biochemistry, Belgrade, Serbia
| | - Jelena Munjas
- University of Belgrade Faculty of Pharmacy, Department for Medical Biochemistry, Belgrade, Serbia
| | - Tatjana Milenković
- Mother and Child Health Care Institute of Serbia “Dr Vukan Čupić”, Department of Endocrinology, Belgrade, Serbia
| | - Aleksandra Stefanović
- University of Belgrade Faculty of Pharmacy, Department for Medical Biochemistry, Belgrade, Serbia
| | - Jelena Vekić
- University of Belgrade Faculty of Pharmacy, Department for Medical Biochemistry, Belgrade, Serbia
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Type 1 diabetes: genes associated with disease development. Cent Eur J Immunol 2021; 45:439-453. [PMID: 33658892 PMCID: PMC7882399 DOI: 10.5114/ceji.2020.103386] [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: 03/27/2019] [Accepted: 01/02/2020] [Indexed: 11/17/2022] Open
Abstract
Type 1 diabetes (T1D) is the third most common autoimmune disease which develops due to genetic and environmental risk factors. Based on the World Health Organization (WHO) report from 2014 the number of people suffering from all types of diabetes ascended to 422 million, compared to 108 million in 1980. It was calculated that this number will double by the end of 2030. In 2015 American Diabetes Association (ADA) announced that 30.3 million Americans (that is 9.4% of the overall population) had diabetes of which only approximately 1.25 million had T1D. Nowadays, T1D represents roughly 10% of adult diabetes cases total. Multiple genetic abnormalities at different loci have been found to contribute to type 1 diabetes development. The analysis of genome-wide association studies (GWAS) of T1D has identified over 50 susceptible regions (and genes within these regions). Many of these regions are defined by single nucleotide polymorphisms (SNPs) but molecular mechanisms through which they increase or lower the risk of diabetes remain unknown. Genetic factors (in existence since birth) can be detected long before the emergence of immunological or clinical markers. Therefore, a comprehensive understanding of the multiple genetic factors underlying T1D is extremely important for further clinical trials and development of personalized medicine for diabetic patients. We present an overview of current studies and information about regions in the human genome associated with T1D. Moreover, we also put forward information about epigenetic modifications, non-coding RNAs and environmental factors involved in T1D development and onset.
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Gale MJ, Scruggs BA, Flaxel CJ. Diabetic eye disease: A review of screening and management recommendations. Clin Exp Ophthalmol 2021; 49:128-145. [DOI: 10.1111/ceo.13894] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/04/2020] [Accepted: 12/13/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Michael J. Gale
- Casey Eye Institute, Department of Ophthalmology Oregon Health & Science University Portland Oregon USA
| | - Brittni A. Scruggs
- Casey Eye Institute, Department of Ophthalmology Oregon Health & Science University Portland Oregon USA
| | - Christina J. Flaxel
- Casey Eye Institute, Department of Ophthalmology Oregon Health & Science University Portland Oregon USA
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Bianchi S, Martínez Allo VC, Massimino M, Lavignolle Heguy MDR, Borzone FR, Gomez Bustillo S, Chasseing NA, Libertun C, Montaner AD, Rabinovich GA, Toscano MA, Lux-Lantos VA, Bianchi MS. Oligonucleotide IMT504 Improves Glucose Metabolism and Controls Immune Cell Mediators in Female Diabetic NOD Mice. Nucleic Acid Ther 2020; 31:155-171. [PMID: 33347786 DOI: 10.1089/nat.2020.0901] [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] [Indexed: 12/16/2022] Open
Abstract
Type 1 diabetes occurs as a consequence of progressive autoimmune destruction of beta cells. A potential treatment for this disease should address the immune attack on beta cells and their preservation/regeneration. The objective of this study was to elucidate whether the immunomodulatory synthetic oligonucleotide IMT504 was able to ameliorate diabetes in NOD mice and to provide further understanding of its mechanism of action. We found that IMT504 restores glucose homeostasis in a diabetes mouse model similar to human type 1 diabetes, by regulating expression of immune modulatory factors and improving beta cell function. IMT504 treatment markedly improved fasting glycemia, insulinemia, and homeostatic model assessment of beta cell function (HOMA-Beta cell) index. Moreover, this treatment increased islet number and decreased apoptosis, insulitis, and CD45+ pancreas-infiltrating leukocytes. In a long-term treatment, we observed improvement of glucose metabolism up to 9 days after IMT504 cessation and increased survival after 15 days of the last IMT504 injection. We postulate that interleukin (IL)-12B (p40), possibly acting as a homodimer, and Galectin-3 (Gal-3) may function as mediators of this immunomodulatory action. Overall, these results validate the therapeutic activity of IMT504 as a promising drug for type 1 diabetes and suggest possible downstream mediators of its immunomodulatory effect.
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Affiliation(s)
- Stefania Bianchi
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Verónica C Martínez Allo
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Milena Massimino
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María Del R Lavignolle Heguy
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Francisco R Borzone
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Sofía Gomez Bustillo
- Instituto de Ciencia y Tecnología César Milstein-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación Pablo Cassará, Buenos Aires, Argentina
| | - Norma A Chasseing
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Carlos Libertun
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.,Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Alejandro D Montaner
- Instituto de Ciencia y Tecnología César Milstein-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación Pablo Cassará, Buenos Aires, Argentina
| | - Gabriel A Rabinovich
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.,Departmento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Marta A Toscano
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Victoria A Lux-Lantos
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María S Bianchi
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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Zhang X, Gao B, Xu B. No association between the vitamin D-binding protein (DBP) gene polymorphisms (rs7041 and rs4588) and multiple sclerosis and type 1 diabetes mellitus: A meta-analysis. PLoS One 2020; 15:e0242256. [PMID: 33180889 PMCID: PMC7661054 DOI: 10.1371/journal.pone.0242256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 10/29/2020] [Indexed: 01/05/2023] Open
Abstract
Background The association between polymorphisms in vitamin D-binding protein (DBP) gene and the risk of multiple sclerosis (MS) and type 1 diabetes mellitus (T1DM) has been investigated in many studies, but the studies showed controversial results. The rationale for this meta-analysis was to determine whether DBP polymorphisms increases the risk of MS and T1DM by pooling data. Methods Potentially relevant studies were searched using GWAS Catalog, PubMed, Embase, CNKI and WANFANG databases up to November 2019. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were performed to estimate the associations in a fixed-effects or random-effects model. Results A total of 13 studies were enrolled in this meta-analysis, including eight studies for MS and five for T1DM. The overall results showed that there was no significant association of DBP rs7041 and rs4588 polymorphisms with the risk of MS and T1DM under any genetic model. Similarly, subgroup analysis by ethnicity revealed that no significant association of rs7041 and rs4588 polymorphisms with the risk of MS and T1DM was observed in white or non-white racial groups. Conclusions This meta-analysis provides evidence that DBP rs7041 and rs4588 polymorphisms may not be associated with an increased risk in MS and T1DM. However, these findings need further validation by larger-scale epidemiological studies and genome-wide association studies (GWASs) in different populations.
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Affiliation(s)
- Xin Zhang
- Department of Neurology, Shenyang First People’s Hospital, Shenyang, Liaoning Province, China
| | - Bai Gao
- Department of Nerve Function, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Bing Xu
- Department of Neurology, Shenyang First People’s Hospital, Shenyang, Liaoning Province, China
- * E-mail:
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Resanović I, Zarić B, Radovanović J, Sudar-Milovanović E, Gluvić Z, Jevremović D, Isenović ER. Hyperbaric Oxygen Therapy and Vascular Complications in Diabetes Mellitus. Angiology 2020; 71:876-885. [PMID: 32638622 DOI: 10.1177/0003319720936925] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Vascular complications in patients with diabetes mellitus (DM) are common. Since impaired oxygen balance in plasma plays an important role in the pathogenesis of chronic DM-associated complications, the administration of hyperbaric oxygen therapy (HBOT) has been recommended to influence development of vascular complications. Hyperbaric oxygen therapy involves inhalation of 100% oxygen under elevated pressure from 1.6 to 2.8 absolute atmospheres in hyperbaric chambers. Hyperbaric oxygen therapy increases plasma oxygen solubility, contributing to better oxygen diffusion to distant tissues and preservation of the viability of tissues reversibly damaged by atherosclerosis-induced ischemia, along with microcirculation restoration. Hyperbaric oxygen therapy exerts antiatherogenic, antioxidant, and cardioprotective effects by altering the level and composition of plasma fatty acids and also by promoting signal transduction through membranes, which are impaired by hyperglycemia and hypoxia. In addition, HBOT affects molecules involved in the regulation of nitric oxide synthesis and in that way exerts anti-inflammatory and angiogenic effects in patients with DM. In this review, we explore the recent literature related to the effects of HBOT on DM-related vascular complications.
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Affiliation(s)
- Ivana Resanović
- Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Božidarka Zarić
- Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Jelena Radovanović
- Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Emina Sudar-Milovanović
- Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvić
- Department of Endocrinology and Diabetes, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Serbia
| | - Danimir Jevremović
- Faculty of Stomatology in Pancevo, University Business Academy, Novi Sad, Serbia
| | - Esma R Isenović
- Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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Zamanfar D, Aarabi M, Amini M, Monajati M. Prevalence of autoantibodies in type 1 diabetes mellitus pediatrics in Mazandaran, North of Iran. J Pediatr Endocrinol Metab 2020; 33:1299-1305. [PMID: 32809953 DOI: 10.1515/jpem-2019-0396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 05/13/2020] [Indexed: 01/02/2023]
Abstract
Objectives Type 1 diabetes is an autoimmune disease. Its most important immunologic markers are pancreatic beta-cell autoantibodies. This study aimed to determine diabetes mellitus antibodies frequency among children and adolescents with type 1 diabetes. Methods This descriptive study evaluated the frequency of four diabetes autoantibodies (glutamic acid decarboxylase 65 autoantibodies [GADA], islet cell autoantibodies [ICA], insulin autoantibodies [IAA], tyrosine phosphatase-like insulinoma antigen-2 antibodies [IA-2A]) and their serum level in children and adolescents diagnosed with type 1 diabetes mellitus at the diabetes department of Bou-Ali-Sina Hospital and Baghban Clinic, Sari, Iran, from March 2012 to March 2018. The relationship between the level of different antibodies and age, gender, and diabetes duration were determined. A two-sided p value less than 0.05 indicated statistical significance. Results One hundred forty-two eligible patient records were screened. The average age at diabetes diagnosis was 4.2 ± 4.4 years. The median duration of diabetes was 34.0 (12.7-69.7) months. 53.5% of patients were female, and 81.7% of them had at least one positive autoantibody, and ICA in 66.2%, GADA in 56.3%, IA-2A in 40.1%, and IAA in 21.8% were positive. The type of the autoantibodies and their serum level was similar between females and males but there was a higher rate of positive autoantibodies in females. The level of IA-2A and ICA were in positive and weak correlation with age at diagnosis. Conclusions More than 80% of pediatric and adolescent patients with type 1 diabetes were autoantibody-positive. ICA and GADA were the most frequently detected autoantibodies. The presence of antibodies was significantly higher in females.
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Affiliation(s)
- Daniel Zamanfar
- Department of Pediatric Endocrinology, Diabetes Research Center of Mazandaran, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohsen Aarabi
- Department of Epidemiology, Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Monireh Amini
- Medical School, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mahila Monajati
- Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Iran
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Li N, Jiang D, He Q, He F, Li Y, Deng C, Li F. microRNA-181c-5p promotes the formation of insulin-producing cells from human induced pluripotent stem cells by targeting smad7 and TGIF2. Cell Death Dis 2020; 11:462. [PMID: 32541687 PMCID: PMC7295798 DOI: 10.1038/s41419-020-2668-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 12/28/2022]
Abstract
Generating insulin-producing cells (IPCs) from human pluripotent stem cells is a promising method for studying the molecular mechanism underlying pancreas development and a potential treatment source for type 1 diabetes. Previous studies have shown that miR-181c-5p is highly enriched in adult islets; however, its role in pancreatic β cell differentiation is poorly understood. In this study, we differentiated human induced pluripotent stem cells (hiPSCs) into IPCs in a stepwise process that recapitulated pancreas organogenesis and observed that miR-181c-5p continuously accumulated throughout the entire differentiation process. hiPSCs were transduced with lentiviral vectors containing human miR-181c-5p precursor, which significantly increased the endodermal markers SOX17, FOXA2, CXCR4 and GATA4 and pancreatic endocrine-specific gene expression, including PDX1, NKX6.1, MAFA and Insulin. miR-181c-5p overexpression exerted little effect on the efficiency of definitive endoderm, whereas it promoted the differentiation of pancreatic progenitors and IPCs, especially for NKX6.1-positive and insulin-positive cells differentiation. Transplanted these cells exhibit glucose-stimulated C-peptide secretion in vivo and protect mice from chemically induced diabetes. It was found that miR-181c-5p directly targets the 3'UTR of smad7 and TGIF2 mRNA, which are known to be endogenous repressors of TGF-β-smad2/3 signaling, to decrease their mRNA and protein levels. Furthermore, overexpressed miR-181c-5p led to an elevation of the smad2/3 phosphorylation levels in hiPSC-derived cells, while treatment with smad2/3 inhibitors following miR-181c-5p overexpression had opposite effects on IPC formation. These results suggest that miR-181c-5p is critically involved in pancreatic lineage commitment through direct repression of smad7 and TGIF2 and that it modulates TGF-β-smad2/3 signaling activation and increases the feasibility of using patient-specific hiPSCs for β cell replacement therapy for type 1 diabetes.
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Affiliation(s)
- Ning Li
- Translational Medicine Collaborative Innovation Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Shenzhen Cell Therapy Public Service Platform, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Shenzhen key Laboratory of Stem Cell Research and Clinical Transformation, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Doukou Jiang
- Translational Medicine Collaborative Innovation Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Shenzhen Cell Therapy Public Service Platform, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Qian He
- Translational Medicine Collaborative Innovation Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Shenzhen Cell Therapy Public Service Platform, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Integrated Chinese and Western Medicine Postdoctoral research station, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Fei He
- Translational Medicine Collaborative Innovation Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Shenzhen Cell Therapy Public Service Platform, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Integrated Chinese and Western Medicine Postdoctoral research station, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Yang Li
- Translational Medicine Collaborative Innovation Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Shenzhen Cell Therapy Public Service Platform, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Chunyan Deng
- Translational Medicine Collaborative Innovation Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Shenzhen Cell Therapy Public Service Platform, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.,Shenzhen key Laboratory of Stem Cell Research and Clinical Transformation, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Furong Li
- Translational Medicine Collaborative Innovation Center, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China. .,Shenzhen Cell Therapy Public Service Platform, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China. .,Shenzhen key Laboratory of Stem Cell Research and Clinical Transformation, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
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Naseri R, Navabi SJ, Samimi Z, Mishra AP, Nigam M, Chandra H, Olatunde A, Tijjani H, Morais-Urano RP, Farzaei MH. Targeting Glycoproteins as a therapeutic strategy for diabetes mellitus and its complications. Daru 2020; 28:333-358. [PMID: 32006343 PMCID: PMC7095136 DOI: 10.1007/s40199-020-00327-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 01/10/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Glycoproteins are organic compounds formed from proteins and carbohydrates, which are found in many parts of the living systems including the cell membranes. Furthermore, impaired metabolism of glycoprotein components plays the main role in the pathogenesis of diabetes mellitus. The aim of this study is to investigate the influence of glycoprotein levels in the treatment of diabetes mellitus. METHODS All relevant papers in the English language were compiled by searching electronic databases, including Scopus, PubMed and Cochrane library. The keywords of glycoprotein, diabetes mellitus, glycan, glycosylation, and inhibitor were searched until January 2019. RESULTS Glycoproteins are pivotal elements in the regulation of cell proliferation, growth, maturation and signaling pathways. Moreover, they are involved in drug binding, drug transportation, efflux of chemicals and stability of therapeutic proteins. These functions, structure, composition, linkages, biosynthesis, significance and biological effects are discussed as related to their use as a therapeutic strategy for the treatment of diabetes mellitus and its complications. CONCLUSIONS The findings revealed several chemical and natural compounds have significant beneficial effects on glycoprotein metabolism. The comprehension of glycoprotein structure and functions are very essential and inevitable to enhance the knowledge of glycoengineering for glycoprotein-based therapeutics as may be required for the treatment of diabetes mellitus and its associated complications. Graphical abstract.
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Affiliation(s)
- Rozita Naseri
- Internal Medicine Department, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Jafar Navabi
- Internal Medicine Department, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zeinab Samimi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Abhay Prakash Mishra
- Department of Pharmaceutical Chemistry, Hemwati Nandan Bahuguna Garhwal (A Central) University, Srinagar Garhwal, Uttarakhand, 246174, India.
| | - Manisha Nigam
- Department of Biochemistry, Hemwati Nandan Bahuguna Garhwal University, Srinagar Garhwal, Uttarakhand, 246174, India
| | - Harish Chandra
- Department of Microbiology, Gurukul Kangri Vishwavidhyalya, Haridwar, Uttarakhand, 249404, India
| | - Ahmed Olatunde
- Department of Biochemistry, Abubakar Tafawa Balewa University, Bauchi, Nigeria
| | - Habibu Tijjani
- Natural Product Research Laboratory, Department of Biochemistry, Bauchi State University, Gadau, Nigeria
| | - Raquel P Morais-Urano
- Instituto de Química de São Carlos, Universidade de São Paulo, 13560-970, São Carlos, SP, Brasil
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Tabatabaeian H, Rao A, Ramos A, Chu T, Sudol M, Lim YP. The emerging roles of WBP2 oncogene in human cancers. Oncogene 2020; 39:4621-4635. [PMID: 32393834 PMCID: PMC7286818 DOI: 10.1038/s41388-020-1318-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/21/2020] [Accepted: 04/24/2020] [Indexed: 12/15/2022]
Abstract
WW domain-binding protein 2 (WBP2) is an emerging oncoprotein. Over the past decade, WBP2 surfaced as a key node connecting key signaling pathways associated with ER/PR, EGFR, PI3K, Hippo, and Wnt in cancer. In addition to the oncogenic functions of WBP2, this review discusses the latest research regarding the multilevel regulation and modes of action of WBP2 and how they can be exploited for molecular medicine. In translational research, evidence supports the role of WBP2 as a biomarker for early detection, prognosis, and companion diagnostics in breast cancer. Finally, we envision new trends in WBP2 research in the space of molecular etiology of cancer, targeted therapeutics, and precision medicine.
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Affiliation(s)
- Hossein Tabatabaeian
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
| | - Angad Rao
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
| | - Alisha Ramos
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
| | - Tinghine Chu
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 117456, Singapore
| | - Marius Sudol
- Department of Physiology, National University of Singapore, Mechanobiology Institute, Singapore, 117597, Singapore
- Institute for Molecular and Cell Biology (IMCB, A*STAR), Singapore, 138673, Singapore
- Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Yoon Pin Lim
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore.
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 117456, Singapore.
- National University Cancer Institute, Singapore, 119082, Singapore.
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Gordon J, Beresford-Hulme L, Bennett H, Tank A, Edmonds C, McEwan P. Relationship between hypoglycaemia, body mass index and quality of life among patients with type 1 diabetes: Observations from the DEPICT clinical trial programme. Diabetes Obes Metab 2020; 22:857-865. [PMID: 31970881 DOI: 10.1111/dom.13972] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 01/06/2020] [Accepted: 01/16/2020] [Indexed: 11/27/2022]
Abstract
AIMS To demonstrate the relationships between hypoglycaemia, body mass index (BMI) and quality of life, and to examine the impact of dapagliflozin on patient-reported treatment satisfaction in patients with type 1 diabetes mellitus (T1DM), using data from the DEPICT (Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes) clinical trial programme. METHODS A two-stage modelling approach, using a linear regression framework, was adopted to evaluate the relationship between hypoglycaemia, BMI and quality of life. Hypoglycaemia fear score (HFS) was modelled as a function of hypoglycaemic events (non-severe documented symptomatic and severe) and, subsequently, quality of life (as measured by the EQ-5D questionnaire) was modelled as a function of HFS and BMI. A linked evidence approach correlated the relationship between treatment, hypoglycaemic events and glycated haemoglobin (HbA1c), to the relationships captured within the regression models. The proportion of patients achieving increased patient-reported treatment satisfaction, as measured by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) total score, was compared between study arms. RESULTS Incident severe hypoglycaemia was associated with significantly higher HFS (coefficient estimate [CE] 14.62, P=0.004). The frequency of symptomatic hypoglycaemic events was associated with a significantly higher HFS (log transposed, CE 1.32, P=0.026). Higher HFS and higher BMI were both independently associated with a significantly lower EQ-5D score (HFS: CE -0.0024, P<0.001; BMI: CE -0.0026, P=0.016). Significantly higher proportions of dapagliflozin-treated patients achieved ≥3-point increases in DTSQ total score compared to patients in the placebo group. CONCLUSION The results of this study demonstrated that increases in hypoglycaemia and BMI were associated with reduced quality of life in people with T1DM. Dapagliflozin-treated patients achieved a reduction in HbA1c whilst avoiding an increase in hypoglycaemic events. The results also showed that treatment with dapagliflozin was associated with an improvement in treatment satisfaction.
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Affiliation(s)
- Jason Gordon
- Health Economics and Outcomes Research Ltd, Birmingham, UK
| | | | | | | | | | - Phil McEwan
- Health Economics and Outcomes Research Ltd, Cardiff, UK
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Issar T, Yan A, Kwai NCG, Poynten AM, Borire AA, Arnold R, Krishnan AV. Altered peripheral nerve structure and function in latent autoimmune diabetes in adults. Diabetes Metab Res Rev 2020; 36:e3260. [PMID: 31833206 DOI: 10.1002/dmrr.3260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 11/14/2019] [Accepted: 11/27/2019] [Indexed: 11/07/2022]
Abstract
AIM The present study was undertaken to investigate mechanisms of peripheral nerve dysfunction in latent autoimmune diabetes in adults (LADA). MATERIALS AND METHODS Participants with LADA (n = 15) underwent median nerve ultrasonography and nerve excitability to examine axonal structure and function, in comparison to cohorts of type 1 diabetes (n = 15), type 2 diabetes (n = 23) and healthy controls (n = 26). The LADA group was matched for diabetes duration, glycaemic control, and neuropathy severity with the type 1 and type 2 diabetes groups. A validated mathematical model of the human axon was utilized to investigate the pathophysiological basis of nerve dysfunction. RESULTS The most severe changes in nerve structure and function were noted in the LADA group. The LADA cohort demonstrated a significant increase in nerve cross-sectional area compared to type 1 participants and controls. Compared to type 1 and 2 diabetes, measures of threshold electrotonus, which assesses nodal and internodal conductances, were significantly worse in LADA in response to both depolarising currents and hyperpolarising currents. In the recovery cycle, participants with LADA had a significant increase in the relative refractory period. Mathematical modelling of excitability recordings indicated the basis of nerve dysfunction in LADA was different to type 1 and 2 diabetes. CONCLUSIONS Participants with LADA exhibited more severe changes in nerve function and different underlying pathophysiological mechanisms compared to participants with type 1 or 2 diabetes. Intensive management of risk factors to delay the progression of neuropathy in LADA may be required.
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Affiliation(s)
- Tushar Issar
- Prince of Wales Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
| | - Aimy Yan
- Prince of Wales Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
| | - Natalie C G Kwai
- Prince of Wales Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
- Department of Exercise Physiology, UNSW Sydney, Sydney, New South Wales, Australia
| | - Ann M Poynten
- Department of Endocrinology, Prince of Wales Hospital, Sydney, New South Wales, Australia
| | - Adeniyi A Borire
- Prince of Wales Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
| | - Ria Arnold
- Department of Exercise Physiology, UNSW Sydney, Sydney, New South Wales, Australia
| | - Arun V Krishnan
- Prince of Wales Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
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Rios-Arce ND, Dagenais A, Feenstra D, Coughlin B, Kang HJ, Mohr S, McCabe LR, Parameswaran N. Loss of interleukin-10 exacerbates early Type-1 diabetes-induced bone loss. J Cell Physiol 2020; 235:2350-2365. [PMID: 31538345 PMCID: PMC6899206 DOI: 10.1002/jcp.29141] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 08/23/2019] [Indexed: 01/08/2023]
Abstract
Type-1 diabetes (T1D) increases systemic inflammation, bone loss, and risk for bone fractures. Levels of the anti-inflammatory cytokine interleukin-10 (IL-10) are decreased in T1D, however their role in T1D-induced osteoporosis is unknown. To address this, diabetes was induced in male IL-10 knockout (KO) and wild-type (WT) mice. Analyses of femur and vertebral trabecular bone volume fraction identified bone loss in T1D-WT mice at 4 and 12 weeks, which in T1D-IL-10-KO mice was further reduced at 4 weeks but not 12 weeks. IL-10 deficiency also increased the negative effects of T1D on cortical bone. Osteoblast marker osterix was decreased, while osteoclast markers were unchanged, suggesting that IL-10 promotes anabolic processes. MC3T3-E1 osteoblasts cultured under high glucose conditions displayed a decrease in osterix which was prevented by addition of IL-10. Taken together, our results suggest that IL-10 is important for promoting osteoblast maturation and reducing bone loss during early stages of T1D.
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Affiliation(s)
- Naiomy Deliz Rios-Arce
- Department of Physiology, Michigan State University, East Lansing, Michigan
- Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, Michigan
| | - Andrew Dagenais
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Derrick Feenstra
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Brandon Coughlin
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Ho Jun Kang
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Susanne Mohr
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Laura R. McCabe
- Department of Physiology, Michigan State University, East Lansing, Michigan
- Department of Radiology, Michigan State University, East Lansing, Michigan
- Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan
- These authors contributed equally to this work are co-senior and co-corresponding authors
| | - Narayanan Parameswaran
- Department of Physiology, Michigan State University, East Lansing, Michigan
- Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, Michigan
- These authors contributed equally to this work are co-senior and co-corresponding authors
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Zhao F, Liu X, Wang Z, Lang H, Zhang T, Wang R, Lin X, He D, Shi P, Pang X. Novel Mouse miRNA Chr13_novelMiR7354-5p Improves Bone-Marrow-Derived Mesenchymal Stem Cell Differentiation into Insulin-Producing Cells. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 19:1110-1122. [PMID: 32059337 PMCID: PMC7016162 DOI: 10.1016/j.omtn.2020.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 12/22/2019] [Accepted: 01/02/2020] [Indexed: 12/18/2022]
Abstract
MicroRNAs (miRNAs) that play key roles in the generation of insulin-producing cells from stem cells provide a cell-based approach for insulin replacement therapy. In this study, we used next-generation sequencing to detect the miRNA expression profile of normal mouse pancreatic β cells, non-β cells, bone marrow mesenchymal stem cells (BM-MSCs), and adipose-derived stem cells (ADSCs) and determined relative miRNA expression levels in mouse pancreatic β cells. After the novel mouse miRNA candidates were identified using miRDeep 2.0, we found that Chr13_novelMiR7354-5p, a novel miRNA candidate, significantly promoted the differentiation of BM-MSCs into insulin-producing cells in vitro. Furthermore, Chr13_novelMiR7354-5p-transfected BM-MSCs reversed hyperglycemia in streptozotocin (STZ)-treated diabetic mice. In addition, bioinformatics analyses, a luciferase reporter assay, and western blotting demonstrated that Chr13_novelMiR7354-5p targeted Notch1 and Rbpj. Our results provide compelling evidence of the existence of 65 novel mouse miRNA candidates and present a new treatment strategy to generate insulin-producing cells from stem cells.
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Affiliation(s)
- Feng Zhao
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Street, Shenbei New District, Shenyang City 110122, Liaoning Province, China
| | - Xiaoyu Liu
- Department of Obstetrics and Gynecology, Center for Assisted Reproduction, Shengjing Hospital of China Medical University, 39 Huaxiang Street, Tiexi District, Shenyang City 110022, Liaoning Province, China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang City 110004, Liaoning Province, China
| | - Hongxin Lang
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Street, Shenbei New District, Shenyang City 110122, Liaoning Province, China
| | - Tao Zhang
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Street, Shenbei New District, Shenyang City 110122, Liaoning Province, China
| | - Rui Wang
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Street, Shenbei New District, Shenyang City 110122, Liaoning Province, China
| | - Xuewen Lin
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Street, Shenbei New District, Shenyang City 110122, Liaoning Province, China
| | - Dan He
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Street, Shenbei New District, Shenyang City 110122, Liaoning Province, China
| | - Ping Shi
- Shenyang Amnion Bioengineering and Technology R&D Center, 155-5 Chuangxin Street, Hunnan District, Shenyang City 110015, Liaoning Province, China
| | - Xining Pang
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Street, Shenbei New District, Shenyang City 110122, Liaoning Province, China; Shenyang Amnion Bioengineering and Technology R&D Center, 155-5 Chuangxin Street, Hunnan District, Shenyang City 110015, Liaoning Province, China.
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