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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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Pala K, Sun KX, Krogvold L, Dahl-Jørgensen K, Reddy S. Distribution of glutathione peroxidase-1 immunoreactive cells in pancreatic islets from type 1 diabetic donors and non-diabetic donors with and without islet cell autoantibodies is variable and independent of disease. Cell Tissue Res 2025. [DOI: 10.1007/s00441-025-03955-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 01/30/2025] [Indexed: 04/03/2025]
Abstract
Abstract
During type 1 diabetes (T1D), oxidative stress in beta cells may cause early beta cell dysfunction and initiate autoimmunity. Mouse islets express lower levels of reactive oxygen species (ROS) clearing enzymes, such as glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase than several other tissues. It remains unclear if human beta cells show a similar deficiency during T1D or exhibit a higher degree of intrinsic resistance to oxidative stress. We compared islet cell distributions and determined graded intensities of glutathione peroxidase1 (GPX1), a key enzymatic mediator involved in detoxifying hydrogen peroxide, by applying combined immunohistochemistry for GPX1, insulin and glucagon, in pancreatic sections from new-onset T1D (group 1), non-diabetic autoantibody-negative (group 2), non-diabetic autoantibody-positive (group 3) and long-term diabetic (group 4) donors. Islets from all study groups demonstrated either uniform but graded staining intensities for GPX1 in almost all islet cells or strong staining in selective islet cells with weaker intensities in the remaining cells. GPX1 was present in selective glucagon cells and insulin cells, including in cells negative for both hormones, with stronger intensities in a higher percentage of glucagon than insulin cells. It was absent in a higher percentage of beta cells than glucagon cells independent of disease or autoantibody positivity. We conclude that a proportion of human beta cells and glucagon cells express GPX1 but show heterogeneity in its distribution and intensities, independent of disease or autoantibody status. Our studies highlight important differences in the expression of GPX1 in islet cell-types between mice and humans.
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Alahmari LA, Ali LS, Fansa HA, Alshaya DS, Al-Salmi FA, El-Hallous EI, Eldesoqui M, Gad Elsaid F, Fayad E, El-Mansy AA, Alsharif G, Khalil DY, Mahmood MB, Khalil RY, Rashwan HM, El-Sawah SG. Antioxidant and Antiapoptotic Effects of Selenium And Nano Selenium-Loaded Exosomes on Hepatic Dysfunction of Type 1 Diabetic Rats. JOURNAL OF EXPERIMENTAL ZOOLOGY. PART A, ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY 2025; 343:211-219. [PMID: 39535481 DOI: 10.1002/jez.2881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024]
Abstract
Mesenchymal stem cells-derived exosomes (MSCs-EXs) applications have brought a key breakthrough in treating type 1 diabetes mellitus (T1DM) and its diabetic complications. However, various recent strategies aimed to construct prominent engineered EXs with greater precision and higher efficiency for diabetes syndrome were conducted. In this research, we seek to enhance the medicinal potentialities of MSCs-EXs on type 1 diabetic rats' hepatic complications, via loading with either selenium (Se) or nano selenium (NSe) particles. For consecutive 4-weeks, rats were divided into 8 groups as; control, EXs, EXs + Se, EXs + NSe, STZ-diabetic (D), D + EXs, D + EXs + Se, and D + EXs + NSe groups. The three diabetic-treated groups manifested a significant reduction in hepatic contents of oxidative stress (OS) (MDA, NO, and H2O2) inflammatory (IL-6, TNF-α, and TGF-β), and apoptotic (P53, BAX, caspase-3, and Bcl2) markers, with marked elevation in hepatic antioxidant levels (GSH, GPX, SOD, and CAT). Such results were supported by the marked diminish in serum total proteins, liver function enzymes (AST, ALT, and bilirubin), and both serum and liver lipid profile fractions. In addition, hepatic histological examination showed marked improvement in liver architecture of all treated diabetic rats' groups, compared to diabetic untreated rats. Significantly, diabetic rats with EXs loaded with NSe exhibited the most therapeutic superiority.
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Affiliation(s)
- Layla A Alahmari
- Department of Community Health, College of Applied Medical Sciences, Northern Border University, Arar, Saudi Arabia
| | - Lashin S Ali
- Department of Basic Medical Science, Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan
- Physiology Department, Faculty of Medicine, Mansoura University, Mansours, Egypt
| | - Hoda A Fansa
- Department of Basic Dental Sciences, Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan
- Department of Oral Biology, Faculty of Dentistry, Alexandria University, Egypt
| | - Dalal S Alshaya
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Fawziah A Al-Salmi
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
| | - Ehab I El-Hallous
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| | - Mamdouh Eldesoqui
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Diriyah, Riyadh, Saudi Arabia
| | - Fahmy Gad Elsaid
- Department of Biology, College of Science, King Khalid University, Asir, Abha, Saudi Arabia
| | - Eman Fayad
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Ahmed A El-Mansy
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa, Jordan
- Department of Medical Histology & Cell Biology, Faculty of Medicine, Mansoura University, Mansours, Egypt
| | - Ghadi Alsharif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University of Health Sciences, Jeddah, Saudi Arabia
- Department of Biomedical Research, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Dlovan Y Khalil
- Biology Department, Faculty of Science, Sulaimani University, Sulaimaniyah, Iraq
| | - Maryam Bakir Mahmood
- Obstetrics & Gynecology Department, College of Medicine, Slaimani University, Sulaymaniyah, Iraq
| | - Rozhan Yassin Khalil
- Obstetrics & Gynecology Department, College of Medicine, Slaimani University, Sulaymaniyah, Iraq
| | - Hanan M Rashwan
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| | - Shady G El-Sawah
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
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Yin W, Zou S, Sha M, Sun L, Gong H, Xiong C, Huang X, Wang J, Zhang Y, Li X, Liang J, Chang X, Wang S, Su D, Guo W, Zhang Y, Wu T, Chen F. Gain of pancreatic beta cell-specific SCD1 improves glucose homeostasis by maintaining functional beta cell mass under metabolic stress. Diabetologia 2025; 68:629-645. [PMID: 39690249 DOI: 10.1007/s00125-024-06343-w] [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: 07/26/2024] [Accepted: 10/31/2024] [Indexed: 12/19/2024]
Abstract
AIMS/HYPOTHESIS The key pancreatic beta cell transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA) is critical for the maintenance of mature beta cell function and phenotype. The expression levels and/or activities of MafA are reduced when beta cells are chronically exposed to diabetogenic stress, such as hyperglycaemia (i.e. glucotoxicity). Interventional targets and adjuvant therapies to abate MafA loss in beta cells may provide evidence to support the effective treatment of diabetes. In this study, we aimed to investigate the function of stearoyl-CoA desaturase 1 (SCD1) in the stabilisation of MafA expression and activity in order to maintain functional beta cell mass, with a view to suppressing the development of type 2 diabetes. METHODS SCD1 expression levels were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. Pancreatic beta cell-specific Scd1 knockin (βSCD1KI) mice were generated to study the role of SCD1 in beta cell function and identity. The protein-to-protein interactions between SCD1 and MafA were detected in MIN6 and HEK293A cells. We used experiments including chromatin immunoprecipitation, cell-based ubiquitination assay and fatty acid composition analysis to investigate the specific molecular mechanism underlying the effect of SCD1 on the restoration of MafA and beta cell function under glucotoxic conditions. RESULTS SCD1 expression was reduced in beta cells of humans with type 2 diabetes and in HFD-fed and db/db mice compared with healthy controls, which was attributed to glucotoxicity-induced Scd1 promoter histone deacetylation. Gain-of-function of SCD1 in beta cells improved insulin deficiency, glucose intolerance and beta cell dedifferentiation/transdifferentiation in the HFD-induced mouse model of diabetes. Mechanistically, SCD1 directly bound to the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and stabilised nuclear MafA through interrupting MafA-HRD1 interactions in mouse islets and MIN6 cells, which inhibited the ubiquitination-mediated degradation of MafA. Moreover, the products of SCD enzyme reactions (mainly oleic acid) also alleviated glucotoxicity-mediated oxidative stress in MIN6 cells. CONCLUSIONS/INTERPRETATION Our findings indicate that SCD1 stabilises beta cell MafA both in desaturase-dependent and -independent manners, thus improving glucose homeostasis under metabolic stress. This provides a potential novel target for precision medicine for the treatment of diabetes.
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Affiliation(s)
- Wenyue Yin
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Suyun Zou
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Min Sha
- Department of Central Laboratory, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Taizhou, Jiangsu, China
| | - Liangjun Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haoqiang Gong
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Can Xiong
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xinyue Huang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianan Wang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuhan Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xirui Li
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jin Liang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wanhua Guo
- Department of Nuclear Medicine, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Yaqin Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Tijun Wu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Fang Chen
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Ahmed I, Chakraborty R, Faizy AF, Moin S. Exploring the key role of DNA methylation as an epigenetic modulator in oxidative stress related islet cell injury in patients with type 2 diabetes mellitus: a review. J Diabetes Metab Disord 2024; 23:1699-1718. [PMID: 39610516 PMCID: PMC11599646 DOI: 10.1007/s40200-024-01496-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/21/2024] [Indexed: 11/30/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterised by impaired insulin secretion and action, often exacerbated by oxidative stress. Recent research has highlighted the intricate involvement of epigenetic mechanisms, particularly DNA methylation, in the pathogenesis of T2DM. This review aims to elucidate the role of DNA methylation as an epigenetic modifier in oxidative stress-mediated beta cell dysfunction, a key component of T2DM pathophysiology. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, is a hallmark feature of T2DM. Beta cells, responsible for insulin secretion, are particularly vulnerable to oxidative damage due to their low antioxidant capacity. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta cells, leading to altered gene expression profiles associated with insulin secretion and cell survival. Furthermore, studies have identified specific genes involved in beta cell function and survival that undergo DNA methylation changes in response to oxidative stress in T2DM. These epigenetic modifications can perpetuate beta cell dysfunction by dysregulating key pathways essential for insulin secretion, such as the insulin signalling cascade and mitochondrial function. Understanding the interplay between DNA methylation, oxidative stress, and beta cell dysfunction holds promise for developing novel therapeutic strategies for T2DM. Targeting aberrant DNA methylation patterns may offer new avenues for restoring beta cell function and improving glycemic control in patients with T2DM. However, further research is needed to elucidate the complex mechanisms underlying epigenetic regulation in T2DM and to translate these findings into clinical interventions.
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Affiliation(s)
- Istiaque Ahmed
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Ritoja Chakraborty
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Abul Faiz Faizy
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Shagufta Moin
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
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Demircan K, Chillon TS, Bang J, Gladyshev VN, Schomburg L. Selenium, diabetes, and their intricate sex-specific relationship. Trends Endocrinol Metab 2024; 35:781-792. [PMID: 38599899 DOI: 10.1016/j.tem.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 04/12/2024]
Abstract
Selenium (Se) is an essential trace element, which is inserted as selenocysteine (Sec) into selenoproteins during biosynthesis, orchestrating their expression and activity. Se is associated with both beneficial and detrimental health effects; deficient supply or uncontrolled supplementation raises concerns. In particular, Se was associated with an increased incidence of type 2 diabetes (T2D) in a secondary analysis of a randomized controlled trial (RCT). In this review, we discuss the intricate relationship between Se and diabetes and the limitations of the available clinical and experimental studies. Recent evidence points to sexual dimorphism and an association of Se deficiency with gestational diabetes mellitus (GDM). We highlight the emerging evidence linking high Se status with improved prognosis in patients with T2D and lower risk of macrovascular complications.
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Affiliation(s)
- Kamil Demircan
- Institute for Experimental Endocrinology, Max Rubner Center, Charité University Berlin, Germany
| | - Thilo Samson Chillon
- Institute for Experimental Endocrinology, Max Rubner Center, Charité University Berlin, Germany
| | - Jeyoung Bang
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Vadim N Gladyshev
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Lutz Schomburg
- Institute for Experimental Endocrinology, Max Rubner Center, Charité University Berlin, Germany.
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Li F, Hong X, Wang H, Li W, Chen L, Wang L, Zhao B, Wang S, Jiang H, Wang Z. Association of Dietary Selenium Intake with Type 2 Diabetes in Middle-Aged and Older Adults in China. Nutrients 2024; 16:2367. [PMID: 39064810 PMCID: PMC11279410 DOI: 10.3390/nu16142367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/17/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The relationship between distinct dietary selenium intake and type 2 diabetes (T2D) is still a topic of uncertainty. This study examined the relationship between dietary selenium intake and T2D risk among middle-aged and older Chinese adults. Dietary selenium intake was assessed through three 24 h recalls, using data from the China Health and Nutrition Survey. To investigate the relationship and the potential dose-response pattern between selenium intake and the likelihood of developing T2D, we employed both the restricted cubic spline analysis and the Cox proportional hazards model as our analytical tools. A cohort of 5970 participants aged ≥ 50 years was followed for an average of 5.44 years. The results revealed a V-shaped correlation between selenium intake and T2D risk, with the lowest risk observed at approximately 45 µg/day. Below this level, the risk decreased with an increasing selenium intake, while the risk increased between 45 and 100 µg/day. No significant association was found beyond 100 µg/day. These findings suggest that both low and high selenium consumption may increase T2D risk, highlighting the importance of maintaining a balanced selenium intake for T2D prevention.
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Affiliation(s)
- Fangyuan Li
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
| | - Xi Hong
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
| | - Huijun Wang
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
| | - Weiyi Li
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
| | - Lili Chen
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
| | - Liusen Wang
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
| | - Boya Zhao
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
| | - Shaoshunzi Wang
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
| | - Hongru Jiang
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
| | - Zhihong Wang
- Office of National Nutrition Plan, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 27 Nanwei Road, Beijing 100050, China; (F.L.); (X.H.); (H.W.); (W.L.); (L.C.); (L.W.); (B.Z.); (S.W.)
- Key Laboratory of Public Nutrition and Health, National Health Commission of the People’s Republic of China, Beijing 100050, China
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Robertson RP. Antioxidants for Early Treatment of Type 2 Diabetes in Rodents and Humans: Lost in Translation? Diabetes 2024; 73:653-658. [PMID: 38387049 PMCID: PMC11043055 DOI: 10.2337/db23-0901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/13/2024] [Indexed: 02/24/2024]
Abstract
Reactive oxygen species (ROS) are formed by virtually all tissues. In normal concentrations they facilitate many physiologic activities, but in excess they cause oxidative stress and tissue damage. Local antioxidant enzyme synthesis in cells is regulated by the cytoplasmic KEAP-1/Nrf2 complex, which is stimulated by ROS, to release Nrf2 for entry into the nucleus, where it upregulates antioxidant gene expression. Major antioxidant enzymes include glutathione peroxidase (GPx), catalase (CAT), superoxide dismutases (SOD), hemoxygenases (HO), and peroxiredoxins (Prdx). Notably, the pancreatic islet β-cell does not express GPx or CAT, which puts it at greater risk for ROS damage caused by postprandial hyperglycemia. Experimentally, overexpression of GPx in β-cell lines and isolated islets, as well as in vivo studies using genetic models of type 2 diabetes (T2D), has demonstrated enhanced protection against hyperglycemia and oxidative stress. Oral treatment of diabetic rodents with ebselen, a GPx mimetic that is approved for human clinical use, reproduced these findings. Prdx detoxify hydrogen peroxide and reduce lipid peroxides. This suggests that pharmacologic development of more potent, β-cell-specific antioxidants could be valuable as a treatment for oxidative stress due to postprandial hyperglycemia in early T2D in humans. ARTICLE HIGHLIGHTS
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Affiliation(s)
- R. Paul Robertson
- Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA
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9
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Leenders F, de Koning EJP, Carlotti F. Pancreatic β-Cell Identity Change through the Lens of Single-Cell Omics Research. Int J Mol Sci 2024; 25:4720. [PMID: 38731945 PMCID: PMC11083883 DOI: 10.3390/ijms25094720] [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: 03/15/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 05/13/2024] Open
Abstract
The main hallmark in the development of both type 1 and type 2 diabetes is a decline in functional β-cell mass. This decline is predominantly attributed to β-cell death, although recent findings suggest that the loss of β-cell identity may also contribute to β-cell dysfunction. This phenomenon is characterized by a reduced expression of key markers associated with β-cell identity. This review delves into the insights gained from single-cell omics research specifically focused on β-cell identity. It highlights how single-cell omics based studies have uncovered an unexpected level of heterogeneity among β-cells and have facilitated the identification of distinct β-cell subpopulations through the discovery of cell surface markers, transcriptional regulators, the upregulation of stress-related genes, and alterations in chromatin activity. Furthermore, specific subsets of β-cells have been identified in diabetes, such as displaying an immature, dedifferentiated gene signature, expressing significantly lower insulin mRNA levels, and expressing increased β-cell precursor markers. Additionally, single-cell omics has increased insight into the detrimental effects of diabetes-associated conditions, including endoplasmic reticulum stress, oxidative stress, and inflammation, on β-cell identity. Lastly, this review outlines the factors that may influence the identification of β-cell subpopulations when designing and performing a single-cell omics experiment.
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Affiliation(s)
| | | | - Françoise Carlotti
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (F.L.); (E.J.P.d.K.)
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Khalil DY, Hussein RH, El-Kholy WM. Mesenchymal Stem Cell-Derived Exosomes Loaded with Selenium or Nano Selenium as a Novel Therapeutic Paradigm for Streptozotocin-Induced Type 1 Diabetes in Rats. BIOLOGY 2024; 13:253. [PMID: 38666865 PMCID: PMC11048049 DOI: 10.3390/biology13040253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024]
Abstract
Type 1 diabetes mellitus (T1DM) is a metabolic disorder characterized by hyperglycemia due to insulin insufficiency as a consequence of the pancreatic β-cells' auto-immune attack. Nowadays, the application of mesenchymal stem cell-derived exosomes (MSCs-Exs) as the main cell-free therapy for diabetes treatment is becoming more and more extensive. In non-autologous therapy, researchers are moving towards a new strategy based on loading MSC-Exs with certain drugs, aimed at maintaining and maximizing the function of exosomes at the function site and enhancing their efficiency and safety. This study aims to explore and compare the therapeutic potentialities of mesenchymal stem cell-derived exosomes (MSCs-Exs) loaded with either selenium (Se) or nano selenium (NSe), a natural antioxidant micronutrient, in the management of T1DM in rats. In our 4-week experiment, six rat groups were included, namely, control, Ex+Se, Ex+NSe, STZ-diabetic (D), D+ Ex+Se, and D+Ex+NSe groups. Both diabetic-treated groups showed marked pancreatic regenerative antioxidant, immunomodulatory, anti-inflammatory, and anti-apoptotic capacities, with the D+Ex+NSe injection showing superiority in managing diabetes hazards, as evidenced by various biochemical and histological assessments.
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Affiliation(s)
- Dlovan Y. Khalil
- Virology Department, Central Health Laboratory, Ministry of Health, Sulaymaniyah 46012, Iraq
- Department of Biology, College of Science, Slaimani University, Sulaymaniyah 46001, Iraq;
| | - Ridah H. Hussein
- Department of Biology, College of Science, Slaimani University, Sulaymaniyah 46001, Iraq;
| | - Wafaa M. El-Kholy
- Zoology Department, Faculty of Science, Mansoura University, Mansoura P.O. Box 11432, Egypt;
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11
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Lu Y, Tian H, Peng H, Wang Q, Bunnell BA, Bazan NG, Hong S. Novel lipid mediator 7 S,14 R-docosahexaenoic acid: biogenesis and harnessing mesenchymal stem cells to ameliorate diabetic mellitus and retinal pericyte loss. Front Cell Dev Biol 2024; 12:1380059. [PMID: 38533089 PMCID: PMC10963555 DOI: 10.3389/fcell.2024.1380059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 02/29/2024] [Indexed: 03/28/2024] Open
Abstract
Introduction: Stem cells can be used to treat diabetic mellitus and complications. ω3-docosahexaenoic acid (DHA) derived lipid mediators are inflammation-resolving and protective. This study found novel DHA-derived 7S,14R-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid (7S,14R-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7S,14R-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic db/db mice. Methods: MSCs treated with 7S,14R-diHDHA were delivered into db/db mice i.v. every 5 days for 35 days. Results: Blood glucose levels in diabetic mice were lowered by 7S,14R-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7S,14R-diHDHA-treated MSCs increased insulin+ β-cell ratio and decreased glucogan+ α-cell ratio in islets, as well as reduced macrophages in pancreas. 7S,14R-diHDHA induced MSC functions in promoting MIN6 β-cell viability and insulin secretion. 7S,14R-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7S,14R-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in db/db mice. Discussion: Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7S,14R-diHDHA-primed MSCs.
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Affiliation(s)
- Yan Lu
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
| | - Haibin Tian
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Tongji University, Shanghai, China
| | - Hongying Peng
- Biostatistics, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Quansheng Wang
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bruce A. Bunnell
- Tulane University School of Medicine, Center for Stem Cell Research and Regenerative Medicine, New Orleans, LA, United States
| | - Nicolas G. Bazan
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Department of Ophthalmology, School of Medicine, L.S.U. Health, New Orleans, LA, United States
| | - Song Hong
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Department of Ophthalmology, School of Medicine, L.S.U. Health, New Orleans, LA, United States
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12
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Baumel-Alterzon S, Katz LS, Lambertini L, Tse I, Heidery F, Garcia-Ocaña A, Scott DK. NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function. Diabetologia 2024; 67:547-560. [PMID: 38206362 PMCID: PMC11521447 DOI: 10.1007/s00125-023-06071-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 11/13/2023] [Indexed: 01/12/2024]
Abstract
AIMS/HYPOTHESIS All forms of diabetes result from insufficient functional beta cell mass. Due to the relatively limited expression of several antioxidant enzymes, beta cells are highly vulnerable to pathological levels of reactive oxygen species (ROS), which can lead to the reduction of functional beta cell mass. During early postnatal ages, both human and rodent beta cells go through a burst of proliferation that quickly declines with age. The exact mechanisms that account for neonatal beta cell proliferation are understudied but mitochondrial release of moderated ROS levels has been suggested as one of the main drivers. We previously showed that, apart from its conventional role in protecting beta cells from oxidative stress, the nuclear factor erythroid 2-related factor 2 (NRF2) is also essential for beta cell proliferation. We therefore hypothesised that NRF2, which is activated by ROS, plays an essential role in beta cell proliferation at early postnatal ages. METHODS Beta cell NRF2 levels and beta cell proliferation were measured in pancreatic sections from non-diabetic human cadaveric donors at different postnatal ages, childhood and adulthood. Pancreatic sections from 1-, 7-, 14- and 28-day-old beta cell-specific Nrf2 (also known as Nfe2l2)-knockout mice (βNrf2KO) or control (Nrf2lox/lox) mice were assessed for beta cell NRF2 levels, beta cell proliferation, beta cell oxidative stress, beta cell death, nuclear beta cell pancreatic duodenal homeobox protein 1 (PDX1) levels and beta cell mass. Seven-day-old βNrf2KO and Nrf2lox/lox mice were injected daily with N-acetylcysteine (NAC) or saline (154 mmol/l NaCl) to explore the potential contribution of oxidative stress to the phenotypes seen in βNrf2KO mice at early postnatal ages. RNA-seq was performed on 7-day-old βNrf2KO and Nrf2lox/lox mice to investigate the mechanisms by which NRF2 stimulates beta cell proliferation at early postnatal ages. Mitochondrial biogenesis and function were determined using dispersed islets from 7-day-old βNrf2KO and Nrf2lox/lox mice by measuring MitoTracker intensity, mtDNA/gDNA ratio and ATP/ADP ratio. To study the effect of neonatal beta cell-specific Nrf2 deletion on glucose homeostasis in adulthood, blood glucose, plasma insulin and insulin secretion were determined and a GTT was performed on 3-month-old βNrf2KO and Nrf2lox/lox mice fed on regular diet (RD) or high-fat diet (HFD). RESULTS The expression of the master antioxidant regulator NRF2 was increased at early postnatal ages in both human (1 day to 19 months old, 31%) and mouse (7 days old, 57%) beta cells, and gradually declined with age (8% in adult humans, 3.77% in adult mice). A significant correlation (R2=0.568; p=0.001) was found between beta cell proliferation and NRF2 levels in human beta cells. Seven-day-old βNrf2KO mice showed reduced beta cell proliferation (by 65%), beta cell nuclear PDX1 levels (by 23%) and beta cell mass (by 67%), and increased beta cell oxidative stress (threefold) and beta cell death compared with Nrf2lox/lox control mice. NAC injections increased beta cell proliferation in 7-day-old βNrf2KO mice (3.4-fold) compared with saline-injected βNrf2KO mice. Interestingly, RNA-seq of islets isolated from 7-day-old βNrf2KO mice revealed reduced expression of mitochondrial RNA genes and genes involved in the electron transport chain. Islets isolated from 7-day old βNrf2KO mice presented reduced MitoTracker intensity (by 47%), mtDNA/gDNA ratio (by 75%) and ATP/ADP ratio (by 68%) compared with islets from Nrf2lox/lox littermates. Lastly, HFD-fed 3-month-old βNrf2KO male mice displayed a significant reduction in beta cell mass (by 35%), a mild increase in non-fasting blood glucose (1.2-fold), decreased plasma insulin (by 14%), and reduced glucose tolerance (1.3-fold) compared with HFD-fed Nrf2lox/lox mice. CONCLUSIONS/INTERPRETATION Our study highlights NRF2 as an essential transcription factor for maintaining neonatal redox balance, mitochondrial biogenesis and function and beta cell growth, and for preserving functional beta cell mass in adulthood under metabolic stress. DATA AVAILABILITY Sequencing data are available in the NCBI Gene Expression Omnibus, accession number GSE242718 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242718 ).
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Affiliation(s)
- Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Liora S Katz
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Luca Lambertini
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Isabelle Tse
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fatema Heidery
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adolfo Garcia-Ocaña
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope, Duarte, CA, USA
| | - Donald K Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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13
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Kimani CN, Reuter H, Kotzé SH, Venter P, Ramharack P, Muller CJF. Pancreatic beta cell regenerative potential of Zanthoxylum chalybeum Engl. Aqueous stem bark extract. JOURNAL OF ETHNOPHARMACOLOGY 2024; 320:117374. [PMID: 37944876 DOI: 10.1016/j.jep.2023.117374] [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: 08/20/2023] [Revised: 10/18/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Zanthoxylum chalybeum Engl. is endemic to Africa and has been used traditionally to treat diabetes mellitus. Moreover, its pharmacological efficacy has been confirmed experimentally using in vitro and in vivo models of diabetes. However, the effects of Z. chalybeum extracts and its major constituent compounds on beta cell and islet regeneration are not clear. Further, the mechanisms associated with observed antidiabetic effects at the beta cell level are not fully elucidated. AIM OF THE STUDY We determined the beta cell regenerative efficacy of Z. chalybeum aqueous stem bark extract, identified the chemical compounds in Z. chalybeum aqueous stem bark extracts and explored their putative mechanisms of action. MATERIALS AND METHODS Phytochemical profiling of the Z. chalybeum extract was achieved using ultra high-performance liquid chromatography hyphenated to high-resolution mass spectrometry. Thereafter, molecular interactions of the compounds with beta cell regeneration targets were evaluated via molecular docking. In vitro, effects of the extract on cell viability, proliferation, apoptosis and oxidative stress were investigated in RIN-5F beta cells exposed to palmitate or streptozotocin. In vivo, pancreas tissue sections from streptozotocin-induced diabetic male Wistar rats treated with Z. chalybeum extract were stained for insulin, glucagon, pancreatic duodenal homeobox protein 1 (Pdx-1) and Ki-67. RESULTS Based on ligand target and molecular docking interactions diosmin was identified as a dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) inhibitor. In vitro, Z. chalybeum augmented cell viability and cell proliferation while in palmitate-pre-treated cells, the extract significantly increased cell activity after 72 h. In vivo, although morphometric analysis showed decreased islet and beta cell size and density, observation of increased Pdx-1 and Ki-67 immunoreactivity in extract-treated islets suggests that Z. chalybeum extract has mild beta cell regenerative potential mediated by increased cell proliferation. CONCLUSIONS Overall, the mitogenic effects observed in vitro, were not robust enough to elicit sufficient recovery of functional beta cell mass in our in vivo model, in the context of a sustained diabetic milieu. However, the identification of diosmin as a potential Dyrk1A inhibitor merits further inquiry into the attendant molecular interactions.
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Affiliation(s)
- Clare Njoki Kimani
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa; Department of Non-communicable Diseases, Institute of Primate Research, PO Box 24481, Karen, Nairobi, Kenya.
| | - Helmuth Reuter
- Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa
| | - Sanet Henriët Kotzé
- Division of Clinical Anatomy, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa; Division of Anatomy, Department of Biomedical Sciences, School of Veterinary Medicine, Ross University, PO Box 334, Basseterre, Saint Kitts and Nevis
| | - Pieter Venter
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa
| | - Pritika Ramharack
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Christo John Frederick Muller
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Centre for Cardio-Metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, 3886, South Africa
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14
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Gallardo-Villanueva P, Fernández-Marcelo T, Villamayor L, Valverde AM, Ramos S, Fernández-Millán E, Martín MA. Synergistic Effect of a Flavonoid-Rich Cocoa-Carob Blend and Metformin in Preserving Pancreatic Beta Cells in Zucker Diabetic Fatty Rats. Nutrients 2024; 16:273. [PMID: 38257166 PMCID: PMC10821282 DOI: 10.3390/nu16020273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/13/2024] [Accepted: 01/15/2024] [Indexed: 01/24/2024] Open
Abstract
The loss of functional beta-cell mass in diabetes is directly linked to the development of diabetic complications. Although dietary flavonoids have demonstrated antidiabetic properties, their potential effects on pancreatic beta-cell preservation and their synergistic benefits with antidiabetic drugs remain underexplored. We have developed a potential functional food enriched in flavonoids by combining cocoa powder and carob flour (CCB), which has shown antidiabetic effects. Here, we investigated the ability of the CCB, alone or in combination with metformin, to preserve pancreatic beta cells in an established diabetic context and their potential synergistic effect. Zucker diabetic fatty rats (ZDF) were fed a CCB-rich diet or a control diet, with or without metformin, for 12 weeks. Markers of pancreatic oxidative stress and inflammation, as well as relative beta-cell mass and beta-cell apoptosis, were analyzed. Results demonstrated that CCB feeding counteracted pancreatic oxidative stress by enhancing the antioxidant defense and reducing reactive oxygen species. Moreover, the CCB suppressed islet inflammation by preventing macrophage infiltration into islets and overproduction of pro-inflammatory cytokines, along with the inactivation of nuclear factor kappa B (NFκB). As a result, the CCB supplementation prevented beta-cell apoptosis and the loss of beta cells in ZDF diabetic animals. The observed additive effect when combining the CCB with metformin underscores its potential as an adjuvant therapy to delay the progression of type 2 diabetes.
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Affiliation(s)
- Paula Gallardo-Villanueva
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain; (P.G.-V.); (T.F.-M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (L.V.); (A.M.V.); (S.R.)
| | - Tamara Fernández-Marcelo
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain; (P.G.-V.); (T.F.-M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (L.V.); (A.M.V.); (S.R.)
| | - Laura Villamayor
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (L.V.); (A.M.V.); (S.R.)
- Instituto de Investigaciones Biomedicas Sols-Morreale (IIB-CSIC), 28029 Madrid, Spain
| | - Angela M. Valverde
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (L.V.); (A.M.V.); (S.R.)
- Instituto de Investigaciones Biomedicas Sols-Morreale (IIB-CSIC), 28029 Madrid, Spain
| | - Sonia Ramos
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (L.V.); (A.M.V.); (S.R.)
- Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN-CSIC), 28040 Madrid, Spain
| | - Elisa Fernández-Millán
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain; (P.G.-V.); (T.F.-M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (L.V.); (A.M.V.); (S.R.)
| | - María Angeles Martín
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (L.V.); (A.M.V.); (S.R.)
- Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN-CSIC), 28040 Madrid, Spain
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15
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Tanday N, Tarasov AI, Moffett RC, Flatt PR, Irwin N. Pancreatic islet cell plasticity: Pathogenic or therapeutically exploitable? Diabetes Obes Metab 2024; 26:16-31. [PMID: 37845573 DOI: 10.1111/dom.15300] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/07/2023] [Accepted: 09/18/2023] [Indexed: 10/18/2023]
Abstract
The development of pancreatic islet endocrine cells is a tightly regulated process leading to the generation of distinct cell types harbouring different hormones in response to small changes in environmental stimuli. Cell differentiation is driven by transcription factors that are also critical for the maintenance of the mature islet cell phenotype. Alteration of the insulin-secreting β-cell transcription factor set by prolonged metabolic stress, associated with the pathogenesis of diabetes, obesity or pregnancy, results in the loss of β-cell identity through de- or transdifferentiation. Importantly, the glucose-lowering effects of approved and experimental antidiabetic agents, including glucagon-like peptide-1 mimetics, novel peptides and small molecules, have been associated with preventing or reversing β-cell dedifferentiation or promoting the transdifferentiation of non-β-cells towards an insulin-positive β-cell-like phenotype. Therefore, we review the manifestations of islet cell plasticity in various experimental settings and discuss the physiological and therapeutic sides of this phenomenon, focusing on strategies for preventing β-cell loss or generating new β-cells in diabetes. A better understanding of the molecular mechanisms underpinning islet cell plasticity is a prerequisite for more targeted therapies to help prevent β-cell decline in diabetes.
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Affiliation(s)
- Neil Tanday
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
| | - Andrei I Tarasov
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - R Charlotte Moffett
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Nigel Irwin
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland
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16
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Rabah HM, Mohamed DA, Mariah RA, Abd El-Khalik SR, Khattab HA, AbuoHashish NA, Abdelsattar AM, Raslan MA, Farghal EE, Eltokhy AK. Novel insights into the synergistic effects of selenium nanoparticles and metformin treatment of letrozole - induced polycystic ovarian syndrome: targeting PI3K/Akt signalling pathway, redox status and mitochondrial dysfunction in ovarian tissue. Redox Rep 2023; 28:2160569. [PMID: 36661246 PMCID: PMC9870018 DOI: 10.1080/13510002.2022.2160569] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
PURPOSE Polycystic ovary syndrome (PCOS) has a series of reproductive and metabolic consequences. Although the link between PCOS, IR, and obesity, their impact on the pathogenesis of PCOS has yet to be determined. Dysfunction of PI3K/AKT pathway has been reported as the main cause of IR in PCOS. This study purposed to explore the effects of selenium nanoparticles (SeNPs) alone and combined with metformin (MET) in a PCOS-IR rat model. METHODS After 3 weeks of treatment with SeNPs and/or MET, biochemical analysis of glycemic & lipid profiles, and serum reproductive hormones was performed. Inflammatory, oxidative stress, and mitochondrial dysfunction markers were determined colormetrically. The expression of PI3K and Akt genes were evaluated by Real-time PCR. Histopathological examination and Immunohistochemical analysis of Ki-67 expression were performed. RESULTS The results showed that treatment with SeNPs and/or MET significantly attenuated insulin sensitivity, lipid profile, sex hormones levels, inflammatory, oxidative stress and mitochondrial functions markers. Additionally, PI3K and Akt genes expression were significantly upregulated with improved ovarian histopathological changes. CONCLUSION Combined SeNPs and MET therapy could be potential therapeutic agent for PCOS-IR model via modulation of the PI3K/Akt pathway, enhancing anti-inflammatory and anti-oxidant properties and altered mitochondrial functions. HighlightsThe strong relationship between obesity, insulin resistance, and polycystic ovarian syndrome.Disturbance of the PI3K/Akt signaling pathway is involved in the progression of polycystic ovary syndrome-insulin resistance (PCOS-IR).In PCOS-IR rats, combined SeNPs and metformin therapy considerably alleviated IR by acting on the PI3K/Akt signaling pathway.The combination of SeNPs and metformin clearly repaired ovarian polycystic pathogenesis and improved hormonal imbalance in PCOS-IR rats.
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Affiliation(s)
- Hanem M. Rabah
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Darin A. Mohamed
- Histopathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Reham A. Mariah
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Haidy A. Khattab
- Medical Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | | | - Mohamed A. Raslan
- Gynecology and Obstetrics Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Eman E. Farghal
- Clinical and Chemical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Amira K. Eltokhy
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt, Amira K. Eltokhy ; Medical Biochemistry Department, Faculty of Medicine, Tanta University, El Geesh Street, Tanta, Egypt
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17
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Vived C, Lee-Papastavros A, Aparecida da Silva Pereira J, Yi P, MacDonald TL. β Cell Stress and Endocrine Function During T1D: What Is Next to Discover? Endocrinology 2023; 165:bqad162. [PMID: 37947352 DOI: 10.1210/endocr/bqad162] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/27/2023] [Accepted: 11/07/2023] [Indexed: 11/12/2023]
Abstract
Canonically, type 1 diabetes (T1D) is a disease characterized by autoreactive T cells as perpetrators of endocrine dysfunction and β cell death in the spiral toward loss of β cell mass, hyperglycemia, and insulin dependence. β Cells have mostly been considered as bystanders in a flurry of autoimmune processes. More recently, our framework for understanding and investigating T1D has evolved. It appears increasingly likely that intracellular β cell stress is an important component of T1D etiology/pathology that perpetuates autoimmunity during the progression to T1D. Here we discuss the emerging and complex role of β cell stress in initiating, provoking, and catalyzing T1D. We outline the bridges between hyperglycemia, endoplasmic reticulum stress, oxidative stress, and autoimmunity from the viewpoint of intrinsic β cell (dys)function, and we extend this discussion to the potential role for a therapeutic β cell stress-metabolism axis in T1D. Lastly, we mention research angles that may be pursued to improve β cell endocrine function during T1D. Biology gleaned from studying T1D will certainly overlap to innovate therapeutic strategies for T2D, and also enhance the pursuit of creating optimized stem cell-derived β cells as endocrine therapy.
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Affiliation(s)
- Celia Vived
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | | | - Jéssica Aparecida da Silva Pereira
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Peng Yi
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Diabetes Program, Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Tara L MacDonald
- Section for Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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18
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Chaudière J. Biological and Catalytic Properties of Selenoproteins. Int J Mol Sci 2023; 24:10109. [PMID: 37373256 DOI: 10.3390/ijms241210109] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/06/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Selenocysteine is a catalytic residue at the active site of all selenoenzymes in bacteria and mammals, and it is incorporated into the polypeptide backbone by a co-translational process that relies on the recoding of a UGA termination codon into a serine/selenocysteine codon. The best-characterized selenoproteins from mammalian species and bacteria are discussed with emphasis on their biological function and catalytic mechanisms. A total of 25 genes coding for selenoproteins have been identified in the genome of mammals. Unlike the selenoenzymes of anaerobic bacteria, most mammalian selenoenzymes work as antioxidants and as redox regulators of cell metabolism and functions. Selenoprotein P contains several selenocysteine residues and serves as a selenocysteine reservoir for other selenoproteins in mammals. Although extensively studied, glutathione peroxidases are incompletely understood in terms of local and time-dependent distribution, and regulatory functions. Selenoenzymes take advantage of the nucleophilic reactivity of the selenolate form of selenocysteine. It is used with peroxides and their by-products such as disulfides and sulfoxides, but also with iodine in iodinated phenolic substrates. This results in the formation of Se-X bonds (X = O, S, N, or I) from which a selenenylsulfide intermediate is invariably produced. The initial selenolate group is then recycled by thiol addition. In bacterial glycine reductase and D-proline reductase, an unusual catalytic rupture of selenium-carbon bonds is observed. The exchange of selenium for sulfur in selenoproteins, and information obtained from model reactions, suggest that a generic advantage of selenium compared with sulfur relies on faster kinetics and better reversibility of its oxidation reactions.
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Affiliation(s)
- Jean Chaudière
- CBMN (CNRS, UMR 5248), University of Bordeaux, 33600 Pessac, France
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19
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Zhang F, Li X, Wei Y. Selenium and Selenoproteins in Health. Biomolecules 2023; 13:biom13050799. [PMID: 37238669 DOI: 10.3390/biom13050799] [Citation(s) in RCA: 94] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/19/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Selenium is a trace mineral that is essential for health. After being obtained from food and taken up by the liver, selenium performs various physiological functions in the body in the form of selenoproteins, which are best known for their redox activity and anti-inflammatory properties. Selenium stimulates the activation of immune cells and is important for the activation of the immune system. Selenium is also essential for the maintenance of brain function. Selenium supplements can regulate lipid metabolism, cell apoptosis, and autophagy, and have displayed significant alleviating effects in most cardiovascular diseases. However, the effect of increased selenium intake on the risk of cancer remains unclear. Elevated serum selenium levels are associated with an increased risk of type 2 diabetes, and this relationship is complex and nonlinear. Selenium supplementation seems beneficial to some extent; however, existing studies have not fully explained the influence of selenium on various diseases. Further, more intervention trials are needed to verify the beneficial or harmful effects of selenium supplementation in various diseases.
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Affiliation(s)
- Fan Zhang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuelian Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yumiao Wei
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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20
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Dludla PV, Mabhida SE, Ziqubu K, Nkambule BB, Mazibuko-Mbeje SE, Hanser S, Basson AK, Pheiffer C, Kengne AP. Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress. World J Diabetes 2023; 14:130-146. [PMID: 37035220 PMCID: PMC10075035 DOI: 10.4239/wjd.v14.i3.130] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/26/2022] [Accepted: 02/28/2023] [Indexed: 03/15/2023] Open
Abstract
Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D). Beyond the detrimental effects of insulin resistance, inflammation and oxidative stress have emerged as critical features of T2D that define β-cell dysfunction. Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D. Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D. Such effects illustrate a pathological relationship between an abnormal inflammatory response and generation of oxidative stress during the progression of T2D. The current review explores preclinical and clinical research on the patho-logical implications of inflammation and oxidative stress during the development of β-cell dysfunction in T2D. Moreover, important molecular mechanisms and relevant biomarkers involved in this process are discussed to divulge a pathological link between inflammation and oxidative stress during β-cell failure in T2D. Underpinning the clinical relevance of the review, a systematic analysis of evidence from randomized controlled trials is covered, on the potential therapeutic effects of some commonly used antidiabetic agents in modulating inflammatory makers to improve β-cell function.
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Affiliation(s)
- Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Sihle E Mabhida
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
| | - Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho 2745, South Africa
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | | | - Sidney Hanser
- Department of Physiology and Environmental Health, University of Limpopo, Sovenga 0727, South Africa
| | - Albert Kotze Basson
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
| | - Andre Pascal Kengne
- Department of Medicine, University of Cape Town, Cape Town 7500, South Africa
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Tygerberg 7505, South Africa
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21
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Nrf2 and Antioxidant Response in Animal Models of Type 2 Diabetes. Int J Mol Sci 2023; 24:ijms24043082. [PMID: 36834496 PMCID: PMC9961396 DOI: 10.3390/ijms24043082] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/18/2023] [Accepted: 01/30/2023] [Indexed: 02/09/2023] Open
Abstract
This perspective examines the proposition that chronically elevated blood glucose levels caused by type 2 diabetes (T2D) harm body tissues by locally generating reactive oxygen species (ROS). A feed-forward scenario is described in which the initial onset of defective beta cell function T2D becomes sustained and causes chronic elevations in blood glucose, which flood metabolic pathways throughout the body, giving rise to abnormally high local levels of ROS. Most cells can defend themselves via a full complement of antioxidant enzymes that are activated by ROS. However, the beta cell itself does not contain catalase or glutathione peroxidases and thereby runs a greater risk of ROS-induced damage. In this review, previously published experiments are revisited to examine the concept that chronic hyperglycemia can lead to oxidative stress in the beta cell, how this relates to the absence of beta cell glutathione peroxidase (GPx) activity, and whether this deficiency might be ameliorated by genetic enrichment of beta cell GPx and by oral antioxidants, including ebselen, a GPx mimetic.
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22
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Turck D, Bohn T, Castenmiller J, de Henauw S, Hirsch‐Ernst K, Knutsen HK, Maciuk A, Mangelsdorf I, McArdle HJ, Peláez C, Pentieva K, Siani A, Thies F, Tsabouri S, Vinceti M, Aggett P, Crous Bou M, Cubadda F, Ciccolallo L, de Sesmaisons Lecarré A, Fabiani L, Titz A, Naska A. Scientific opinion on the tolerable upper intake level for selenium. EFSA J 2023; 21:e07704. [PMID: 36698500 PMCID: PMC9854220 DOI: 10.2903/j.efsa.2023.7704] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for selenium. Systematic reviews of the literature were conducted to identify evidence regarding excess selenium intake and clinical effects and potential biomarkers of effect, risk of chronic diseases and impaired neuropsychological development in humans. Alopecia, as an early observable feature and a well-established adverse effect of excess selenium exposure, is selected as the critical endpoint on which to base a UL for selenium. A lowest-observed-adverse-effect-level (LOAEL) of 330 μg/day is identified from a large randomised controlled trial in humans (the Selenium and Vitamin E Cancer Prevention Trial (SELECT)), to which an uncertainty factor of 1.3 is applied. A UL of 255 μg/day is established for adult men and women (including pregnant and lactating women). ULs for children are derived from the UL for adults using allometric scaling (body weight0.75). Based on available intake data, adult consumers are unlikely to exceed the UL, except for regular users of food supplements containing high daily doses of selenium or regular consumers of Brazil nuts. No risk has been reported with the current levels of selenium intake in European countries from food (excluding food supplements) in toddlers and children, and selenium intake arising from the natural content of foods does not raise reasons for concern. Selenium-containing supplements in toddlers and children should be used with caution, based on individual needs.
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23
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Huang YC, Combs GF, Wu TL, Zeng H, Cheng WH. Selenium status and type 2 diabetes risk. Arch Biochem Biophys 2022; 730:109400. [PMID: 36122760 PMCID: PMC9707339 DOI: 10.1016/j.abb.2022.109400] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 12/15/2022]
Abstract
Optimal selenium (Se) status is necessary for overall health. That status can be affected by food intake pattern, age, sex, and health status. At nutritional levels of intake, Se functions metabolically as an essential constituent of some two dozen selenoproteins, most, if not all, of which have redox functions. Insufficient dietary intake of Se reduces, to varying degrees, the expression of these selenoproteins. Recent clinical and animal studies have indicated that both insufficient and excessive Se intakes may increase risk of type 2 diabetes mellitus (T2D), perhaps by way of selenoprotein actions. In this review, we discuss the current evidence linking Se status and T2D risk, and the roles of 14 selenoproteins and other proteins involved in selenoprotein biosynthesis. Understanding such results can inform the setting of safe and adequate Se intakes.
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Affiliation(s)
- Ying-Chen Huang
- Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, MS, USA
| | - Gerald F Combs
- Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA
| | - Tung-Lung Wu
- Department of Mathematics and Statistics, Mississippi State University, Mississippi State, MS, USA
| | - Huawei Zeng
- USDA, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND, USA
| | - Wen-Hsing Cheng
- Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, MS, USA.
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24
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Zhao J, Zou H, Huo Y, Wei X, Li Y. Emerging roles of selenium on metabolism and type 2 diabetes. Front Nutr 2022; 9:1027629. [PMID: 36438755 PMCID: PMC9686347 DOI: 10.3389/fnut.2022.1027629] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/10/2022] [Indexed: 07/22/2023] Open
Abstract
Selenium is recognized as an essential element for human health and enters human body mainly via diet. Selenium is a key constituent in selenoproteins, which exert essential biological functions, including antioxidant and anti-inflammatory effects. Several selenoproteins including glutathione peroxidases, selenoprotein P and selenoprotein S are known to play roles in the regulation of type 2 diabetes. Although there is a close association between certain selenoproteins with glucose metabolism or insulin resistance, the relationship between selenium and type 2 diabetes is complex and remains uncertain. Here we review recent advances in the field with an emphasis on roles of selenium on metabolism and type 2 diabetes. Understanding the association between selenium and type 2 diabetes is important for developing clinical practice guidelines, establishing and implementing effective public health policies, and ultimately combating relative health issues.
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25
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Ojeda ML, Nogales F, Carreras O, Pajuelo E, Gallego-López MDC, Romero-Herrera I, Begines B, Moreno-Fernández J, Díaz-Castro J, Alcudia A. Different Effects of Low Selenite and Selenium-Nanoparticle Supplementation on Adipose Tissue Function and Insulin Secretion in Adolescent Male Rats. Nutrients 2022; 14:nu14173571. [PMID: 36079831 PMCID: PMC9459699 DOI: 10.3390/nu14173571] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/20/2022] [Accepted: 08/26/2022] [Indexed: 11/23/2022] Open
Abstract
Adolescence is a period of intense growth and endocrine changes, and obesity and insulin-resistance processes during this period have lately been rising. Selenium (Se) homeostasis is related to lipid metabolism depending on the form and dose of Se. This study tests the actions of low-dose selenite and Se nanoparticles (SeNPs) on white (WAT) and brown adipose tissue (BAT) deposition, insulin secretion, and GPx1, IRS-1 and FOXO3a expression in the WAT of adolescent rats as regards oxidative stress, adipocyte length and adipokine secretion. Four groups of male adolescent rats were treated: control (C), low selenite supplementation (S), low SeNP supplementation (NS) and moderate SeNP supplementation (NSS). Supplementation was received orally through water intake; NS and NSS rats received two- and tenfold more Se than C animals, respectively. SeNPs were obtained by reducing Se tetrachloride in the presence of ascorbic acid. For the first time in vivo, it was demonstrated that low selenite supplementation contributed to increased adipogenesis via the insulin signaling pathway and LCN2 modulation, while low SeNP administration prevented fat depots in WAT via the decrease in insulin signaling and FOXO3a autophagy in WAT, lowering inflammation. These effects were independent of GPx1 expression or activity in WAT. These findings provide data for dietary approaches to prevent obesity and/or anorexia during adolescence. These findings may be relevant to future studies looking at a nutritional approach aimed at pre-venting obesity and/or anorexia in adolescence.
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Affiliation(s)
- María Luisa Ojeda
- Department of Physiology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | - Fátima Nogales
- Department of Physiology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
- Correspondence: ; Tel.: +34-954556518
| | - Olimpia Carreras
- Department of Physiology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | - Eloísa Pajuelo
- Department of Microbiology and Parasitology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | | | - Inés Romero-Herrera
- Department of Physiology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | - Belén Begines
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
| | - Jorge Moreno-Fernández
- Department of Physiology, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, 18071 Granada, Spain
| | - Javier Díaz-Castro
- Department of Physiology, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, 18071 Granada, Spain
| | - Ana Alcudia
- Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
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26
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Handy DE, Loscalzo J. The role of glutathione peroxidase-1 in health and disease. Free Radic Biol Med 2022; 188:146-161. [PMID: 35691509 PMCID: PMC9586416 DOI: 10.1016/0003-2697(88)90167-4.handy 10.1016/j.freeradbiomed.2022.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/01/2022] [Accepted: 06/03/2022] [Indexed: 11/05/2024]
Abstract
Glutathione peroxidase 1 (GPx1) is an important cellular antioxidant enzyme that is found in the cytoplasm and mitochondria of mammalian cells. Like most selenoenzymes, it has a single redox-sensitive selenocysteine amino acid that is important for the enzymatic reduction of hydrogen peroxide and soluble lipid hydroperoxides. Glutathione provides the source of reducing equivalents for its function. As an antioxidant enzyme, GPx1 modulates the balance between necessary and harmful levels of reactive oxygen species. In this review, we discuss how selenium availability and modifiers of selenocysteine incorporation alter GPx1 expression to promote disease states. We review the role of GPx1 in cardiovascular and metabolic health, provide examples of how GPx1 modulates stroke and provides neuroprotection, and consider how GPx1 may contribute to cancer risk. Overall, GPx1 is protective against the development and progression of many chronic diseases; however, there are some situations in which increased expression of GPx1 may promote cellular dysfunction and disease owing to its removal of essential reactive oxygen species.
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Affiliation(s)
- Diane E Handy
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
| | - Joseph Loscalzo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
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27
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Mallone R, Halliez C, Rui J, Herold KC. The β-Cell in Type 1 Diabetes Pathogenesis: A Victim of Circumstances or an Instigator of Tragic Events? Diabetes 2022; 71:1603-1610. [PMID: 35881836 PMCID: PMC9490354 DOI: 10.2337/dbi21-0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022]
Abstract
Recent reports have revived interest in the active role that β-cells may play in type 1 diabetes pathogenesis at different stages of disease. In some studies, investigators suggested an initiating role and proposed that type 1 diabetes may be primarily a disease of β-cells and only secondarily a disease of autoimmunity. This scenario is possible and invites the search for environmental triggers damaging β-cells. Another major contribution of β-cells may be to amplify autoimmune vulnerability and to eventually drive it into an intrinsic, self-detrimental state that turns the T cell-mediated homicide into a β-cell suicide. On the other hand, protective mechanisms are also mounted by β-cells and may provide novel therapeutic targets to combine immunomodulatory and β-cell protective agents. This integrated view of autoimmunity as a disease of T-cell/β-cell cross talk will ultimately advance our understanding of type 1 diabetes pathogenesis and improve our chances of preventing or reversing disease progression.
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Affiliation(s)
- Roberto Mallone
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
| | - Clémentine Halliez
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
| | - Jinxiu Rui
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT
| | - Kevan C. Herold
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT
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28
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Handy DE, Loscalzo J. The role of glutathione peroxidase-1 in health and disease. Free Radic Biol Med 2022; 188:146-161. [PMID: 35691509 PMCID: PMC9586416 DOI: 10.1016/j.freeradbiomed.2022.06.004] [Citation(s) in RCA: 119] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/01/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023]
Abstract
Glutathione peroxidase 1 (GPx1) is an important cellular antioxidant enzyme that is found in the cytoplasm and mitochondria of mammalian cells. Like most selenoenzymes, it has a single redox-sensitive selenocysteine amino acid that is important for the enzymatic reduction of hydrogen peroxide and soluble lipid hydroperoxides. Glutathione provides the source of reducing equivalents for its function. As an antioxidant enzyme, GPx1 modulates the balance between necessary and harmful levels of reactive oxygen species. In this review, we discuss how selenium availability and modifiers of selenocysteine incorporation alter GPx1 expression to promote disease states. We review the role of GPx1 in cardiovascular and metabolic health, provide examples of how GPx1 modulates stroke and provides neuroprotection, and consider how GPx1 may contribute to cancer risk. Overall, GPx1 is protective against the development and progression of many chronic diseases; however, there are some situations in which increased expression of GPx1 may promote cellular dysfunction and disease owing to its removal of essential reactive oxygen species.
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Affiliation(s)
- Diane E Handy
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
| | - Joseph Loscalzo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
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29
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Stancill JS, Hansen PA, Mathison AJ, Schmidt EE, Corbett JA. Deletion of Thioredoxin Reductase Disrupts Redox Homeostasis and Impairs β-Cell Function. FUNCTION (OXFORD, ENGLAND) 2022; 3:zqac034. [PMID: 35873655 PMCID: PMC9301323 DOI: 10.1093/function/zqac034] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/17/2022] [Accepted: 06/27/2022] [Indexed: 01/07/2023]
Abstract
Reactive oxygen species (ROS) have been implicated as mediators of pancreatic β-cell damage. While β-cells are thought to be vulnerable to oxidative damage, we have shown, using inhibitors and acute depletion, that thioredoxin reductase, thioredoxin, and peroxiredoxins are the primary mediators of antioxidant defense in β-cells. However, the role of this antioxidant cycle in maintaining redox homeostasis and β-cell survival in vivo remains unclear. Here, we generated mice with a β-cell specific knockout of thioredoxin reductase 1 (Txnrd1fl/fl; Ins1Cre/+ , βKO). Despite blunted glucose-stimulated insulin secretion, knockout mice maintain normal whole-body glucose homeostasis. Unlike pancreatic islets with acute Txnrd1 inhibition, βKO islets do not demonstrate increased sensitivity to ROS. RNA-sequencing analysis revealed that Txnrd1-deficient β-cells have increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated genes, and altered expression of genes involved in heme and glutathione metabolism, suggesting an adaptive response. Txnrd1-deficient β-cells also have decreased expression of factors controlling β-cell function and identity which may explain the mild functional impairment. Together, these results suggest that Txnrd1-knockout β-cells compensate for loss of this essential antioxidant pathway by increasing expression of Nrf2-regulated antioxidant genes, allowing for protection from excess ROS at the expense of normal β-cell function and identity.
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Affiliation(s)
| | - Polly A Hansen
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA
| | - Angela J Mathison
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA,Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Edward E Schmidt
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MN 59717, USA,Redox Biology Laboratory, University of Veterinary Medicine, Budapest 1078, Hungary
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30
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Moon JS, Riopel M, Seo JB, Herrero-Aguayo V, Isaac R, Lee YS. HIF-2α Preserves Mitochondrial Activity and Glucose Sensing in Compensating β-Cells in Obesity. Diabetes 2022; 71:1508-1524. [PMID: 35472707 PMCID: PMC9233300 DOI: 10.2337/db21-0736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 04/08/2022] [Indexed: 11/13/2022]
Abstract
In obesity, increased mitochondrial metabolism with the accumulation of oxidative stress leads to mitochondrial damage and β-cell dysfunction. In particular, β-cells express antioxidant enzymes at relatively low levels and are highly vulnerable to oxidative stress. Early in the development of obesity, β-cells exhibit increased glucose-stimulated insulin secretion in order to compensate for insulin resistance. This increase in β-cell function under the condition of enhanced metabolic stress suggests that β-cells possess a defense mechanism against increased oxidative damage, which may become insufficient or decline at the onset of type 2 diabetes. Here, we show that metabolic stress induces β-cell hypoxia inducible factor 2α (HIF-2α), which stimulates antioxidant gene expression (e.g., Sod2 and Cat) and protects against mitochondrial reactive oxygen species (ROS) and subsequent mitochondrial damage. Knockdown of HIF-2α in Min6 cells exaggerated chronic high glucose-induced mitochondrial damage and β-cell dysfunction by increasing mitochondrial ROS levels. Moreover, inducible β-cell HIF-2α knockout mice developed more severe β-cell dysfunction and glucose intolerance on a high-fat diet, along with increased ROS levels and decreased islet mitochondrial mass. Our results provide a previously unknown mechanism through which β-cells defend against increased metabolic stress to promote β-cell compensation in obesity.
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Affiliation(s)
- Jae-Su Moon
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Matthew Riopel
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Jong Bae Seo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Vicente Herrero-Aguayo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Maimonides Institute of Biomedical Research of Cordoba, Cordoba, Spain
| | - Roi Isaac
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Yun Sok Lee
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Corresponding author: Yun Sok Lee,
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Gorini F, Vassalle C. Selenium and Selenoproteins at the Intersection of Type 2 Diabetes and Thyroid Pathophysiology. Antioxidants (Basel) 2022; 11:antiox11061188. [PMID: 35740085 PMCID: PMC9227825 DOI: 10.3390/antiox11061188] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 02/04/2023] Open
Abstract
Type 2 diabetes (T2D) is considered one of the largest global public-health concerns, affecting approximately more than 400 million individuals worldwide. The pathogenesis of T2D is very complex and, among the modifiable risk factors, selenium (Se) has recently emerged as a determinant of T2D pathogenesis and progression. Selenium is considered an essential element with antioxidant properties, and is incorporated into the selenoproteins involved in the antioxidant response. Furthermore, deiodinases, the enzymes responsible for homeostasis and for controlling the activity of thyroid hormones (THs), contain Se. Given the crucial action of oxidative stress in the onset of insulin resistance (IR) and T2D, and the close connection between THs and glucose metabolism, Se may be involved in these fundamental relationships; it may cover a dual role, both as a protective factor and as a risk factor of T2D, depending on its basal plasma concentration and the individual’s diet intake. In this review we discuss the current evidence (from experimental, observational and randomized clinical studies) on how Se is associated with the occurrence of T2D and its influence on the relationship between thyroid pathophysiology, IR and T2D.
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Affiliation(s)
- Francesca Gorini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
- Correspondence:
| | - Cristina Vassalle
- Fondazione CNR-Regione Toscana Gabriele Monasterio, 56124 Pisa, Italy;
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32
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Gansemer ER, Rutkowski DT. Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress. Front Mol Biosci 2022; 9:858142. [PMID: 35601828 PMCID: PMC9114485 DOI: 10.3389/fmolb.2022.858142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
The endoplasmic reticulum (ER) lumen is highly oxidizing compared to other subcellular compartments, and maintaining the appropriate levels of oxidizing and reducing equivalents is essential to ER function. Both protein oxidation itself and other essential ER processes, such as the degradation of misfolded proteins and the sequestration of cellular calcium, are tuned to the ER redox state. Simultaneously, nutrients are oxidized in the cytosol and mitochondria to power ATP generation, reductive biosynthesis, and defense against reactive oxygen species. These parallel needs for protein oxidation in the ER and nutrient oxidation in the cytosol and mitochondria raise the possibility that the two processes compete for electron acceptors, even though they occur in separate cellular compartments. A key molecule central to both processes is NADPH, which is produced by reduction of NADP+ during nutrient catabolism and which in turn drives the reduction of components such as glutathione and thioredoxin that influence the redox potential in the ER lumen. For this reason, NADPH might serve as a mediator linking metabolic activity to ER homeostasis and stress, and represent a novel form of mitochondria-to-ER communication. In this review, we discuss oxidative protein folding in the ER, NADPH generation by the major pathways that mediate it, and ER-localized systems that can link the two processes to connect ER function to metabolic activity.
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Affiliation(s)
- Erica R. Gansemer
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - D. Thomas Rutkowski
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
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Nakamura A. Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Pancreatic β-Cell Mass and Function. Int J Mol Sci 2022; 23:ijms23095104. [PMID: 35563495 PMCID: PMC9105075 DOI: 10.3390/ijms23095104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/27/2022] [Accepted: 04/30/2022] [Indexed: 01/25/2023] Open
Abstract
Sodium-glucose co-transporter-2 inhibitors (SGLT2is) not only have antihyperglycemic effects and are associated with a low risk of hypoglycemia but also have protective effects in organs, including the heart and kidneys. The pathophysiology of diabetes involves chronic hyperglycemia, which causes excessive demands on pancreatic β-cells, ultimately leading to decreases in β-cell mass and function. Because SGLT2is ameliorate hyperglycemia without acting directly on β-cells, they are thought to prevent β-cell failure by reducing glucose overload in this cell type. Several studies have shown that treatment with an SGLT2i increases β-cell proliferation and/or reduces β-cell apoptosis, resulting in the preservation of β-cell mass in animal models of diabetes. In addition, many clinical trials have shown that that SGLT2is improve β-cell function in individuals with type 2 diabetes. In this review, the preclinical and clinical data regarding the effects of SGLT2is on pancreatic β-cell mass and function are summarized and the protective effect of SGLT2is in β-cells is discussed.
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Affiliation(s)
- Akinobu Nakamura
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
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Role of the Transcription Factor MAFA in the Maintenance of Pancreatic β-Cells. Int J Mol Sci 2022; 23:ijms23094478. [PMID: 35562869 PMCID: PMC9101179 DOI: 10.3390/ijms23094478] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/16/2022] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
Pancreatic β-cells are specialized to properly regulate blood glucose. Maintenance of the mature β-cell phenotype is critical for glucose metabolism, and β-cell failure results in diabetes mellitus. Recent studies provide strong evidence that the mature phenotype of β-cells is maintained by several transcription factors. These factors are also required for β-cell differentiation from endocrine precursors or maturation from immature β-cells during pancreatic development. Because the reduction or loss of these factors leads to β-cell failure and diabetes, inducing the upregulation or inhibiting downregulation of these transcription factors would be beneficial for studies in both diabetes and stem cell biology. Here, we discuss one such factor, i.e., the transcription factor MAFA. MAFA is a basic leucine zipper family transcription factor that can activate the expression of insulin in β-cells with PDX1 and NEUROD1. MAFA is indeed indispensable for the maintenance of not only insulin expression but also function of adult β-cells. With loss of MAFA in type 2 diabetes, β-cells cannot maintain their mature phenotype and are dedifferentiated. In this review, we first briefly summarize the functional roles of MAFA in β-cells and then mainly focus on the molecular mechanism of cell fate conversion regulated by MAFA.
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Mooli RGR, Mukhi D, Ramakrishnan SK. Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases. Compr Physiol 2022; 12:3167-3192. [PMID: 35578969 PMCID: PMC10074426 DOI: 10.1002/cphy.c200021] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a "multiple parallel-hit model" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.
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Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Dinić S, Arambašić Jovanović J, Uskoković A, Mihailović M, Grdović N, Tolić A, Rajić J, Đorđević M, Vidaković M. Oxidative stress-mediated beta cell death and dysfunction as a target for diabetes management. Front Endocrinol (Lausanne) 2022; 13:1006376. [PMID: 36246880 PMCID: PMC9554708 DOI: 10.3389/fendo.2022.1006376] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/05/2022] [Indexed: 11/14/2022] Open
Abstract
The biggest drawback of a current diabetes therapy is the treatment of the consequences not the cause of the disease. Regardless of the diabetes type, preservation and recovery of functional pancreatic beta cells stands as the biggest challenge in the treatment of diabetes. Free radicals and oxidative stress are among the major mediators of autoimmune destruction of beta cells in type 1 diabetes (T1D) or beta cell malfunction and death provoked by glucotoxicity and insulin resistance in type 2 diabetes (T2D). Additionally, oxidative stress reduces functionality of beta cells in T2D by stimulating their de-/trans-differentiation through the loss of transcription factors critical for beta cell development, maturity and regeneration. This review summarizes up to date clarified redox-related mechanisms involved in regulating beta cell identity and death, underlining similarities and differences between T1D and T2D. The protective effects of natural antioxidants on the oxidative stress-induced beta cell failure were also discussed. Considering that oxidative stress affects epigenetic regulatory mechanisms involved in the regulation of pancreatic beta cell survival and insulin secretion, this review highlighted huge potential of epigenetic therapy. Special attention was paid on application of the state-of-the-art CRISPR/Cas9 technology, based on targeted epigenome editing with the purpose of changing the differentiation state of different cell types, making them insulin-producing with ability to attenuate diabetes. Clarification of the above-mentioned mechanisms could provide better insight into diabetes etiology and pathogenesis, which would allow development of novel, potentially more efficient therapeutic strategies for the prevention or reversion of beta cell loss.
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Steinbrenner H, Duntas LH, Rayman MP. The role of selenium in type-2 diabetes mellitus and its metabolic comorbidities. Redox Biol 2022; 50:102236. [PMID: 35144052 PMCID: PMC8844812 DOI: 10.1016/j.redox.2022.102236] [Citation(s) in RCA: 111] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/04/2022] [Accepted: 01/12/2022] [Indexed: 02/07/2023] Open
Abstract
This review addresses the role of the essential trace element, selenium, in type-2 diabetes mellitus (T2DM) and its metabolic co-morbidities, i.e., metabolic syndrome, obesity and non-alcoholic fatty liver disease. We refer to the dietary requirements of selenium and the key physiological roles of selenoproteins. We explore the dysregulated fuel metabolism in T2DM and its co-morbidities, emphasizing the relevance of inflammation and oxidative stress. We describe the epidemiology of observational and experimental studies of selenium in diabetes and related conditions, explaining that the interaction between selenium status and glucose control is not limited to hyperglycemia but extends to hypoglycemia. We propose that the association between high plasma/serum selenium and T2DM/fasting plasma glucose observed in many cross-sectional studies may rely on the upregulation of hepatic selenoprotein-P biosynthesis in conditions of hyperglycemia and insulin resistance. While animal studies have revealed potential molecular mechanisms underlying adverse effects of severe selenium/selenoprotein excess and deficiency in the pathogenesis of insulin resistance and β-cell dysfunction, their translational significance is rather limited. Importantly, dietary selenium supplementation does not appear to be a major causal factor for the development of T2DM in humans though we cannot currently exclude a small contribution of selenium on top of other risk factors, in particular if it is ingested at high (supranutritional) doses. Elevated selenium biomarkers that are often measured in T2DM patients are more likely to be a consequence, rather than a cause, of diabetes.
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Cui C, Li T, Xie Y, Yang J, Fu C, Qiu Y, Shen L, Ni Q, Wang Q, Nie A, Ning G, Wang W, Gu Y. Enhancing Acsl4 in absence of mTORC2/Rictor drove β-cell dedifferentiation via inhibiting FoxO1 and promoting ROS production. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166261. [PMID: 34455055 DOI: 10.1016/j.bbadis.2021.166261] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 08/16/2021] [Accepted: 08/24/2021] [Indexed: 02/07/2023]
Abstract
Rapamycin insensitive companion of mechanistic target of Rapamycin (Rictor), the key component of mTOR complex 2 (mTORC2), controls both β-cell proliferation and function. We sought to study whether long chain acyl-CoA synthetase 4 (Acsl4) worked downstream of Rictor/mTORC2 to maintain β-cell functional mass. We found Acsl4 was positively regulated by Rictor at transcriptional and posttranslational levels in mouse β-cell. Infecting adenovirus expressing Acsl4 in β-cell-specific-Rictor-knockout (βRicKO) islets and Min6 cells knocking down Rictor with lentivirus-expressing siRNA-oligos targeting Rictor(siRic), recovered the β-cell dysplasia but not dysfunction. Cell bioenergetic experiment performed with Seahorse XF showed that Acsl4 could not rescue the dampened glucose oxidation in Rictor-lacking β-cell, but further promoted lipid oxidation. Transposase-Accessible Chromatin (ATAC) and H3K27Ac chromatin immunoprecipitation (ChIP) sequencing studies reflected the epigenetic elevated molecular signature for β-cell dedifferentiation and mitigated oxidative defense/response. These results were confirmed by the observations of elevated acetylation and ubiquitination of FoxO1, increased protein levels of Gpx1 and Hif1an, excessive reactive oxygen species (ROS) production and diminished MafA in Acsl4 overexpressed Rictor-lacking β-cells. In these cells, antioxidant treatment significantly recovered MafA level and insulin content. Inducing lipid oxidation alone could not mimic the effect of Acsl4 in Rictor lacking β-cell. Our study suggested that Acsl4 function in β-cell was context dependent and might facilitate β-cell dedifferentiation with attenuated Rictor/mTORC2 activity or insulin signaling via posttranslational inhibiting FoxO1 and epigenetically enhancing ROS induced MafA degradation.
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Affiliation(s)
- Canqi Cui
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tingting Li
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Xie
- Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Yang
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenyang Fu
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yixuan Qiu
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Linyan Shen
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qicheng Ni
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qidi Wang
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Aifang Nie
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Weiqing Wang
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanyun Gu
- Shanghai National Research Centre for Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Bosma KJ, Andrei SR, Katz LS, Smith AA, Dunn JC, Ricciardi VF, Ramirez MA, Baumel-Alterzon S, Pace WA, Carroll DT, Overway EM, Wolf EM, Kimple ME, Sheng Q, Scott DK, Breyer RM, Gannon M. Pharmacological blockade of the EP3 prostaglandin E 2 receptor in the setting of type 2 diabetes enhances β-cell proliferation and identity and relieves oxidative damage. Mol Metab 2021; 54:101347. [PMID: 34626853 PMCID: PMC8529552 DOI: 10.1016/j.molmet.2021.101347] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/02/2021] [Accepted: 09/23/2021] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE Type 2 diabetes is characterized by hyperglycemia and inflammation. Prostaglandin E2, which signals through four G protein-coupled receptors (EP1-4), is a mediator of inflammation and is upregulated in diabetes. We have shown previously that EP3 receptor blockade promotes β-cell proliferation and survival in isolated mouse and human islets ex vivo. Here, we analyzed whether systemic EP3 blockade could enhance β-cell mass and identity in the setting of type 2 diabetes using mice with a spontaneous mutation in the leptin receptor (Leprdb). METHODS Four- or six-week-old, db/+, and db/db male mice were treated with an EP3 antagonist daily for two weeks. Pancreata were analyzed for α-cell and β-cell proliferation and β-cell mass. Islets were isolated for transcriptomic analysis. Selected gene expression changes were validated by immunolabeling of the pancreatic tissue sections. RESULTS EP3 blockade increased β-cell mass in db/db mice through enhanced β-cell proliferation. Importantly, there were no effects on α-cell proliferation. EP3 blockade reversed the changes in islet gene expression associated with the db/db phenotype and restored the islet architecture. Expression of the GLP-1 receptor was slightly increased by EP3 antagonist treatment in db/db mice. In addition, the transcription factor nuclear factor E2-related factor 2 (Nrf2) and downstream targets were increased in islets from db/db mice in response to treatment with an EP3 antagonist. The markers of oxidative stress were decreased. CONCLUSIONS The current study suggests that EP3 blockade promotes β-cell mass expansion in db/db mice. The beneficial effects of EP3 blockade may be mediated through Nrf2, which has recently emerged as a key mediator in the protection against cellular oxidative damage.
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Affiliation(s)
- Karin J Bosma
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Spencer R Andrei
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Liora S Katz
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ashley A Smith
- Dept. of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Jennifer C Dunn
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Marisol A Ramirez
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA; Dept. of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - William A Pace
- Dept. of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Darian T Carroll
- Dept. of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Emily M Overway
- Dept. of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Elysa M Wolf
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
| | - Michelle E Kimple
- Dept. of Medicine, University of Wisconsin, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Quanhu Sheng
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA; Dept. of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Donald K Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Richard M Breyer
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Maureen Gannon
- Dept. of Veterans Affairs Tennessee Valley Authority, Nashville, TN, USA; Dept. of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Dept. of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
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40
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Leenders F, Groen N, de Graaf N, Engelse MA, Rabelink TJ, de Koning EJP, Carlotti F. Oxidative Stress Leads to β-Cell Dysfunction Through Loss of β-Cell Identity. Front Immunol 2021; 12:690379. [PMID: 34804002 PMCID: PMC8601632 DOI: 10.3389/fimmu.2021.690379] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 09/28/2021] [Indexed: 12/04/2022] Open
Abstract
Pancreatic β-cell failure is a critical event in the onset of both main types of diabetes mellitus but underlying mechanisms are not fully understood. β-cells have low anti-oxidant capacity, making them more susceptible to oxidative stress. In type 1 diabetes (T1D), reactive oxygen species (ROS) are associated with pro-inflammatory conditions at the onset of the disease. Here, we investigated the effects of hydrogen peroxide-induced oxidative stress on human β-cells. We show that primary human β-cell function is decreased. This reduced function is associated with an ER stress response and the shuttling of FOXO1 to the nucleus. Furthermore, oxidative stress leads to loss of β-cell maturity genes MAFA and PDX1, and to a concomitant increase in progenitor marker expression of SOX9 and HES1. Overall, we propose that oxidative stress-induced β-cell failure may result from partial dedifferentiation. Targeting antioxidant mechanisms may preserve functional β-cell mass in early stages of development of T1D.
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Affiliation(s)
- Floris Leenders
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Nathalie Groen
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Natascha de Graaf
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Marten A Engelse
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Ton J Rabelink
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Eelco J P de Koning
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.,Hubrecht Institute, KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, Utrecht, Netherlands
| | - Françoise Carlotti
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
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Ikegami H, Babaya N, Noso S. β-Cell failure in diabetes: Common susceptibility and mechanisms shared between type 1 and type 2 diabetes. J Diabetes Investig 2021; 12:1526-1539. [PMID: 33993642 PMCID: PMC8409822 DOI: 10.1111/jdi.13576] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/24/2022] Open
Abstract
Diabetes mellitus is etiologically classified into type 1, type 2 and other types of diabetes. Despite distinct etiologies and pathogenesis of these subtypes, many studies have suggested the presence of shared susceptibilities and underlying mechanisms in β-cell failure among different types of diabetes. Understanding these susceptibilities and mechanisms can help in the development of therapeutic strategies regardless of the diabetes subtype. In this review, we discuss recent evidence indicating the shared genetic susceptibilities and common molecular mechanisms between type 1, type 2 and other types of diabetes, and highlight the future prospects as well.
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Affiliation(s)
- Hiroshi Ikegami
- Department of Endocrinology, Metabolism and DiabetesFaculty of MedicineKindai UniversityOsaka‐sayama, OsakaJapan
| | - Naru Babaya
- Department of Endocrinology, Metabolism and DiabetesFaculty of MedicineKindai UniversityOsaka‐sayama, OsakaJapan
| | - Shinsuke Noso
- Department of Endocrinology, Metabolism and DiabetesFaculty of MedicineKindai UniversityOsaka‐sayama, OsakaJapan
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42
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Siehler J, Blöchinger AK, Meier M, Lickert H. Engineering islets from stem cells for advanced therapies of diabetes. Nat Rev Drug Discov 2021; 20:920-940. [PMID: 34376833 DOI: 10.1038/s41573-021-00262-w] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2021] [Indexed: 12/20/2022]
Abstract
Diabetes mellitus is a metabolic disorder that affects more than 460 million people worldwide. Type 1 diabetes (T1D) is caused by autoimmune destruction of β-cells, whereas type 2 diabetes (T2D) is caused by a hostile metabolic environment that leads to β-cell exhaustion and dysfunction. Currently, first-line medications treat the symptomatic insulin resistance and hyperglycaemia, but do not prevent the progressive decline of β-cell mass and function. Thus, advanced therapies need to be developed that either protect or regenerate endogenous β-cell mass early in disease progression or replace lost β-cells with stem cell-derived β-like cells or engineered islet-like clusters. In this Review, we discuss the state of the art of stem cell differentiation and islet engineering, reflect on current and future challenges in the area and highlight the potential for cell replacement therapies, disease modelling and drug development using these cells. These efforts in stem cell and regenerative medicine will lay the foundations for future biomedical breakthroughs and potentially curative treatments for diabetes.
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Affiliation(s)
- Johanna Siehler
- Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, Germany.,Technical University of Munich, Medical Faculty, Munich, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Anna Karolina Blöchinger
- Technical University of Munich, Medical Faculty, Munich, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
| | - Matthias Meier
- Technical University of Munich, Medical Faculty, Munich, Germany.,Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany
| | - Heiko Lickert
- Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, Germany. .,Technical University of Munich, Medical Faculty, Munich, Germany. .,German Center for Diabetes Research (DZD), Neuherberg, Germany. .,Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany.
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Ahi EP, Tsakoumis E, Brunel M, Schmitz M. Transcriptional study reveals a potential leptin-dependent gene regulatory network in zebrafish brain. FISH PHYSIOLOGY AND BIOCHEMISTRY 2021; 47:1283-1298. [PMID: 34236575 PMCID: PMC8302498 DOI: 10.1007/s10695-021-00967-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/12/2021] [Indexed: 06/01/2023]
Abstract
The signal mediated by leptin hormone and its receptor is a major regulator of body weight, food intake and metabolism. In mammals and many teleost fish species, leptin has an anorexigenic role and inhibits food intake by influencing the appetite centres in the hypothalamus. However, the regulatory connections between leptin and downstream genes mediating its appetite-regulating effects are still not fully explored in teleost fish. In this study, we used a loss of function leptin receptor zebrafish mutant and real-time quantitative PCR to assess brain expression patterns of several previously identified anorexigenic genes downstream of leptin signal under different feeding conditions (normal feeding, 7-day fasting, 2 and 6-h refeeding). These downstream factors include members of cart genes, crhb and gnrh2, as well as selected genes co-expressed with them based on a zebrafish co-expression database. Here, we found a potential gene expression network (GRN) comprising the abovementioned genes by a stepwise approach of identifying co-expression modules and predicting their upstream regulators. Among the transcription factors (TFs) predicted as potential upstream regulators of this GRN, we found expression pattern of sp3a to be correlated with transcriptional changes of the downstream gene network. Interestingly, the expression and transcriptional activity of Sp3 orthologous gene in mammals have already been implicated to be under the influence of leptin signal. These findings suggest a potentially conserved regulatory connection between leptin and sp3a, which is predicted to act as a transcriptional driver of a downstream gene network in the zebrafish brain.
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Affiliation(s)
- Ehsan Pashay Ahi
- Department of Organismal Biology, Comparative Physiology, Evolutionary Biology Centre, Uppsala University, Norbyvägen 18A, SE-752 36 Uppsala, Sweden
- Organismal and Evolutionary Biology Research Programme, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland
| | - Emmanouil Tsakoumis
- Department of Organismal Biology, Comparative Physiology, Evolutionary Biology Centre, Uppsala University, Norbyvägen 18A, SE-752 36 Uppsala, Sweden
| | - Mathilde Brunel
- Department of Molecular Sciences, Swedish University of Agricultural Sciences, Allmas Allé 5, SE-750 07 Uppsala, Sweden
| | - Monika Schmitz
- Department of Organismal Biology, Comparative Physiology, Evolutionary Biology Centre, Uppsala University, Norbyvägen 18A, SE-752 36 Uppsala, Sweden
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Dhounchak S, Popp SK, Brown DJ, Laybutt DR, Biden TJ, Bornstein SR, Parish CR, Simeonovic CJ. Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes. PLoS One 2021; 16:e0252607. [PMID: 34086738 PMCID: PMC8177513 DOI: 10.1371/journal.pone.0252607] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 05/19/2021] [Indexed: 12/24/2022] Open
Abstract
Heparan sulfate proteoglycans (HSPGs) consist of a core protein with side chains of the glycosaminoglycan heparan sulfate (HS). We have previously identified (i) the HSPGs syndecan-1 (SDC1), and collagen type XVIII (COL18) inside mouse and human islet beta cells, and (ii) a critical role for HS in beta cell survival and protection from reactive oxygen species (ROS). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress contributes to oxidative stress and type 2 diabetes (T2D) by depleting beta cell HSPGs/HS. A rapid loss of intra-islet/beta cell HSPGs, HS and heparanase (HPSE, an HS-degrading enzyme) accompanied upregulation of islet ER stress gene expression in both young T2D-prone db/db and Akita Ins2WT/C96Y mice. In MIN6 beta cells, HSPGs, HS and HPSE were reduced following treatment with pharmacological inducers of ER stress (thapsigargin or tunicamycin). Treatment of young db/db mice with Tauroursodeoxycholic acid (TUDCA), a chemical protein folding chaperone that relieves ER stress, improved glycemic control and increased intra-islet HSPG/HS. In vitro, HS replacement with heparin (a highly sulfated HS analogue) significantly increased the survival of wild-type and db/db beta cells and restored their resistance to hydrogen peroxide-induced death. We conclude that ER stress inhibits the synthesis/maturation of HSPG core proteins which are essential for HS assembly, thereby exacerbating oxidative stress and promoting beta cell failure. Diminished intracellular HSPGs/HS represent a previously unrecognized critical link bridging ER stress, oxidative stress and beta cell failure in T2D.
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Affiliation(s)
- Sarita Dhounchak
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Sarah K. Popp
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Debra J. Brown
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - D. Ross Laybutt
- Garvan Institute of Medical Research, St Vincent’s Clinical School, The University of NSW (UNSW), Sydney, New South Wales, Australia
| | - Trevor J. Biden
- Garvan Institute of Medical Research, St Vincent’s Clinical School, The University of NSW (UNSW), Sydney, New South Wales, Australia
| | - Stefan R. Bornstein
- Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany
| | - Christopher R. Parish
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Charmaine J. Simeonovic
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
- * E-mail:
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45
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A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes. Nutrients 2021; 13:nu13051593. [PMID: 34068827 PMCID: PMC8151793 DOI: 10.3390/nu13051593] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/30/2021] [Accepted: 05/07/2021] [Indexed: 01/09/2023] Open
Abstract
Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.
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46
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Omori K, Nakamura A, Miyoshi H, Yamauchi Y, Kawata S, Takahashi K, Kitao N, Nomoto H, Kameda H, Cho KY, Terauchi Y, Atsumi T. Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing β-Cell Mass in db/db Mice. Diabetes 2021; 70:917-931. [PMID: 33608422 DOI: 10.2337/db20-0881] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 01/22/2021] [Indexed: 11/13/2022]
Abstract
Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related to excess glucose signaling by glucokinase activation toward β-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as β-cell function and mass using a mouse model of type 2 diabetes. Our results showed that in db/db mice with glucokinase haploinsufficiency, glucose tolerance was ameliorated by augmented insulin secretion associated with the increase in β-cell mass when compared with db/db mice. Gene expression profiling and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of db/db mice was associated with lower expression of stress-related genes, greater expression of transcription factors involved in the maintenance and maturation of β-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve β-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signaling in β-cells by inhibiting glucokinase could prevent β-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving β-cell mass. Therefore, glucokinase inactivation in β-cells, paradoxically, could be a potential strategy for the treatment of type 2 diabetes.
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Affiliation(s)
- Kazuno Omori
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akinobu Nakamura
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hideaki Miyoshi
- Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine Hokkaido University, Sapporo, Japan
| | - Yuki Yamauchi
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shinichiro Kawata
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kiyohiko Takahashi
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoyuki Kitao
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiroshi Nomoto
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiraku Kameda
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kyu Yong Cho
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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47
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Benáková Š, Holendová B, Plecitá-Hlavatá L. Redox Homeostasis in Pancreatic β-Cells: From Development to Failure. Antioxidants (Basel) 2021; 10:antiox10040526. [PMID: 33801681 PMCID: PMC8065646 DOI: 10.3390/antiox10040526] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 12/16/2022] Open
Abstract
Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxifying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thioredoxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplasmic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded protein response and insulin misfolding along with excessive hydrogen peroxide production. This together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and eventually cell death.
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Affiliation(s)
- Štěpánka Benáková
- Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; (Š.B.); (B.H.)
- First Faculty of Medicine, Charles University, Katerinska 1660/32, 121 08 Prague, Czech Republic
| | - Blanka Holendová
- Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; (Š.B.); (B.H.)
| | - Lydie Plecitá-Hlavatá
- Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; (Š.B.); (B.H.)
- Department of Mitochondrial Physiology, Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
- Correspondence: ; Tel.: +420-296-442-285
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48
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Mosialou I, Shikhel S, Luo N, Petropoulou PI, Panitsas K, Bisikirska B, Rothman NJ, Tenta R, Cariou B, Wargny M, Sornay-Rendu E, Nickolas T, Rubin M, Confavreux CB, Kousteni S. Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes. J Exp Med 2021; 217:151926. [PMID: 32639539 PMCID: PMC7537391 DOI: 10.1084/jem.20191261] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 03/28/2020] [Accepted: 05/15/2020] [Indexed: 12/30/2022] Open
Abstract
Regulation of food intake is a recently identified endocrine function of bone that is mediated by Lipocalin-2 (LCN2). Osteoblast-secreted LCN2 suppresses appetite and decreases fat mass while improving glucose metabolism. We now show that serum LCN2 levels correlate with insulin levels and β-cell function, indices of healthy glucose metabolism, in obese mice and obese, prediabetic women. However, LCN2 serum levels also correlate with body mass index and insulin resistance in the same individuals and are increased in obese mice. To dissect this apparent discrepancy, we modulated LCN2 levels in mice. Silencing Lcn2 expression worsens metabolic dysfunction in genetic and diet-induced obese mice. Conversely, increasing circulating LCN2 levels improves metabolic parameters and promotes β-cell function in mouse models of β-cell failure acting as a growth factor necessary for β-cell adaptation to higher metabolic load. These results indicate that LCN2 up-regulation is a protective mechanism to counteract obesity-induced glucose intolerance by decreasing food intake and promoting adaptive β-cell proliferation.
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Affiliation(s)
- Ioanna Mosialou
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY
| | - Steven Shikhel
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY
| | - Na Luo
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY
| | | | - Konstantinos Panitsas
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY
| | - Brygida Bisikirska
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY
| | - Nyanza J Rothman
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY
| | - Roxane Tenta
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY
| | - Bertrand Cariou
- Université de Nantes, Centre Hospitalier Universitaire Nantes, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, l'Institut du thorax, Nantes, France
| | - Matthieu Wargny
- Université de Nantes, Centre Hospitalier Universitaire Nantes, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, l'Institut du thorax, Nantes, France
| | - Elisabeth Sornay-Rendu
- Institut national de la santé et de la recherche médicale Unités Mixtes de Recherche 1033, Université de Lyon, Hospices Civils de Lyon, Lyon, France
| | - Thomas Nickolas
- Department of Medicine Nephrology, Columbia University Medical Center, New York, NY
| | - Mishaela Rubin
- Department of Medicine Endocrinology, Columbia University Medical Center, New York, NY
| | - Cyrille B Confavreux
- Institut national de la santé et de la recherche médicale Unités Mixtes de Recherche 1033, Université de Lyon, Hospices Civils de Lyon, Lyon, France
| | - Stavroula Kousteni
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY
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49
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Sim EZ, Shiraki N, Kume S. Recent progress in pancreatic islet cell therapy. Inflamm Regen 2021; 41:1. [PMID: 33402224 PMCID: PMC7784351 DOI: 10.1186/s41232-020-00152-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 12/15/2020] [Indexed: 01/10/2023] Open
Abstract
Human pluripotent stem cells (PSCs), including human embryonic stem cells and induced pluripotent stem cells, are promising cell sources in regenerating pancreatic islets through in vitro directed differentiation. Recent progress in this research field has made it possible to generate glucose-responsive pancreatic islet cells from PSCs. Single-cell RNA sequencing techniques have been applied to analyze PSC-derived endocrine beta-cells, which are then compared with human islets. This has led to the identification of novel signaling pathways and molecules involved in lineage commitment during pancreatic differentiation and maturation processes. Single-cell transcriptomics are also used to construct a detailed map of in vivo endocrine differentiation of developing mouse embryos to study pancreatic islet development. Mimicking those occurring in vivo, it was reported that differentiating PSCs can generate similar islet cell structures, while metabolomics analysis highlighted key components involved in PSC-derived pancreatic islet cell function, providing information for the improvement of in vitro pancreatic maturation procedures. In addition, cell transplantation into diabetic animal models, together with the cell delivery system, is studied to ensure the therapeutic potentials of PSC-derived pancreatic islet cells. Combined with gene-editing technology, the engineered mutation-corrected PSC lines originated from diabetes patients could be differentiated into functional pancreatic islet cells, suggesting possible autologous cell therapy in the future. These PSC-derived pancreatic islet cells are a potential tool for studies of disease modeling and drug testing. Herein, we outlined the directed differentiation procedures of PSC-derived pancreatic islet cells, novel findings through transcriptome and metabolome studies, and recent progress in disease modeling.
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Affiliation(s)
- Erinn Zixuan Sim
- School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8501, Japan
| | - Nobuaki Shiraki
- School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8501, Japan
| | - Shoen Kume
- School of Life Science and Technology, Tokyo Institute of Technology, 4259-B-25 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa, 226-8501, Japan.
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50
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Rastogi A, Severance EG, Jacobs HM, Conlin SM, Islam ST, Timme-Laragy AR. Modulating glutathione thiol status alters pancreatic β-cell morphogenesis in the developing zebrafish (Danio rerio) embryo. Redox Biol 2021; 38:101788. [PMID: 33321464 PMCID: PMC7744774 DOI: 10.1016/j.redox.2020.101788] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/26/2020] [Accepted: 11/03/2020] [Indexed: 01/07/2023] Open
Abstract
Emerging evidence suggests that redox-active chemicals perturb pancreatic islet development. To better understand potential mechanisms for this, we used zebrafish (Danio rerio) embryos to investigate roles of glutathione (GSH; predominant cellular redox buffer) and the transcription factor Nrf2a (Nfe2l2a; zebrafish Nrf2 co-ortholog) in islet morphogenesis. We delineated critical windows of susceptibility to redox disruption of β-cell morphogenesis, interrogating embryos at 24, 48 and 72 h post fertilization (hpf) and visualized Nrf2a expression in the pancreas using whole-mount immunohistochemistry at 96 hpf. Chemical GSH modulation at 48 hpf induced significant islet morphology changes at 96 hpf. Pro-oxidant exposures to tert-butylhydroperoxide (77.6 μM; 10-min at 48 hpf) or tert-butylhydroquinone (1 μM; 48-56 hpf) decreased β-cell cluster area at 96 hpf. Conversely, exposures to antioxidant N-acetylcysteine (bolsters GSH pools; 100 μM; 48-72 hpf) or sulforaphane (activates Nrf2a; 20 μM; 48-72 hpf) significantly increased islet areas. Nrf2a was also stabilized in β-cells: 10-min exposures to 77.6 μM tert-butylhydroperoxide significantly increased Nrf2a protein compared to control islet cells that largely lack stabilized Nrf2a; 10-min exposures to higher (776 μM) tert-butylhydroperoxide concentration stabilized Nrf2a throughout the pancreas. Using biotinylated-GSH to visualize in situ protein glutathionylation, islet cells displayed high protein glutathionylation, indicating oxidized GSH pools. The 10-min high (776 μM) tert-butylhydroperoxide exposure (induced Nrf2a globally) decreased global protein glutathionylation at 96 hpf. Mutant fish expressing inactive Nrf2a were protected against tert-butylhydroperoxide-induced abnormal islet morphology. Our data indicate that disrupted redox homeostasis and Nrf2a stabilization during pancreatic β-cell development impact morphogenesis, with implications for disease states at later life stages. Our work identifies a potential molecular target (Nrf2) that mediates abnormal β-cell morphology in response to redox disruptions. Moreover, our findings imply that developmental exposure to exogenous stressors at distinct windows of susceptibility could diminish the reserve redox capacity of β-cells, rendering them vulnerable to later-life stresses and disease.
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Affiliation(s)
- Archit Rastogi
- Molecular & Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA, 01003, USA
| | - Emily G Severance
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, 01003, USA
| | - Haydee M Jacobs
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, 01003, USA
| | - Sarah M Conlin
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, 01003, USA
| | - Sadia T Islam
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, 01003, USA
| | - Alicia R Timme-Laragy
- Molecular & Cellular Biology Graduate Program, University of Massachusetts, Amherst, MA, 01003, USA; Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, 01003, USA.
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